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Sample records for cardioselective dominant-negative thyroid

  1. Cardioselective Dominant-negative Thyroid Hormone Receptor (Δ337T) Modulates Myocardial Metabolism and Contractile Dfficiency

    SciTech Connect

    Hyyti, Outi M.; Olson, Aaron; Ge, Ming; Ning, Xue-Han; Buroker, Norman E.; Chung, Youngran; Jue, Thomas; Portman, Michael A.

    2008-06-03

    Dominant- negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRβ1 mutation Δ337T. Isolated working Δ337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Δ337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV˙ O2). Unlabeled substrate Fc from endogenous sources was higher in Δ337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Δ337T. CE and Fc differences were reversed by pacing Δ337T to Con rates, accompanied by an increase in FFA Fc. Δ337T hearts lacked the ability to increase MV˙ O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Δ337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.

  2. A targeted dominant negative mutation of the thyroid hormone α1 receptor causes increased mortality, infertility, and dwarfism in mice

    PubMed Central

    Kaneshige, Masahiro; Suzuki, Hideyo; Kaneshige, Kumiko; Cheng, Jun; Wimbrow, Heather; Barlow, Carrolee; Willingham, Mark C.; Cheng, Sheue-yann

    2001-01-01

    Mutations in the thyroid hormone receptor β (TRβ) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TRα gene could lead to a similar disease. To address this question, we prepared mutant mice by targeting mutant thyroid hormone receptor kindred PV (PV) mutation to the TRα gene locus by means of homologous recombination (TRα1PV mice). The PV mutation was derived from a patient with severe resistance to thyroid hormone that has a frameshift of the C-terminal 14 aa of TRβ1. We knocked in the same PV mutation to the corresponding TRα gene locus to compare the phenotypes of TRα1PV/+ mice with those of TRβPV/+ mice. TRα1PV/+ mice were viable, indicating that the mutation of the TRα gene is not embryonic lethal. In drastic contrast to the TRβPV/+ mice, which do not exhibit a growth abnormality, TRα1PV/+ mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TRβPV/+ mice, which have a hyperactive thyroid, TRα1PV/+ mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TRα1PV/+ mice was unique from those of TRβPV/+ mice. The distinct phenotypes exhibited by TRα1PV/+ and TRβPV/+ mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TRα1PV/+ mice may be used as a tool to uncover human diseases associated with mutations in the TRα gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities. PMID:11734632

  3. Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only

    PubMed Central

    Fumel, Betty; Froment, Pascal; Holzenberger, Martin; Livera, Gabriel; Monget, Philippe; Fouchécourt, Sophie

    2015-01-01

    Background In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. Methods The TRαAMI knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter. Findings We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRαAMI specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRαAMI-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRαAMI-ARO males showed normal fertility. This phenotype is similar to TRαAMI-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRαAMI-ARO. Conclusions/Significance We concluded that the presence of a mutant TRαAMI allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis. PMID:25793522

  4. Dominant negative effect of mutated thyroid stimulating hormone receptor (P556L) causes hypothyroidism in C.RF-Tshr(hyt/wild) mice.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2012-01-01

    C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice.

  5. Dominant negative myostatin produces hypertrophy without hyperplasia in muscle.

    PubMed

    Zhu, X; Hadhazy, M; Wehling, M; Tidball, J G; McNally, E M

    2000-05-26

    Myostatin, a TGF-beta family member, is a negative regulator of muscle growth. Here, we generated transgenic mice that expressed myostatin mutated at its cleavage site under the control of a muscle specific promoter creating a dominant negative myostatin. These mice exhibited a significant (20-35%) increase in muscle mass that resulted from myofiber hypertrophy and not from myofiber hyperplasia. We also evaluated the role of myostatin in muscle degenerative states, such as muscular dystrophy, and found significant downregulation of myostatin. Thus, further inhibition of myostatin may permit increased muscle growth in muscle degenerative disorders.

  6. β1-Integrin Cytoplasmic Subdomains Involved in Dominant Negative Function

    PubMed Central

    Retta, S. Francesco; Balzac, Fiorella; Ferraris, Piercarlo; Belkin, Alexey M.; Fässler, Reinhard; Humphries, Martin J.; De Leo, Giacomo; Silengo, Lorenzo; Tarone, Guido

    1998-01-01

    The β1-integrin cytoplasmic domain consists of a membrane proximal subdomain common to the four known isoforms (“common” region) and a distal subdomain specific for each isoform (“variable” region). To investigate in detail the role of these subdomains in integrin-dependent cellular functions, we used β1A and β1B isoforms as well as four mutants lacking the entire cytoplasmic domain (β1TR), the variable region (β1COM), or the common region (β1ΔCOM-B and β1ΔCOM-A). By expressing these constructs in Chinese hamster ovary and β1 integrin-deficient GD25 cells (Wennerberg et al., J Cell Biol 132, 227–238, 1996), we show that β1B, β1COM, β1ΔCOM-B, and β1ΔCOM-A molecules are unable to support efficient cell adhesion to matrix proteins. On exposure to Mn++ ions, however, β1B, but none of the mutants, can mediate cell adhesion, indicating specific functional properties of this isoform. Analysis of adhesive functions of transfected cells shows that β1B interferes in a dominant negative manner with β1A and β3/β5 integrins in cell spreading, focal adhesion formation, focal adhesion kinase tyrosine phosphorylation, and fibronectin matrix assembly. None of the β1 mutants tested shows this property, indicating that the dominant negative effect depends on the specific combination of common and B subdomains, rather than from the absence of the A subdomain in the β1B isoform. PMID:9529373

  7. beta1-integrin cytoplasmic subdomains involved in dominant negative function.

    PubMed

    Retta, S F; Balzac, F; Ferraris, P; Belkin, A M; Fässler, R; Humphries, M J; De Leo, G; Silengo, L; Tarone, G

    1998-04-01

    The beta1-integrin cytoplasmic domain consists of a membrane proximal subdomain common to the four known isoforms ("common" region) and a distal subdomain specific for each isoform ("variable" region). To investigate in detail the role of these subdomains in integrin-dependent cellular functions, we used beta1A and beta1B isoforms as well as four mutants lacking the entire cytoplasmic domain (beta1TR), the variable region (beta1COM), or the common region (beta1 deltaCOM-B and beta1 deltaCOM-A). By expressing these constructs in Chinese hamster ovary and beta1 integrin-deficient GD25 cells (Wennerberg et al., J Cell Biol 132, 227-238, 1996), we show that beta1B, beta1COM, beta1 deltaCOM-B, and beta1 deltaCOM-A molecules are unable to support efficient cell adhesion to matrix proteins. On exposure to Mn++ ions, however, beta1B, but none of the mutants, can mediate cell adhesion, indicating specific functional properties of this isoform. Analysis of adhesive functions of transfected cells shows that beta1B interferes in a dominant negative manner with beta1A and beta3/beta5 integrins in cell spreading, focal adhesion formation, focal adhesion kinase tyrosine phosphorylation, and fibronectin matrix assembly. None of the beta1 mutants tested shows this property, indicating that the dominant negative effect depends on the specific combination of common and B subdomains, rather than from the absence of the A subdomain in the beta1B isoform.

  8. Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres

    PubMed Central

    Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

    2015-01-01

    Abstract Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca2+ from intracellular pools. We observed that both hyperosmotic shock-induced Ca2+ transients and RVI were inhibited by Gd3+, ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca2+ induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca2+ from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na+–K+–Cl− cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca2+ transients were abolished by the Ca2+ chelator BAPTA, the level of P-SPAKSer373 in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca2+. We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. Key points Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock

  9. Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres.

    PubMed

    Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

    2015-09-01

    Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca(2+) from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca(2+) response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca(2+) release from the sarcoplasmic reticulum, activation of the Na(+) -K(+) -Cl(-) cotransporter by SPAK, and the RVI response. Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca(2+) from intracellular pools. We observed that both hyperosmotic shock-induced Ca(2+) transients and RVI were inhibited by Gd(3+) , ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca(2+) induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2

  10. A Dominant-Negative fur Mutation in Bradyrhizobium japonicum

    PubMed Central

    Benson, Heather P.; LeVier, Kristin; Guerinot, Mary Lou

    2004-01-01

    In many bacteria, the ferric uptake regulator (Fur) protein plays a central role in the regulation of iron uptake genes. Because iron figures prominently in the agriculturally important symbiosis between soybean and its nitrogen-fixing endosymbiont Bradyrhizobium japonicum, we wanted to assess the role of Fur in the interaction. We identified a fur mutant by selecting for manganese resistance. Manganese interacts with the Fur protein and represses iron uptake genes. In the presence of high levels of manganese, bacteria with a wild-type copy of the fur gene repress iron uptake systems and starve for iron, whereas fur mutants fail to repress iron uptake systems and survive. The B. japonicum fur mutant, as expected, fails to repress iron-regulated outer membrane proteins in the presence of iron. Unexpectedly, a wild-type copy of the fur gene cannot complement the fur mutant. Expression of the fur mutant allele in wild-type cells leads to a fur phenotype. Unlike a B. japonicum fur-null mutant, the strain carrying the dominant-negative fur mutation is unable to form functional, nitrogen-fixing nodules on soybean, mung bean, or cowpea, suggesting a role for a Fur-regulated protein or proteins in the symbiosis. PMID:14973020

  11. The dominant negative mutant Artemis enhances tumor cell radiosensitivity.

    PubMed

    Liu, Hai; Sun, XiaoNan; Zhang, Shuo; Ge, WeiTing; Zhu, YongLiang; Zhang, JiaWei; Zheng, Shu

    2011-10-01

    Tumor radioresistance often leads to treatment failure during radiotherapy. New strategies like developing radiosensitizer are clinically important. Intervention with DNA double-strand break repair is an effective way to modulate tumor cell radiosensitivity. This study focused on the mutant Artemis fragment-enhanced radiosensitivity of human cervical cancer cells. We constructed two pEGFP-C1-based eukaryotic expression vectors encoding full-length and the mutant Artemis fragment (D37N-413aa), respectively. HeLa cells were stably transfected with these plasmids or vector. Cell survival was measured by the clonogenic assay. The γH2AX foci assay was used to monitor DNA repair after irradiation. Co-immunoprecipitation and Western blot analysis were performed to study protein interaction and phosphorylation of Artemis. Expression of the mutant Artemis fragment (D37N-413aa) delayed DNA DSB rejoining after irradiation, thereby enhanced radiosensitivity of HeLa cell. Further experiments indicate that this mutant Artemis fragment bind to DNA-PKcs and ATM, inhibited phosphorylation of endogenous Artemis, the key molecule for DNA repair and cell radiosensitivity. The dominant negative mutant Artemis fragment (D37N-413aa) enhanced tumor cell radiosensitivity through blocking activity of endogenous Artemis and DNA repair. It is the first time to modulate tumor cell radiosensitivity via targeting Artemis. This novel mechanism of radiosensitivity strongly suggests the potential role of Artemis in cancer therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. [Thyroiditis].

    PubMed

    Buffet, Camille; Groussin, Lionel

    2013-02-01

    The diagnosis of thyroiditis encompasses a broad spectrum of thyroid disorders. Analysis of signs and symptoms, biochemical changes, neck ultrasound characteristics and radioactive iodine uptake values allows an accurate diagnosis. Recent studies of the whole genome have helped to identify many susceptibility genes for autoimmune thyroiditis. However, none of these genes contribute to a significant increase in risk of developing this thyroiditis. Clinical awareness of the characteristic presentations of exceptional thyroiditis (acute suppurative thyroiditis, Riedel's thyroiditis) is an important issue. Selenium administration seems to be beneficial for reducing the incidence of thyroiditis. Finally, certain drug-induced thyroiditis remains a therapeutic challenge for the physician.

  13. Thyroiditis

    MedlinePlus

    ... Hashimoto’s thyroiditis is the most common cause of hypothyroidism in the United States. Postpartum thyroiditis, which causes ... hormone levels in the blood) followed by temporary hypothyroidism, is a common cause of thyroid problems after ...

  14. Thyroid

    MedlinePlus

    Thyroid is used to treat the symptoms of hypothyroidism (a condition where the thyroid gland does not produce enough thyroid hormone). Symptoms of hypothyroidism include lack of energy, depression, constipation, weight gain, ...

  15. Cardioselectivity, kinetics, hemodynamics, and metabolic effects of xamoterol.

    PubMed

    Jennings, G; Bobik, A; Oddie, C; Restall, R

    1984-05-01

    Xamoterol is a new orally active partial beta-adrenoceptor agonist. Its kinetics, hemodynamic and metabolic effects, and cardioselectivity were investigated in eight normal subjects. Plasma xamoterol concentrations after 100 micrograms/kg iv declined biexponentially over 8 hr and t 1/2 beta averaged 2.6 hr. Resting heart rate (HR) increased slightly in the supine position but was unchanged on sitting. Systolic blood pressure (SBP) rose by 5 to 10 mm Hg and cardiac index (CI) rose 15% to 20%. Both parameters were above control values 6 hr after dosing, when plasma xamoterol concentrations had fallen to about 10 ng/ml. There were no changes in diastolic or mean arterial pressure (MAP). During graded exercise the effects of xamoterol on HR and SBP were the reverse of those at rest, with lowering of exercise HR and SBP at higher work loads. CI during exercise was not altered by xamoterol. Doses of xamoterol were calculated from the kinetic data to give plasma concentrations of 100, 200, 400, and 800 ng/ml. HR and blood pressure effects at each xamoterol level were compared before and after inhibition of cardiovascular reflexes with prazosin, atropine, and clonidine. Hemodynamic effects of xamoterol and isoproterenol were compared. Before autonomic block xamoterol increased HR by 10 bpm and MAP by 7 mm Hg at the highest dose. After autonomic block there was a 200% to 300% rise in HR at each dose and MAP still rose. The rise in MAP after block could be entirely accounted for by a 23% increase in CI because total peripheral resistance did not change. The effects of isoproterenol after autonomic block were a rise in HR and a fall in MAP. Metabolic responses to xamoterol were measured at the four dose levels. There was a dose-related increase in nonesterified fatty acids and a fall in plasma lactate levels but no changes in plasma renin activity or blood glucose. Results suggest that xamoterol is a cardioselective partial beta-adrenoceptor agonist in man.

  16. Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101.

    PubMed

    Iguchi, S; Iwamura, H; Nishizaki, M; Hayashi, A; Senokuchi, K; Kobayashi, K; Sakaki, K; Hachiya, K; Ichioka, Y; Kawamura, M

    1992-06-01

    A novel, highly cardioselective ultra short-acting beta-blocker, ONO-1101, has been developed for application in the emergency treatment of tachycardia and better control of heart rate in surgery. This agent is approximately nine times more potent in beta-blocking activity in vivo and eight times more cardioselective in vitro than esmolol. This beta-blocking drug has a short duration of activity, enabling rapid recovery after cessation of administration if side effects occur. It can be used safely in patients suffering from acute heart disease and represents a major therapeutic advance in the treatment of heart disease.

  17. Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa.

    PubMed

    Mendes, Hugo F; Cheetham, Michael E

    2008-10-01

    Mutations in the dim light photoreceptor protein rod opsin cause autosomal dominant retinitis pigmentosa. The majority of these mutations (class II) lead to protein misfolding. For example, the common class II rod opsin mutation P23H misfolds and is retained in the ER, prior to retrotranslocation and degradation by the proteasome. If degradation fails then the protein can aggregate to form intracellular inclusions. Furthermore, mutant opsin exerts a dominant negative effect on the wild-type (WT) protein. Here we show that the toxic gain of function and dominant negative properties of misfolded rod opsin in cells can be alleviated by drug treatments targeted against a range of cellular pathways. P23H rod opsin aggregation, inclusion formation with associated caspase activation and cell death were reduced by kosmotropes, molecular chaperone inducers and mToR inhibition. But these treatments did not enhance mutant opsin folding or reduce the dominant negative effect of P23H rod opsin. In contrast, retinoids acted as pharmacological chaperones to enhance P23H folding and reduce the dominant negative effect on WT rod opsin processing, as well as reducing toxic gains of function. Therefore, the suppression of the dominant negative effects of protein misfolding required enhanced folding of the mutant protein, whereas suppression of toxic gain of function effects did not require improved folding per se. These studies suggest that some forms of rhodopsin RP may be treated by targeting protein folding and reducing protein aggregation.

  18. Structure of the G60A mutant of Ras: Implications for the Dominant Negative Effect.

    SciTech Connect

    Ford,B.; Skowronek, K.; Boykevisch, S.; Bar-Sagi, D.; Nassar, N.

    2005-01-01

    Substituting alanine for glycine at position 60 in v-H-Ras generated a dominant negative mutant that completely abolished the ability of v-H-Ras to transform NIH 3T3 cells and to induce germinal vesicle breakdown in Xenopus oocytes. The crystal structure of the GppNp-bound form of RasG60A unexpectedly shows that the switch regions adopt an open conformation reminiscent of the structure of the nucleotide-free form of Ras in complex with Sos. Critical residues that normally stabilize the guanine nucleotide and the Mg{sup 2+} ion have moved considerably. Sos binds to RasG60A but is unable to catalyze nucleotide exchange. Our data suggest that the dominant negative effect observed for RasG60A{center_dot}GTP could result from the sequestering of Sos in a non-productive Ras-GTP-guanine nucleotide exchange factor ternary complex.

  19. A Novel Method to Screen for Dominant Negative ATM Mutations in Familial Breast Cancer

    DTIC Science & Technology

    2005-04-01

    carry dominant negative mutation in ATM due to natural variation amongst LCLs. Microarrays have been performed to determine differences in gene expression... genes that are altered in their expression in ATMmutation carriers. The validation of this data in carriers of different ATM mutation indicated that the...heterozygous carriers of T727 1 G mutation display a gene expression phenotype that appears identical to carriers of protein truncating mutations in

  20. Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia*

    PubMed Central

    Arribas-González, Esther; de Juan-Sanz, Jaime; Aragón, Carmen; López-Corcuera, Beatriz

    2015-01-01

    Hyperekplexia or startle disease is a rare clinical syndrome characterized by an exaggerated startle in response to trivial tactile or acoustic stimuli. This neurological disorder can have serious consequences in neonates, provoking brain damage and/or sudden death due to apnea episodes and cardiorespiratory failure. Hyperekplexia is caused by defective inhibitory glycinergic neurotransmission. Mutations in the human SLC6A5 gene encoding the neuronal GlyT2 glycine transporter are responsible for the presynaptic form of the disease. GlyT2 mediates synaptic glycine recycling, which constitutes the main source of releasable transmitter at glycinergic synapses. Although the majority of GlyT2 mutations detected so far are recessive, a dominant negative mutant that affects GlyT2 trafficking does exist. In this study, we explore the properties and structural alterations of the S512R mutation in GlyT2. We analyze its dominant negative effect that retains wild-type GlyT2 in the endoplasmic reticulum (ER), preventing surface expression. We show that the presence of an arginine rather than serine 512 provoked transporter misfolding, enhanced association to the ER-chaperone calnexin, altered association with the coat-protein complex II component Sec24D, and thereby impeded ER exit. The S512R mutant formed oligomers with wild-type GlyT2 causing its retention in the ER. Overexpression of calnexin rescued wild-type GlyT2 from the dominant negative effect of the mutant, increasing the amount of transporter that reached the plasma membrane and dampening the interaction between the wild-type and mutant GlyT2. The ability of chemical chaperones to overcome the dominant negative effect of the disease mutation on the wild-type transporter was demonstrated in heterologous cells and primary neurons. PMID:25480793

  1. Molecular basis of the dominant negative effect of a glycine transporter 2 mutation associated with hyperekplexia.

    PubMed

    Arribas-González, Esther; de Juan-Sanz, Jaime; Aragón, Carmen; López-Corcuera, Beatriz

    2015-01-23

    Hyperekplexia or startle disease is a rare clinical syndrome characterized by an exaggerated startle in response to trivial tactile or acoustic stimuli. This neurological disorder can have serious consequences in neonates, provoking brain damage and/or sudden death due to apnea episodes and cardiorespiratory failure. Hyperekplexia is caused by defective inhibitory glycinergic neurotransmission. Mutations in the human SLC6A5 gene encoding the neuronal GlyT2 glycine transporter are responsible for the presynaptic form of the disease. GlyT2 mediates synaptic glycine recycling, which constitutes the main source of releasable transmitter at glycinergic synapses. Although the majority of GlyT2 mutations detected so far are recessive, a dominant negative mutant that affects GlyT2 trafficking does exist. In this study, we explore the properties and structural alterations of the S512R mutation in GlyT2. We analyze its dominant negative effect that retains wild-type GlyT2 in the endoplasmic reticulum (ER), preventing surface expression. We show that the presence of an arginine rather than serine 512 provoked transporter misfolding, enhanced association to the ER-chaperone calnexin, altered association with the coat-protein complex II component Sec24D, and thereby impeded ER exit. The S512R mutant formed oligomers with wild-type GlyT2 causing its retention in the ER. Overexpression of calnexin rescued wild-type GlyT2 from the dominant negative effect of the mutant, increasing the amount of transporter that reached the plasma membrane and dampening the interaction between the wild-type and mutant GlyT2. The ability of chemical chaperones to overcome the dominant negative effect of the disease mutation on the wild-type transporter was demonstrated in heterologous cells and primary neurons.

  2. Dominant Negative Pleiotrophin Induces Tetraploidy and Aneuploidy in U87MG Human Glioblastoma Cells

    PubMed Central

    Chang, Yunchao; Berenson, James R.; Wang, Zhaoyi; Deuel, Thomas F.

    2007-01-01

    Summary Pleiotrophin (PTN, Ptn) is an 18 kD secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant negative PTN (U87MG/PTN 1–40 cells); here, we report that the dominant negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells. PMID:17067552

  3. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles.

    PubMed

    Beaumont, Kimberley A; Shekar, Sri N; Shekar, Sri L; Newton, Richard A; James, Michael R; Stow, Jennifer L; Duffy, David L; Sturm, Richard A

    2007-09-15

    The human melanocortin-1 receptor (MC1R) is a G-protein coupled receptor involved in the regulation of pigmentation. Several MC1R variant alleles are associated with red hair, fair skin and increased skin cancer risk. We have performed a systematic functional analysis of nine common MC1R variants and correlated these results with the strength of the genetic association of each variant allele with pigmentation phenotypes. In vitro expression studies revealed that variant receptors with reduced cell surface expression, including V60L, D84E, R151C, I155T, R160W and R163Q, showed a corresponding impairment in cAMP coupling. The R142H and D294H variants demonstrated normal cell surface expression, but had reduced functional responses, indicating that altered G-protein coupling may be responsible for this loss of function. The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R. In co-expression studies, the D84E, R151C, I155T and R160W variants showed a dominant negative effect on wild-type receptor cell surface expression, which was reflected in a decreased ability to elevate intracellular cAMP levels. The D294H variant also demonstrated a dominant negative effect on wild-type MC1R cAMP signalling, but had no effect on wild-type surface expression. Importantly, comparison of the in vitro receptor characteristics with skin and hair colour data of individuals both homozygous and heterozygous for MC1R variant alleles revealed parallels between variant MC1R cell surface expression, functional ability, dominant negative activity and their effects on human pigmentation. These findings show the first direct correlations between variant MC1R biochemical properties and pigmentation phenotype.

  4. Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants

    NASA Astrophysics Data System (ADS)

    Steed, Paul M.; Tansey, Malú G.; Zalevsky, Jonathan; Zhukovsky, Eugene A.; Desjarlais, John R.; Szymkowski, David E.; Abbott, Christina; Carmichael, David; Chan, Cheryl; Cherry, Lisa; Cheung, Peter; Chirino, Arthur J.; Chung, Hyo H.; Doberstein, Stephen K.; Eivazi, Araz; Filikov, Anton V.; Gao, Sarah X.; Hubert, René S.; Hwang, Marian; Hyun, Linus; Kashi, Sandhya; Kim, Alice; Kim, Esther; Kung, James; Martinez, Sabrina P.; Muchhal, Umesh S.; Nguyen, Duc-Hanh T.; O'Brien, Christopher; O'Keefe, Donald; Singer, Karen; Vafa, Omid; Vielmetter, Jost; Yoder, Sean C.; Dahiyat, Bassil I.

    2003-09-01

    Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.

  5. Dominant-Negative Proteins in Herpesviruses – From Assigning Gene Function to Intracellular Immunization

    PubMed Central

    Mühlbach, Hermine; Mohr, Christian A.; Ruzsics, Zsolt; Koszinowski, Ulrich H.

    2009-01-01

    Investigating and assigning gene functions of herpesviruses is a process, which profits from consistent technical innovation. Cloning of bacterial artificial chromosomes encoding herpesvirus genomes permits nearly unlimited possibilities in the construction of genetically modified viruses. Targeted or randomized screening approaches allow rapid identification of essential viral proteins. Nevertheless, mapping of essential genes reveals only limited insight into function. The usage of dominant-negative (DN) proteins has been the tool of choice to dissect functions of proteins during the viral life cycle. DN proteins also facilitate the analysis of host-virus interactions. Finally, DNs serve as starting-point for design of new antiviral strategies. PMID:21994555

  6. A Dominant Negative Zebrafish Ahr2 Partially Protects Developing Zebrafish from Dioxin Toxicity

    PubMed Central

    Lanham, Kevin A.; Prasch, Amy L.; Weina, Kasia M.; Peterson, Richard E.; Heideman, Warren

    2011-01-01

    The toxicity by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is thought to be caused by activation of the aryl hydrocarbon receptor (AHR). However, our understanding of how AHR activation by TCDD leads to toxic effects is poor. Ideally we would like to manipulate AHR activity in specific tissues and at specific times. One route to this is expressing dominant negative AHRs (dnAHRs). This work describes the construction and characterization of dominant negative forms of the zebrafish Ahr2 in which the C-terminal transactivation domain was either removed, or replaced with the inhibitory domain from the Drosophila engrailed repressor protein. One of these dnAhr2s was selected for expression from the ubiquitously active e2fα promoter in transgenic zebrafish. We found that these transgenic zebrafish expressing dnAhr2 had reduced TCDD induction of the Ahr2 target gene cyp1a, as measured by 7-ethoxyresorufin-O-deethylase activity. Furthermore, the cardiotoxicity produced by TCDD, pericardial edema, heart malformation, and reduced blood flow, were all mitigated in the zebrafish expressing the dnAhr2. These results provide in vivo proof-of-principle results demonstrating the effectiveness of dnAHRs in manipulating AHR activity in vivo, and demonstrating that this approach can be a means for blocking TCDD toxicity. PMID:22194803

  7. CRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation.

    PubMed

    Wang, Huajing; Sun, William

    2017-01-28

    With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

    PubMed Central

    Parrett, Christopher J.; Lenoci, Robert V.; Nguyen, Brenda; Russell, Lauren; Jewett, Travis J.

    2016-01-01

    Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors. PMID:27602332

  9. A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization.

    PubMed Central

    Kashles, O; Yarden, Y; Fischer, R; Ullrich, A; Schlessinger, J

    1991-01-01

    Recent studies provide evidence that defective receptors can function as a dominant negative mutation suppressing the action of wild-type receptors. This causes various diminished responses in cell culture and developmental disorders in murine embryogenesis. Here, we describe a model system and a potential mechanism underlying the dominant suppressing response caused by defective epidermal growth factor (EGF) receptors. We used cultured 3T3 cells coexpressing human wild-type receptors and an inactive deletion mutant lacking most of the cytoplasmic domain. When expressed alone, EGF was able to stimulate the dimerization of either wild-type or mutant receptors in living cells as revealed by chemical covalent cross-linking experiments. In response to EGF, heterodimers and homodimers of wild-type and mutant receptors were observed in cells coexpressing both receptor species. However, only homodimers of wild-type EGF receptors underwent EGF-induced tyrosine autophosphorylation in living cells. These results indicate that the integrity of both receptor moieties within receptor dimers is essential for kinase activation and autophosphorylation. Moreover, the presence of mutant receptors in cells expressing wild-type receptors diminished the number of high-affinity binding sites for EGF, reduced the rate of receptor endocytosis and degradation, and diminished biological signalling via EGF receptors. We propose that heterodimerization with defective EGF receptors functions as a dominant negative mutation suppressing the activation and response of normal receptors by formation of unproductive heterodimers. Images PMID:1705006

  10. Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors.

    PubMed

    Parrett, Christopher J; Lenoci, Robert V; Nguyen, Brenda; Russell, Lauren; Jewett, Travis J

    2016-01-01

    Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors.

  11. Cloning and characterization of a dominant-negative vps1 allele of the yeast Saccharomyces cerevisiae.

    PubMed

    Finken-Eigen, M; Müller, S; Köhrer, K

    1997-10-01

    The gene product of the yeast VPS1 gene is a member of a family of high-molecular-weight GTP-binding proteins that are involved in diverse cellular processes. The Vps1 protein (Vps1p) was shown to perform an essential function in the yeast secretory pathway. Here, we report the isolation and characterization of a mutant allele of the VPS1 gene, causing a dominant-negative vacuolar protein sorting (vps) defect, as demonstrated by the mislocalization of the vacuolar hydrolase carboxypeptidase Y (CPY). DNA sequence analysis of the mutant vps1 allele (vps1d-293) revealed a single point mutation, resulting in an amino acid exchange at position 293 from Ala to Asp. The mutation is located downstream of the tripartite GTP-binding motif found in the amino-terminal half of the protein. The observation that expression of wild-type Vps1p partially suppressed the dominant-negative CPY sorting phenotype indicates competition of a non-functional mutant Vps1 protein and a functional wild-type VPS1p for a Vps1p-binding site of an as yet unknown vacuolar protein sorting factor.

  12. Beta-adrenoceptor blocking properties and cardioselectivity of M & B 17,803A.

    PubMed

    Basil, B; Jordan, R; Loveless, A H; Maxwell, D R

    1973-06-01

    1. The beta-adrenoceptor blocking properties of (+/-)-1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane hydrochloride (M&B 17,803A) have been compared with those of practolol and propranolol in the guinea-pig, cat and dog.2. Following either intravenous or oral administration in the cat or dog, M&B 17,803A and practolol had similar potency in antagonizing isoprenaline-induced tachycardia and both showed cardioselectivity, but both were less potent than propranolol.3. M&B 17,803A and practolol had approximately one hundredth the intravenous potency of propranolol in increasing the severity of anaphylactic bronchospasm in the conscious sensitized guinea-pig.4. M&B 17,803A possessed less marked intrinsic sympathomimetic activity than practolol but, like propranolol, it had significant local anaesthetic properties and increased the refractory period of rabbit isolated atria.

  13. Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade.

    PubMed

    McDevitt, D G; Brown, H C; Carruthers, S G; Shanks, R G

    1977-05-01

    Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the

  14. Dental Enamel Structure Is Altered by Expression of Dominant Negative RhoA in Ameloblasts

    PubMed Central

    Li, Yong; Pugach, Megan K.; Kuehl, Melissa A.; Peng, Li; Bouchard, Jessica; Hwang, Soon Y.; Gibson, Carolyn W.

    2011-01-01

    Using in vitrotooth germ cultures and analysis by confocal microscopy, ameloblasts treated with sodium fluoride were found to have elevated amounts of filamentous actin. Because this response is reduced by inhibitors of the Rho/ROCK signaling pathway, we generated mice that express dominant negative RhoA (RhoADN) in ameloblasts for in vivo analysis. Expression of the EGFP-RhoADN fusion protein was evaluated by RT-PCR and immunohistochemistry, and teeth were analyzed by scanning electron microscopy. The 3 strains expressed at either low (TgEGFP-RhoADN-8), intermediate (TgEGFP-RhoADN-2), or high (TgEGFP-RhoADN-13) levels, and the molar teeth from the 3 strains had enamel hypoplasia and surface defects. We conclude that RhoADN expressed in ameloblasts interferes with normal enamel development through the pathway that is induced by sodium fluoride. PMID:21576911

  15. Dental enamel structure is altered by expression of dominant negative RhoA in ameloblasts.

    PubMed

    Li, Yong; Pugach, Megan K; Kuehl, Melissa A; Peng, Li; Bouchard, Jessica; Hwang, Soon Y; Gibson, Carolyn W

    2011-01-01

    Using in vitrotooth germ cultures and analysis by confocal microscopy, ameloblasts treated with sodium fluoride were found to have elevated amounts of filamentous actin. Because this response is reduced by inhibitors of the Rho/ROCK signaling pathway, we generated mice that express dominant negative RhoA (RhoA(DN)) in ameloblasts for in vivo analysis. Expression of the EGFP-RhoA(DN) fusion protein was evaluated by RT-PCR and immunohistochemistry, and teeth were analyzed by scanning electron microscopy. The 3 strains expressed at either low (TgEGFP-RhoA(DN)-8), intermediate (TgEGFP-RhoA(DN)-2), or high (TgEGFP-RhoA(DN)-13) levels, and the molar teeth from the 3 strains had enamel hypoplasia and surface defects. We conclude that RhoA(DN) expressed in ameloblasts interferes with normal enamel development through the pathway that is induced by sodium fluoride. Copyright © 2011 S. Karger AG, Basel.

  16. Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction.

    PubMed

    Kaptein, A; Paillard, V; Saunders, M

    1996-03-15

    Interleukin-6 (IL-6) induces tyrosine phosphorylation and activation of the latent transcription factor Stat3 in HepG2 cells. Mutation of Stat3 tyrosine 705 to phenylalanine (Y705F) inhibits IL-6-induced tyrosine phosphorylation of this Stat3 mutant in transfected HepG2 cells. In cotransfections of HepG2 cells, the Stat3 mutant Y705F causes a reduction of the tyrosine phosphorylation of wild type Stat3-FLAG. Moreover, Y705F inhibits the action of endogenous Stat3 in cotransfected cells, reducing IL-6 induction of a Stat3-responsive reporter construct. Y705F therefore acts as a dominant negative mutation of Stat3.

  17. Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.

    PubMed

    Romanelli Tavares, Vanessa L; Gordon, Christopher T; Zechi-Ceide, Roseli M; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Y; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J; Papsin, Blake C; Torres, Tatiana T; Buermans, Henk; Capelo, Luciane Portas; den Dunnen, Johan T; Guion-Almeida, Maria L; Lyonnet, Stanislas; Amiel, Jeanne; Passos-Bueno, Maria Rita

    2015-04-01

    Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.

  18. Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

    PubMed Central

    Romanelli Tavares, Vanessa L; Gordon, Christopher T; Zechi-Ceide, Roseli M; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Y; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J; Papsin, Blake C; Torres, Tatiana T; Buermans, Henk; Capelo, Luciane Portas; den Dunnen, Johan T; Guion-Almeida, Maria L; Lyonnet, Stanislas; Amiel, Jeanne; Passos-Bueno, Maria Rita

    2015-01-01

    Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1–EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects. PMID:25026904

  19. Use of Dominant-Negative/Substrate Trapping PTP Mutations to Search for PTP Interactors/Substrates.

    PubMed

    Radha, Vegesna

    2016-01-01

    Phosphorylation of proteins on tyrosine residues is the consequence of coordinated action of tyrosine kinases (TKs), and protein tyrosine phosphatases (PTPs). Together, they regulate intermolecular interactions, subcellular localization, and activity of a variety of proteins. The level of total protein-associated tyrosine phosphorylation in eukaryotic cells is only a small fraction of the total phosphorylation. PTPs, which have high specific activity compared to tyrosine kinases, play an important role in maintaining the tyrosine phosphorylation state of proteins and regulate signal transduction pathways and cellular responses. PTPs depend on specific invariant residues that enable binding to substrates phosphorylated at tyrosine and aid catalytic activity. Identification of PTP substrates has helped understand their role in distinct intracellular signaling pathways. Because of their high specific activity, the interaction between tyrosine phosphatases and their substrates is often very transient in the cellular context, and therefore identification of physiological substrates has been difficult. Single-site mutations in the enzymes stabilize interaction between the enzyme and its targets and have been used extensively to identify substrates. The mutations are either of the catalytic cysteine (Cys) residue or other invariant residues and have been classified as substrate-trapping mutants (STMs). These mutants often serve as dominant negatives that can inactivate effector functions of a specific PTP within cells. Considering their association with human disorders, inhibiting specific PTPs is important therapeutically. Since the catalytic domains are largely conserved, developing small-molecule inhibitors to a particular enzyme has proven difficult and therefore alternate strategies to block functions of individual enzymes are seriously being investigated. We provide a description of methods that will be useful to design strategies of using dominant-negative and

  20. Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.

    PubMed

    Willén, Katarina; Edgar, James R; Hasegawa, Takafumi; Tanaka, Nobuyuki; Futter, Clare E; Gouras, Gunnar K

    2017-08-23

    Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation. Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous Aβ also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of Aβ, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy. We demonstrate that Aβ leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of Aβ aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of Aβ as well as tau phosphorylation, mimicking the cellular changes in AD.

  1. Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.

    PubMed

    Gomez-Sintes, Raquel; Bortolozzi, Analia; Artigas, Francesc; Lucas, José J

    2014-09-01

    Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer׳s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  2. The dominant negative thyroid hormone receptor beta-mutant delta337T alters PPAR-alpha signaling in heart

    USDA-ARS?s Scientific Manuscript database

    PPARalpha and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs i...

  3. Dominant-negative effect on adhesion by myelin Po protein truncated in its cytoplasmic domain

    PubMed Central

    1996-01-01

    The myelin Po protein is believed to hold myelin together via interactions of both its extracellular and cytoplasmic domains. We have already shown that the extracellular domains of Po can interact in a homophilic manner (Filbin, M.T., F.S. Walsh, B.D. Trapp, J.A. Pizzey, and G.I. Tennekoon. 1990. Nature (Lond.). 344:871-872). In addition, we have shown that for this homophilic adhesion to take place, the cytoplasmic domain of Po must be intact and most likely interacting with the cytoskeleton; Po proteins truncated in their cytoplasmic domains are not adhesive (Wong, M.H., and M.T. Filbin, 1994. J. Cell Biol. 126:1089-1097). To determine if the presence of these truncated forms of Po could have an effect on the functioning of the full-length Po, we coexpressed both molecules in CHO cells. The adhesiveness of CHO cells expressing both full-length Po and truncated Po was then compared to cells expressing only full-length Po. In these coexpressors, both the full-length and the truncated Po proteins were glycosylated. They reached the surface of the cell in approximately equal amounts as shown by an ELISA and surface labeling, followed by immunoprecipitation. Furthermore, the amount of full-length Po at the cell surface was equivalent to other cell lines expressing only full-length Po that we had already shown to be adhesive. Therefore, there should be sufficient levels of full-length Po at the surface of these coexpressors to measure adhesion of Po. However, as assessed by an aggregation assay, the coexpressors were not adhesive. By 60 min they had not formed large aggregates and were indistinguishable from the control transfected cells not expressing Po. In contrast, in the same time, the cells expressing only the full-length Po had formed large aggregates. This indicates that the truncated forms of Po have a dominant-negative effect on the adhesiveness of the full-length Po. Furthermore, from cross-linking studies, full-length Po, when expressed alone but not when

  4. Cooperative binding of dominant-negative prion protein to kringle domains.

    PubMed

    Ryou, Chongsuk; Prusiner, Stanley B; Legname, Giuseppe

    2003-05-30

    Conversion of the cellular prion protein (PrP(C)) to the pathogenic isoform (PrP(Sc)) is a major biochemical alteration in the progression of prion disease. This conversion process is thought to require interaction between PrP(C) and an as yet unidentified auxiliary factor, provisionally designated protein X. In searching for protein X, we screened a phage display cDNA expression library constructed from prion-infected neuroblastoma (ScN2a) cells and identified a kringle protein domain using full-length recombinant mouse PrP (recMoPrP(23-231), hereafter recMoPrP) expressing a dominant-negative mutation at codon 218 (recMoPrP(Q218K)). In vitro binding analysis using ELISA verified specific interaction of recMoPrP to kringle domains (K(1+2+3)) with higher binding by recMoPrP(Q218K) than by full-length recMoPrP without the mutation. This interaction was confirmed by competitive binding analysis, in which the addition of either a specific anti-kringle antibody or L-lysine abolished the interaction. Biochemical studies of the interactions between K(1+2+3) and various concentrations of both recMoPrP molecules demonstrated binding in a dose-dependent manner. A Hill plot analysis of the data indicates positive cooperative binding of both recMoPrP(Q218K) and recMoPrP to K(1+2+3) with stronger binding by recMoPrP(Q218K). Using full-length and an N-terminally truncated MoPrP(89-231), we demonstrate that N-terminal sequences enable PrP to bind strongly to K(1+2+3). Further characterization with truncated MoPrP(89-231) refolded in different conformations revealed that both alpha-helical and beta-sheet conformations bind to K(1+2+3). Our data demonstrate specific, high-affinity binding of a dominant-negative PrP as well as binding of other PrPs to K(1+2+3). The relevance of such interactions during prion pathogenesis remains to be established.

  5. Alternative Splice Variants Modulates Dominant-Negative Function of Helios in T-Cell Leukemia

    PubMed Central

    Zhao, Shaorong; Liu, Wei; Li, Yinghui; Liu, Pengjiang; Li, Shufang; Dou, Daolei; Wang, Yue; Yang, Rongcun; Xiang, Rong; Liu, Feifei

    2016-01-01

    The molecular defects which lead to multistep incidences of human T-cell leukemia have yet to be identified. The DNA-binding protein Helios (known as IKZF2), a member of the Ikaros family of Krüppel-like zinc-finger proteins, functions pivotally in T-cell differentiation and activation. In this study, we identify three novel short Helios splice variants which are T-cell leukemic specific, and demonstrate their dominant-negative function. We then test the cellular localization of distinct Helios isoforms, as well as their capability to form heterodimer with Ikaros, and the association with complexes comprising histone deacetylase (HDAC). In addition, the ectopic expression of T-cell leukemic Helios isoforms interferes with T-cell proliferation and apoptosis. The gene expression profiling and pathway analysis indicated the enrichment of signaling pathways essential for gene expression, translation, cell cycle checkpoint, and response to DNA damage stimulus. These data indicate the molecular function of Helios to be involved in the leukemogenesis and phenotype of T-cell leukemia, and also reveal Helios deregulation as a novel marker for T-cell leukemia. PMID:27681508

  6. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.

    PubMed

    Lorenzato, Annalisa; Olivero, Martina; Perro, Mario; Brière, Jean Jacques; Rustin, Pierre; Di Renzo, Maria Flavia

    2008-02-15

    The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation.

  7. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

    PubMed Central

    Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J.; van Rossum-Fikkert, Sari E.; Ristic, Dejan; Williams, Gareth J.; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A.; Oostra, Anneke B.; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B.; Maarten Altelaar, A. F.; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P.; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C.

    2015-01-01

    Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, ‘FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

  8. Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice.

    PubMed

    Aida, Yasuko; Shibata, Yoko; Abe, Shuichi; Inoue, Sumito; Kimura, Tomomi; Igarashi, Akira; Yamauchi, Keiko; Nunomiya, Keiko; Kishi, Hiroyuki; Nemoto, Takako; Sato, Masamichi; Sato-Nishiwaki, Michiko; Nakano, Hiroshi; Sato, Kento; Kubota, Isao

    2014-01-01

    Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

  9. Identification of new dominant-negative mutants of anthrax protective antigen using directed evolution.

    PubMed

    Wu, Gaobing; Feng, Chunfang; Cao, Sha; Guo, Aizhen; Liu, Ziduo

    2012-11-01

    The anthrax toxin is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema toxin (EF). The PA moiety carries EF and LF into the cytosol of mammalian cells via a mechanism that depends on the oligomerization of PA and transmembrane pore formation by the PA oligomer. Certain mutants of PA, termed dominant-negative (DN) mutants, can co-oligomerize with wild-type PA and disrupt the translocation ability of the pore. Here, we constructed a PA mutant library by introducing random mutations into domain II of PA and screened three new DN mutants of PA: V377E, T380S, and I432C. All the mutants inhibited the anthrax toxin action against sensitive cells. V377E had the strongest inhibitory effect and was further confirmed to be able to protect mice against a challenge with anthrax lethal toxin. Furthermore, we functionally characterized these mutants. The result showed that these mutations did not impair proteolytic activation or oligomer formation of PA, but impeded the prepore-pore conversion of the oligomer. These DN mutants of PA identified in our study may provide valuable information for elucidating the structure-function relationship of PA and for designing therapeutics for anthrax treatment.

  10. Random Screening for Dominant-Negative Mutants of the Cytomegalovirus Nuclear Egress Protein M50▿

    PubMed Central

    Rupp, Brigitte; Ruzsics, Zsolt; Buser, Christopher; Adler, Barbara; Walther, Paul; Koszinowski, Ulrich H.

    2007-01-01

    Inactivation of gene products by dominant-negative (DN) mutants is a powerful tool to assign functions to proteins. Here, we present a two-step procedure to establish a random screen for DN alleles, using the essential murine cytomegalovirus gene M50 as an example. First, loss-of-function mutants from a linker-scanning library were tested for inhibition of virus reconstitution with the help of FLP-mediated ectopic insertion of the mutants into the viral genome. Second, DN candidates were confirmed by conditional expression of the inhibitory proteins in the virus context. This allowed the quantification of the inhibitory effect, the identification of the morphogenesis block, and the construction of DN mutants with improved activity. Based on these observations a DN mutant of the homologous gene (UL50) in human cytomegalovirus was predicted and constructed. Our data suggest that a proline-rich sequence motif in the variable region of M50/UL50 represents a new functional site which is essential for nuclear egress of cytomegalovirus capsids. PMID:17376929

  11. Random screening for dominant-negative mutants of the cytomegalovirus nuclear egress protein M50.

    PubMed

    Rupp, Brigitte; Ruzsics, Zsolt; Buser, Christopher; Adler, Barbara; Walther, Paul; Koszinowski, Ulrich H

    2007-06-01

    Inactivation of gene products by dominant-negative (DN) mutants is a powerful tool to assign functions to proteins. Here, we present a two-step procedure to establish a random screen for DN alleles, using the essential murine cytomegalovirus gene M50 as an example. First, loss-of-function mutants from a linker-scanning library were tested for inhibition of virus reconstitution with the help of FLP-mediated ectopic insertion of the mutants into the viral genome. Second, DN candidates were confirmed by conditional expression of the inhibitory proteins in the virus context. This allowed the quantification of the inhibitory effect, the identification of the morphogenesis block, and the construction of DN mutants with improved activity. Based on these observations a DN mutant of the homologous gene (UL50) in human cytomegalovirus was predicted and constructed. Our data suggest that a proline-rich sequence motif in the variable region of M50/UL50 represents a new functional site which is essential for nuclear egress of cytomegalovirus capsids.

  12. Sonic Hedgehog Mutations Identified in Holoprosencephaly Patients Can Act in a Dominant Negative Manner

    PubMed Central

    Singh, Samer; Tokhunts, Robert; Baubet, Valerie; Goetz, John A.; Huang, Zhen Jane; Schilling, Neal S.; Black, Kendall E.; MacKenzie, Todd A.; Dahmane, Nadia; Robbins, David J.

    2009-01-01

    Sonic Hedgehog (SHH) plays an important instructional role in vertebrate development, as exemplified by the numerous developmental disorders that occur when the SHH pathway is disrupted. Mutations in the SHH gene are the most common cause of sporadic and inherited Holoprosencephaly (HPE), a developmental disorder that is characterized by defective prosencephalon development. SHH HPE mutations provide a unique opportunity to better understand SHH biogenesis and signaling, and to decipher its role in the development of HPE. Here, we analyzed a panel of SHH HPE missense mutations that encode changes in the amino-terminal active domain of SHH. Our results show that SHH HPE mutations affect SHH biogenesis and signaling at multiple steps, which broadly results in low levels of protein expression, defective processing of SHH into its active form and protein with reduced activity. Additionally, we found that some inactive SHH proteins were able to modulate the activity of wt SHH in a dominant negative manner, both in vitro and in vivo. These findings show for the first time the susceptibility of SHH driven developmental processes to perturbations by low-activity forms of SHH. In conclusion, we demonstrate that SHH mutations found in HPE patients affect distinct steps of SHH biogenesis to attenuate SHH activity to different levels, and suggest that these variable levels of SHH activity might contribute to some of the phenotypic variation found in HPE patients. PMID:19057928

  13. Inhibition of growth of cervical cancer cells using a dominant negative estrogen receptor gene

    PubMed Central

    Au, William W.; Abdou-Salama, Salama; Al-Hendy, Ayman

    2007-01-01

    Objective Estrogen stimulates human papilloma virus oncogene expression, promotes cervical cancer (CC) cell proliferation and prevents apoptosis. Therefore, blockage of estrogen function may have therapeutic application to CC. Methods CasKi CC cells were transfected with an adenovirus expressing a dominant negative estrogen receptor gene (Ad-ER-DN) and their responses were investigated by RT-PCR, Flow Cytometry and Western blot assays. Result Transfected cells showed disturbance of cell colony morphology, reduced HPV E6 and E7 mRNA, interruption of cell proliferation, reduced cyclin D1 protein and expression of apoptosis. Conclusion We report, for the first time, the use of Ad-ER-DN to block estrogen receptors which led to dramatic changes in CC cells that are consistent with the possible reactivation of cellular p53 and Rb function. Their reactivation most likely allowed the recognition of existing chromosome abnormalities as a serious stress signal and the initiation of a cascade of cellular events in response to the stress, including the activation of the core apoptotic machinery which led to self-destruction of the CC cells. PMID:17137618

  14. A dominant negative mutation in the conserved RNA helicase motif 'SAT' causes splicing factor PRP2 to stall in spliceosomes.

    PubMed Central

    Plumpton, M; McGarvey, M; Beggs, J D

    1994-01-01

    To characterize sequences in the RNA helicase-like PRP2 protein of Saccharomyces cerevisiae that are essential for its function in pre-mRNA splicing, a pool of random PRP2 mutants was generated. A dominant negative allele was isolated which, when overexpressed in a wild-type yeast strain, inhibited cell growth by causing a defect in pre-mRNA splicing. This defect was partially alleviated by simultaneous co-overexpression of wild-type PRP2. The dominant negative PRP2 protein inhibited splicing in vitro and caused the accumulation of stalled splicing complexes. Immunoprecipitation with anti-PRP2 antibodies confirmed that dominant negative PRP2 protein competed with its wild-type counterpart for interaction with spliceosomes, with which the mutant protein remained associated. The PRP2-dn1 mutation led to a single amino acid change within the conserved SAT motif that in the prototype helicase eIF-4A is required for RNA unwinding. Purified dominant negative PRP2 protein had approximately 40% of the wild-type level of RNA-stimulated ATPase activity. As ATPase activity was reduced only slightly, but splicing activity was abolished, we propose that the dominant negative phenotype is due primarily to a defect in the putative RNA helicase activity of PRP2 protein. Images PMID:8112301

  15. Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

    PubMed

    Wolf, P S; Pruss, T P; Rand, M J; Smith, R D; Mann, W S; Romano, D V

    1985-12-01

    Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.

  16. Characterization of a novel, dominant negative KCNJ2 mutation associated with Andersen-Tawil syndrome.

    PubMed

    Marrus, Scott B; Cuculich, Phillip S; Wang, Wei; Nerbonne, Jeanne M

    2011-01-01

    Andersen-Tawil syndrome is characterized by periodic paralysis, ventricular ectopy, and dysmorphic features. Approximately 60% of patients exhibit loss-of-function mutations in KCNJ2, which encodes the inwardly rectifying K(+) channel pore forming subunit Kir2.1. Here, we report the identification of a novel KCNJ2 mutation (G211T), resulting in the amino acid substitution D71Y, in a patient presenting with signs and symptoms of Andersen-Tawil syndrome. The functional properties of the mutant subunit were characterized using voltage-clamp experiments on transiently transfected HEK-293 cells and neonatal mouse ventricular myocytes. Whole-cell current recordings of transfected HEK-293 cells demonstrated that the mutant protein Kir2.1-D71Y fails to form functional ion channels when expressed alone, but co-assembles with wild-type Kir2.1 subunits and suppresses wild-type subunit function. Further analysis revealed that current suppression requires at least two mutant subunits per channel. The D71Y mutation does not measurably affect the membrane trafficking of either the mutant or the wild-type subunit or alter the kinetic properties of the currents. Additional experiments revealed that expression of the mutant subunit suppresses native I(K1) in neonatal mouse ventricular myocytes. Simulations predict that the D71Y mutation in human ventricular myocytes will result in a mild prolongation of the action potential and potentially increase cell excitability. These experiments indicate that the Kir2.1-D71Y mutant protein functions as a dominant negative subunit resulting in reduced inwardly rectifying K(+) current amplitudes and altered cellular excitability in patients with Andersen-Tawil syndrome.

  17. Generation of a Retinoblastoma (Rb)1-inducible dominant-negative (DN) mouse model

    PubMed Central

    Tarang, Shikha; Doi, Songila M. S. R.; Gurumurthy, Channabasavaiah B.; Harms, Donald; Quadros, Rolen; Rocha-Sanchez, Sonia M.

    2015-01-01

    Retinoblastoma 1 (Rb1) is an essential gene regulating cellular proliferation, differentiation, and homeostasis. To exert these functions, Rb1 is recruited and physically interacts with a growing variety of signaling pathways. While Rb1 does not appear to be ubiquitously expressed, its expression has been confirmed in a variety of hematopoietic and neuronal-derived cells, including the inner ear hair cells (HCs). Studies in transgenic mice demonstrate that complete germline or conditional Rb1 deletion leads to abnormal cell proliferation, followed by massive apoptosis; making it difficult to fully address Rb1’s biochemical activities. To overcome these limitations, we developed a tetracycline-inducible TetO-CB-myc6-Rb1 (CBRb) mouse model to achieve transient and inducible dominant-negative (DN) inhibition of the endogenous RB1 protein. Our strategy involved fusing the Rb1 gene to the lysosomal protease pre-procathepsin B (CB), thus allowing for further routing of the DN-CBRb fusion protein and its interacting complexes for proteolytic degradation. Moreover, reversibility of the system is achieved upon suppression of doxycycline (Dox) administration. Preliminary characterization of DN-CBRb mice bred to a ubiquitous rtTA mouse line demonstrated a significant inhibition of the endogenous RB1 protein in the inner ear and in a number of other organs where RB1 is expressed. Examination of the postnatal (P) DN-CBRb mice inner ear at P10 and P28 showed the presence of supernumerary inner HCs (IHCs) in the lower turns of the cochleae, which corresponds to the described expression domain of the endogenous Rb1 gene. Selective and reversible suppression of gene expression is both an experimental tool for defining function and a potential means to medical therapy. Given the limitations associated with Rb1-null mice lethality, this model provides a valuable resource for understanding RB1 activity, relative contribution to HC regeneration and its potential therapeutic

  18. Generation of a Retinoblastoma (Rb)1-inducible dominant-negative (DN) mouse model.

    PubMed

    Tarang, Shikha; Doi, Songila M S R; Gurumurthy, Channabasavaiah B; Harms, Donald; Quadros, Rolen; Rocha-Sanchez, Sonia M

    2015-01-01

    Retinoblastoma 1 (Rb1) is an essential gene regulating cellular proliferation, differentiation, and homeostasis. To exert these functions, Rb1 is recruited and physically interacts with a growing variety of signaling pathways. While Rb1 does not appear to be ubiquitously expressed, its expression has been confirmed in a variety of hematopoietic and neuronal-derived cells, including the inner ear hair cells (HCs). Studies in transgenic mice demonstrate that complete germline or conditional Rb1 deletion leads to abnormal cell proliferation, followed by massive apoptosis; making it difficult to fully address Rb1's biochemical activities. To overcome these limitations, we developed a tetracycline-inducible TetO-CB-myc6-Rb1 (CBRb) mouse model to achieve transient and inducible dominant-negative (DN) inhibition of the endogenous RB1 protein. Our strategy involved fusing the Rb1 gene to the lysosomal protease pre-procathepsin B (CB), thus allowing for further routing of the DN-CBRb fusion protein and its interacting complexes for proteolytic degradation. Moreover, reversibility of the system is achieved upon suppression of doxycycline (Dox) administration. Preliminary characterization of DN-CBRb mice bred to a ubiquitous rtTA mouse line demonstrated a significant inhibition of the endogenous RB1 protein in the inner ear and in a number of other organs where RB1 is expressed. Examination of the postnatal (P) DN-CBRb mice inner ear at P10 and P28 showed the presence of supernumerary inner HCs (IHCs) in the lower turns of the cochleae, which corresponds to the described expression domain of the endogenous Rb1 gene. Selective and reversible suppression of gene expression is both an experimental tool for defining function and a potential means to medical therapy. Given the limitations associated with Rb1-null mice lethality, this model provides a valuable resource for understanding RB1 activity, relative contribution to HC regeneration and its potential therapeutic application.

  19. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

    PubMed

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J; Lipskaia, Larissa; Chemaly, Elie R

    2015-11-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Autoregulation of Fox protein expression to produce dominant negative splicing factors

    PubMed Central

    Damianov, Andrey; Black, Douglas L.

    2010-01-01

    The Fox proteins are a family of regulators that control the alternative splicing of many exons in neurons, muscle, and other tissues. Each of the three mammalian paralogs, Fox-1 (A2BP1), Fox-2 (RBM9), and Fox-3 (HRNBP3), produces proteins with a single RNA-binding domain (RRM) flanked by N- and C-terminal domains that are highly diversified through the use of alternative promoters and alternative splicing patterns. These genes also express protein isoforms lacking the second half of the RRM (FoxΔRRM), due to the skipping of a highly conserved 93-nt exon. Fox binding elements overlap the splice sites of these exons in Fox-1 and Fox-2, and the Fox proteins themselves inhibit exon inclusion. Unlike other cases of splicing autoregulation by RNA-binding proteins, skipping the RRM exon creates an in-frame deletion in the mRNA to produce a stable protein. These FoxΔRRM isoforms expressed from cDNA exhibit highly reduced binding to RNA in vivo. However, we show that they can act as repressors of Fox-dependent splicing, presumably by competing with full-length Fox isoforms for interaction with other splicing factors. Interestingly, the Drosophila Fox homolog contains a nearly identical exon in its RRM domain that also has flanking Fox-binding sites. Thus, rather than autoregulation of splicing controlling the abundance of the regulator, the Fox proteins use a highly conserved mechanism of splicing autoregulation to control production of a dominant negative isoform. PMID:20042473

  1. Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype.

    PubMed

    Gilbert, Merle L; Yang, Linghai; Su, Thomas; McKnight, G Stanley

    2015-03-15

    PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 (Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIαB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIαB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIαB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIαB-expressing mice, but AQP2 protein levels were still reduced in RIαB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus.

  2. Recurring dominant-negative mutations in the AVP-NPII gene cause neurohypophyseal diabetes insipidus

    SciTech Connect

    Repaske, D.R.; Phillips, J.A.; Krishnamani, M.R.S.

    1994-09-01

    Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of arginine vasopressin (or antidiuretic hormone) deficiency that is usually manifest in early childhood with polyuria, polydipsia and an antidiuretic response to exogenous vasopressin or its analogs. The phenotype is postulated to arise from gliosis and depletion of the magnocellular neurons that produce vasopressin in the supraoptic and paraventricular nuclei of the hypothalamus. ADNDI is caused by heterozygosity for a variety of mutations in the AVP-NPII gene which encodes vasopressin, its carrier protein (NPII) and a glycoprotein (copeptin) of unknown function. These mutations include: (1) Ala 19{r_arrow}Thr (G279A) in AVP`s signal peptide, (2) Gly 17{r_arrow}Val (G1740T), (3) Pro 24{r_arrow}Leu (C1761T), (4) Gly 57{r_arrow}Ser (G1859A) and (5) del Glu 47({delta}AGG 1824-26), all of which occur in NPII. In characterizing the AVP-NPII mutations in five non-related ADNDI kindreds, we have detected two kindreds having mutation 1 (G279A), two having mutation 3 (C1761T) and one having mutation 4 (G1859A) without any other allelic changes being detected. Two of these recurring mutations (G279A and G1859A) are transitions that occur at CpG dinucleotides while the third (C1761T) does not. Interestingly, families with the same mutations differed in their ethnicity or in their affected AVP-NPII allele`s associated haplotype of closely linked DNA polymorphisms. Our data indicated that at least three of five known AVP-NPII mutations causing ADNDI tend to recur but the mechanisms by which these dominant-negative mutations cause variable or progressive expression of the ADNDI phenotype remain unclear.

  3. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    PubMed Central

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  4. Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells.

    PubMed

    Farrelly, Angela M; Kilbride, Seán M; Bonner, Caroline; Prehn, Jochen H M; Byrne, Maria M

    2011-11-01

    HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

  5. An evaluation of the effects of nonselective and cardioselective β-blockers on wound healing in Sprague Dawley rats

    PubMed Central

    Raut, Sanket B.; Nerlekar, Sharmada R.; Pawar, Sudhir; Patil, Amol N.

    2012-01-01

    Objectives: To investigate the effect of a nonselective β-blocker (propranolol) and cardioselective β-blocker (metoprolol) on wound healing in rats using incision and excision wound models and to compare the effect of these drugs on wound healing. Materials and Methods: Propranolol and metoprolol were given orally. Sprague Dawley rats of either sex were used. Incision and excision wound models were used to evaluate the wound-healing activity. Effects of metoprolol and propranolol on tensile strength, period of epithelialization, and hydroxyproline content were observed. Histological analysis was done to see collagen deposition and inflammatory infiltrate. Statistical Analysis Used: The data was subjected to analysis of variance (ANOVA) followed by Scheffe's test. P < 0.05 was considered to be statistically significant. Statistical analysis was done using SPSS software version 15.0. Results: Administration of propranolol or metoprolol was shown to decrease tensile strength, delay wound contraction and re-epithelialization, increase inflammatory infiltrate, and reduce collagen density and hydroxyproline levels. Conclusions: The results suggest that nonselective and cardioselective β-blockers delay wound healing and these effects are mediated by β1-receptors. PMID:23112427

  6. Dominant-negative myosin Va impairs retrograde but not anterograde axonal transport of large dense core vesicles.

    PubMed

    Bittins, Claudia Margarethe; Eichler, Tilo Wolf; Hammer, John A; Gerdes, Hans-Hermann

    2010-04-01

    Axonal transport of peptide and hormone-containing large dense core vesicles (LDCVs) is known to be a microtubule-dependent process. Here, we suggest a role for the actin-based motor protein myosin Va specifically in retrograde axonal transport of LDCVs. Using live-cell imaging of transfected hippocampal neurons grown in culture, we measured the speed, transport direction, and the number of LDCVs that were labeled with ectopically expressed neuropeptide Y fused to EGFP. Upon expression of a dominant-negative tail construct of myosin Va, a general reduction of movement in both dendrites and axons was observed. In axons, it was particularly interesting that the retrograde speed of LDCVs was significantly impaired, although anterograde transport remained unchanged. Moreover, particles labeled with the dominant-negative construct often moved in the retrograde direction but rarely in the anterograde direction. We suggest a model where myosin Va acts as an actin-dependent vesicle motor that facilitates retrograde axonal transport.

  7. Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy.

    PubMed

    Warner, Timothy A; Shen, Wangzhen; Huang, Xuan; Liu, Zhong; Macdonald, Robert L; Kang, Jing-Qiong

    2016-08-01

    Genetic epilepsy is a common disorder with phenotypic variation, but the basis for the variation is unknown. Comparing the molecular pathophysiology of mutations in the same epilepsy gene may provide mechanistic insights into the phenotypic heterogeneity. GABRG2 is an established epilepsy gene, and mutations in it produce epilepsy syndromes with varying severities. The disease phenotype in some cases may be caused by simple loss of subunit function (functional haploinsufficiency), while others may be caused by loss-of-function plus dominant negative suppression and other cellular toxicity. Detailed molecular defects and the corresponding seizures and related comorbidities resulting from haploinsufficiency and dominant negative mutations, however, have not been compared. Here we compared two mouse models of GABRG2 loss-of-function mutations associated with epilepsy with different severities, Gabrg2(+/Q390X) knockin (KI) and Gabrg2(+/-) knockout (KO) mice. Heterozygous Gabrg2(+/Q390X) KI mice are associated with a severe epileptic encephalopathy due to a dominant negative effect of the mutation, while heterozygous Gabrg2(+/-) KO mice are associated with mild absence epilepsy due to simple haploinsufficiency. Unchanged at the transcriptional level, KI mice with severe epilepsy had neuronal accumulation of mutant γ2 subunits, reduced remaining functional wild-type subunits in dendrites and synapses, while KO mice with mild epilepsy had no intracellular accumulation of the mutant subunits and unaffected biogenesis of the remaining wild-type subunits. Consequently, KI mice with dominant negative mutations had much less wild-type receptor expression, more severe seizures and behavioural comorbidities than KO mice. This work provides insights into the pathophysiology of epilepsy syndrome heterogeneity and designing mechanism-based therapies. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy

    PubMed Central

    Warner, Timothy A.; Shen, Wangzhen; Huang, Xuan; Liu, Zhong; Macdonald, Robert L.; Kang, Jing-Qiong

    2016-01-01

    Genetic epilepsy is a common disorder with phenotypic variation, but the basis for the variation is unknown. Comparing the molecular pathophysiology of mutations in the same epilepsy gene may provide mechanistic insights into the phenotypic heterogeneity. GABRG2 is an established epilepsy gene, and mutations in it produce epilepsy syndromes with varying severities. The disease phenotype in some cases may be caused by simple loss of subunit function (functional haploinsufficiency), while others may be caused by loss-of-function plus dominant negative suppression and other cellular toxicity. Detailed molecular defects and the corresponding seizures and related comorbidities resulting from haploinsufficiency and dominant negative mutations, however, have not been compared. Here we compared two mouse models of GABRG2 loss-of-function mutations associated with epilepsy with different severities, Gabrg2+/Q390X knockin (KI) and Gabrg2+/- knockout (KO) mice. Heterozygous Gabrg2+/Q390XKI mice are associated with a severe epileptic encephalopathy due to a dominant negative effect of the mutation, while heterozygous Gabrg2+/- KO mice are associated with mild absence epilepsy due to simple haploinsufficiency. Unchanged at the transcriptional level, KI mice with severe epilepsy had neuronal accumulation of mutant γ2 subunits, reduced remaining functional wild-type subunits in dendrites and synapses, while KO mice with mild epilepsy had no intracellular accumulation of the mutant subunits and unaffected biogenesis of the remaining wild-type subunits. Consequently, KI mice with dominant negative mutations had much less wild-type receptor expression, more severe seizures and behavioural comorbidities than KO mice. This work provides insights into the pathophysiology of epilepsy syndrome heterogeneity and designing mechanism-based therapies. PMID:27340224

  9. Disruption of C-Terminal Cytoplasmic Domain of βPS Integrin Subunit Has Dominant Negative Properties in Developing Drosophila

    PubMed Central

    Jannuzi, Alison L.; Bunch, Thomas A.; Brabant, Marc C.; Miller, Steven W.; Mukai, Leona; Zavortink, Michael; Brower, Danny L.

    2002-01-01

    We have analyzed a set of new and existing strong mutations in the myospheroid gene, which encodes the βPS integrin subunit of Drosophila. In addition to missense and other null mutations, three mutants behave as antimorphic alleles, indicative of dominant negative properties. Unlike null alleles, the three antimorphic mutants are synthetically lethal in double heterozygotes with an inflated (αPS2) null allele, and they fail to complement very weak, otherwise viable alleles of myospheroid. Two of the antimorphs result from identical splice site lesions, which create a frameshift in the C-terminal half of the cytoplasmic domain of βPS. The third antimorphic mutation is caused by a stop codon just before the cytoplasmic splice site. These mutant βPS proteins can support cell spreading in culture, especially under conditions that appear to promote integrin activation. Analyses of developing animals indicate that the dominant negative properties are not a result of inefficient surface expression, or simple competition between functional and nonfunctional proteins. These data indicate that mutations disrupting the C-terminal cytoplasmic domain of integrin β subunits can have dominant negative effects in situ, at normal levels of expression, and that this property does not necessarily depend on a specific new protein sequence or structure. The results are discussed with respect to similar vertebrate β subunit cytoplasmic mutations. PMID:11950944

  10. An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations

    SciTech Connect

    Sorrenson, Brie; Suetani, Rachel J.; Bickley, Vivienne M.; George, Peter M.; Williams, Michael J.A.; Scott, Russell S.; McCormick, Sally P.A.

    2011-06-10

    Highlights: {yields} Characterisation of an ABCA1 truncation mutant, C978fsX988, in a pedigree with three ABCA1 mutations. {yields} Functional analysis of C978fsX988 in patient fibroblasts and HEK 293 cells shows no cholesterol efflux function. {yields} Allele-specific quantification shows C978fsX988 not expressed at mRNA level in fibroblasts. {yields} Unlike other ABCA1 truncations, C978fsX988 mutant shows no dominant negative effect at mRNA or protein level. -- Abstract: The ATP binding cassette transporter (ABCA1) A1 is a key determinant of circulating high density lipoprotein cholesterol (HDL-C) levels. Mutations in ABCA1 are a major genetic contributor to low HDL-C levels within the general population. Following the finding of three different ABCA1 mutations, p.C978fsX988, p.T1512M and p.N1800H in a subject with hypoalphalipoproteinemia, we aimed to establish whether the p.C978fsX988 truncation exerted a dominant negative effect on the full-length ABCA1 alleles within family members as has been reported for other ABCA1 truncations. Characterisation of the p.C978fsX988 mutant in transfected HEK 293 cells showed it to be expressed as a GFP fusion protein but lacking in cholesterol efflux function. This was in keeping with results from cholesterol efflux assays in the fibroblasts of p.C978fsX988 carriers which also showed impaired efflux. Allele- specific quantification of p.C978fsX988 mRNA and analysis of ABCA1 protein levels in the fibroblasts of p.C978fsX988 heterozygotes showed negligible levels of mRNA and protein expression. There was no evidence of a dominant negative effect on wildtype or p.N1800H protein levels. We conclude that in the case of the p.C978fsX988 truncated mutant a lack of expression precludes it from having a dominant negative effect.

  11. A high-risk patient with long-QT syndrome with no response to cardioselective beta-blockers.

    PubMed

    Toyota, Naoki; Miyazaki, Aya; Sakaguchi, Heima; Shimizu, Wataru; Ohuchi, Hideo

    2015-09-01

    We present a case of a high-risk 19-year-old female with long-QT syndrome (LQTS) with compound mutations. She had a history of aborted cardiac arrest and syncope and had received treatment with propranolol for 15 years. However, because she developed adult-onset asthma we tried to switch propranolol, a nonselective beta-blocker, to beta-1-cardioselective agents, bisoprolol and metoprolol. These resulted in both a markedly prolonged corrected QT interval and the development of LQTS-associated arrhythmias. Eventually, propranolol was reinitiated at a higher dose with the addition of verapamil, and she has had no further cardiac or asthmatic events for 5 years.

  12. Rhodopsin Gene Expression Determines Rod Outer Segment Size and Rod Cell Resistance to a Dominant-Negative Neurodegeneration Mutant

    PubMed Central

    Price, Brandee A.; Sandoval, Ivette M.; Chan, Fung; Nichols, Ralph; Roman-Sanchez, Ramon; Wensel, Theodore G.; Wilson, John H.

    2012-01-01

    Two outstanding unknowns in the biology of photoreceptors are the molecular determinants of cell size, which is remarkably uniform among mammalian species, and the mechanisms of rod cell death associated with inherited neurodegenerative blinding diseases such as retinitis pigmentosa. We have addressed both questions by performing an in vivo titration with rhodopsin gene copies in genetically engineered mice that express only normal rhodopsin or an autosomal dominant allele, encoding rhodopsin with a disease-causing P23H substitution. The results reveal that the volume of the rod outer segment is proportional to rhodopsin gene expression; that P23H-rhodopsin, the most common rhodopsin gene disease allele, causes cell death via a dominant-negative mechanism; and that long term survival of rod cells carrying P23H-rhodopsin can be achieved by increasing the levels of wild type rhodopsin. These results point to promising directions in gene therapy for autosomal dominant neurodegenerative diseases caused by dominant-negative mutations. PMID:23185477

  13. Identification of Functional Domains in the Cohesin Loader Subunit Scc4 by a Random Insertion/Dominant Negative Screen

    PubMed Central

    Shwartz, Michal; Matityahu, Avi; Onn, Itay

    2016-01-01

    Cohesin is a multi-subunit complex that plays an essential role in genome stability. Initial association of cohesin with chromosomes requires the loader—a heterodimer composed of Scc4 and Scc2. However, very little is known about the loader’s mechanism of action. In this study, we performed a genetic screen to identify functional domains in the Scc4 subunit of the loader. We isolated scc4 mutant alleles that, when overexpressed, have a dominant negative effect on cell viability. We defined a small region in the N terminus of Scc4 that is dominant negative when overexpressed, and on which Scc2/Scc4 activity depends. When the mutant alleles are expressed as a single copy, they are recessive and do not support cell viability, cohesion, cohesin loading or Scc4 chromatin binding. In addition, we show that the mutants investigated reduce, but do not eliminate, the interaction of Scc4 with either Scc2 or cohesin. However, we show that Scc4 cannot bind cohesin in the absence of Scc2. Our results provide new insight into the roles of Scc4 in cohesin loading, and contribute to deciphering the loading mechanism. PMID:27280786

  14. Expanding the prion concept to cancer biology: dominant-negative effect of aggregates of mutant p53 tumour suppressor

    PubMed Central

    Silva, Jerson L.; Rangel, Luciana P.; Costa, Danielly C. F.; Cordeiro, Yraima; De Moura Gallo, Claudia V.

    2013-01-01

    p53 is a key protein that participates in cell-cycle control, and its malfunction can lead to cancer. This tumour suppressor protein has three main domains; the N-terminal transactivation domain, the CTD (C-terminal domain) and the core domain (p53C) that constitutes the sequence-specific DBD (DNA-binding region). Most p53 mutations related to cancer development are found in the DBD. Aggregation of p53 into amyloid oligomers and fibrils has been shown. Moreover, amyloid aggregates of both the mutant and WT (wild-type) forms of p53 were detected in tumour tissues. We propose that if p53 aggregation occurred, it would be a crucial aspect of cancer development, as p53 would lose its WT functions in an aggregated state. Mutant p53 can also exert a dominant-negative regulatory effect on WT p53. Herein, we discuss the dominant-negative effect in light of p53 aggregation and the fact that amyloid-like mutant p53 can convert WT p53 into more aggregated species, leading into gain of function in addition to the loss of tumour suppressor function. In summary, the results obtained in the last decade indicate that cancer may have characteristics in common with amyloidogenic and prion diseases. PMID:24003888

  15. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

    PubMed

    Limberg, Maren M; Zumhagen, Sven; Netter, Michael F; Coffey, Alison J; Grace, Andrew; Rogers, Jane; Böckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze-Bahr, Eric

    2013-05-01

    Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

  16. Dominant-negative mutants of a yeast G-protein beta subunit identify two functional regions involved in pheromone signalling.

    PubMed Central

    Leberer, E; Dignard, D; Hougan, L; Thomas, D Y; Whiteway, M

    1992-01-01

    The STE4 gene, which encodes the beta subunit of the mating response G-protein in the yeast Saccharomyces cerevisiae, was subjected to a saturation mutagenesis using 'doped' oligodeoxynucleotides. We employed a genetic screen to select dominant-negative STE4 mutants, which when overexpressed from the GAL1 promoter, interfered with the signalling function of the wild type protein. The identified inhibitory amino acid alterations define two small regions that are crucially involved in transmitting the mating signal from G beta to downstream components of the signalling pathway. These results underline the positive signalling role of yeast G beta and assign for the first time the positive signalling function of a G-protein beta subunit to specific structural features. Images PMID:1464310

  17. THE GABRG2 MUTATION, Q351X, ASSOCIATED WITH GEFS+ HAS BOTH LOSS OF FUNCTION AND DOMINANT-NEGATIVE SUPPRESSION

    PubMed Central

    Kang, Jing-Qiong; Shen, Wangzhen; Macdonald, Robert L.

    2009-01-01

    The GABAA receptor γ2 subunit mutation, Q351X, associated with generalized epilepsy with febrile seizures plus (GEFS+), created a loss of function with homozygous expression. However, heterozygous γ2(+/−) gene deletion mice are seizure–free, suggesting that the loss of one GABRG2 allele alone in heterozygous patients may not be sufficient to produce epilepsy. Here we show that the mutant γ2 subunit was immature and retained in the endoplasmic reticulum (ER). With heterozygous coexpression of γ2S/γ2S(Q351X) subunits and α1 and β2 subunits, the trafficking deficient mutant γ2 subunit reduced trafficking of wild-type partnering subunits, which was not seen in the hemizygous gene deletion control. Consequently, the function of the heterozygous receptor channel was reduced to less than the hemizygous control and to less than half of the wild-type receptors with a full gene dose. Pulse-chase experiments demonstrated that in the presence of the mutant γ2S(Q351X) subunit, wild-type α1 subunits degraded more substantially within 1 hr of translation. We showed that the basis for this dominant negative effect on wild-type receptors was due to an interaction between mutant and wild-type subunits. The mutant subunit oligomerized with wild-type subunits and trapped them in the ER, subjecting them to glycosylation arrest and ER associated degradation (ERAD) through the ubiquitin proteosome system. Thus we hypothesize that a likely explanation for the GEFS+ phenotype is a dominant-negative suppression of wild-type receptors by the mutant γ2S subunit in combination with loss of mutant γ2S subunit protein function. PMID:19261880

  18. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

    PubMed Central

    McEntagart, Meriel; Williamson, Kathleen A.; Rainger, Jacqueline K.; Wheeler, Ann; Seawright, Anne; De Baere, Elfride; Verdin, Hannah; Bergendahl, L. Therese; Quigley, Alan; Rainger, Joe; Dixit, Abhijit; Sarkar, Ajoy; López Laso, Eduardo; Sanchez-Carpintero, Rocio; Barrio, Jesus; Bitoun, Pierre; Prescott, Trine; Riise, Ruth; McKee, Shane; Cook, Jackie; McKie, Lisa; Ceulemans, Berten; Meire, Françoise; Temple, I. Karen; Prieur, Fabienne; Williams, Jonathan; Clouston, Penny; Németh, Andrea H.; Banka, Siddharth; Bengani, Hemant; Handley, Mark; Freyer, Elisabeth; Ross, Allyson; van Heyningen, Veronica; Marsh, Joseph A.; Elmslie, Frances; FitzPatrick, David R.

    2016-01-01

    Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions. PMID:27108798

  19. Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction in female mice.

    PubMed

    Watson, Peter A; Birdsey, Nicholas; Huggins, Gordon S; Svensson, Eric; Heppe, Daniel; Knaub, Leslie

    2010-12-01

    Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415-2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-γ coactivator-1α and estrogen-related receptor-α content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and

  20. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function.

    PubMed

    de Vries, Annemieke; Flores, Elsa R; Miranda, Barbara; Hsieh, Harn-Mei; van Oostrom, Conny Th M; Sage, Julien; Jacks, Tyler

    2002-03-05

    The p53 tumor suppressor gene is the most frequently mutated gene in human cancers, and germ-line p53 mutations cause a familial predisposition for cancer. Germ-line or sporadic p53 mutations are usually missense and typically affect the central DNA-binding domain of the protein. Because p53 functions as a tetrameric transcription factor, mutant p53 is thought to inhibit the function of wild-type p53 protein. Here, we studied the possible dominant-negative inhibition of wild-type p53 protein by two different, frequently occurring point mutations. The R270H and P275S mutations were targeted into the genome of mouse embryonic stem cells to allow the analysis of the effects of the mutant proteins expressed in normal cells at single-copy levels. In embryonic stem cells, the presence of a heterozygous point-mutated allele resulted in delayed transcriptional activation of several p53 downstream target genes on exposure to gamma irradiation. Doxorubicin-induced apoptosis was severely affected in the mutant embryonic stem cells compared with wild-type cells. Heterozygous mutant thymocytes had a severe defect in p53-dependent apoptotic pathways after treatment with gamma irradiation or doxorubicin, whereas p53-independent apoptotic pathways were intact. Together these data demonstrate that physiological expression of point-mutated p53 can strongly limit overall cellular p53 function, supporting the dominant-negative action of such mutants. Also, cells heterozygous for such mutations may be compromised in terms of tumor suppression and response to chemotherapeutic agents.

  1. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.

    PubMed

    McEntagart, Meriel; Williamson, Kathleen A; Rainger, Jacqueline K; Wheeler, Ann; Seawright, Anne; De Baere, Elfride; Verdin, Hannah; Bergendahl, L Therese; Quigley, Alan; Rainger, Joe; Dixit, Abhijit; Sarkar, Ajoy; López Laso, Eduardo; Sanchez-Carpintero, Rocio; Barrio, Jesus; Bitoun, Pierre; Prescott, Trine; Riise, Ruth; McKee, Shane; Cook, Jackie; McKie, Lisa; Ceulemans, Berten; Meire, Françoise; Temple, I Karen; Prieur, Fabienne; Williams, Jonathan; Clouston, Penny; Németh, Andrea H; Banka, Siddharth; Bengani, Hemant; Handley, Mark; Freyer, Elisabeth; Ross, Allyson; van Heyningen, Veronica; Marsh, Joseph A; Elmslie, Frances; FitzPatrick, David R

    2016-05-05

    Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions. Copyright © 2016 The Authors. Published by Elsevier Inc. All

  2. Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner.

    PubMed

    Banks, Eric A; Toloue, Masoud M; Shi, Qian; Zhou, Zifei Jade; Liu, Jialu; Nicholson, Bruce J; Jiang, Jean X

    2009-02-01

    The connexin (Cx) 50, E48K, mutation is associated with a human dominant congenital cataract; however, the underlying molecular mechanism has not been characterized. The glutamate (E) residue at position 48 is highly conserved across animal species and types of connexins. When expressed in paired Xenopus oocytes, human (h) and chicken (ch) Cx50 E48K mutants showed no electrical coupling. In addition, this mutation acts in a dominant negative manner when paired hetero-typically or hetero-merically with wild-type Cx50, but has no such effect on Cx46, the other lens fiber connexin. A similar loss-of-function and dominant negative effect was observed using dye transfer assays in the same system. By using two different dye transfer methods, with two different tracer dyes, we found chCx50 E48K expressed in chicken lens embryonic fibroblast cells by retroviral infection similarly failed to induce dye coupling, and prevented wild-type chCx50 from forming functional gap junctions. In contrast to its effect on gap junctions, the E48K mutation has no effect on hemichannel activity when assayed using electrical conductance in oocytes, and mechanically induced dye uptake in cells. Cx50 is functionally involved in cell differentiation and lens development, and the E48K mutant promotes primary lens cell differentiation indistinguishable from wild-type chCx50, despite its lack of junctional channel function. Together the data show that mutations affecting gap junctions but not hemichannel function of Cx50 can lead to dominant congenital cataracts in humans. This clearly supports the model of intercellular coupling of fiber cells creating a microcirculation of nutrients and metabolites required for lens transparency.

  3. Expression of a Dominant Negative CELF Protein In Vivo Leads to Altered Muscle Organization, Fiber Size, and Subtype

    PubMed Central

    Berger, Dara S.; Moyer, Michelle; Kliment, Gregory M.; van Lunteren, Erik; Ladd, Andrea N.

    2011-01-01

    Background CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue- and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFΔ) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFΔ) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle. Methodology/Principal Findings Myo-CELFΔ mice exhibit modest changes in CELF-mediated alternative splicing in skeletal muscle, accompanied by a reduction of endomysial and perimysial spaces, an increase in fiber size variability, and an increase in slow twitch muscle fibers. Weight gain and mean body weight, total number of muscle fibers, and overall muscle strength were not affected. Conclusions/Significance Although these findings demonstrate that CELF activity contributes to the normal alternative splicing of a subset of muscle transcripts in vivo, the mildness of the effects in Myo-CELFΔ muscles compared to those in MHC-CELFΔ hearts suggests CELF activity may be less determinative for alternative splicing in skeletal muscle than in heart muscle. Nonetheless, even these small changes in CELF-mediated splicing regulation were sufficient to alter muscle organization and muscle fiber properties affected in myotonic dystrophy. This lends further evidence to the hypothesis that dysregulation of CELF-mediated alternative splicing programs may be responsible for the disruption of these properties during muscle pathogenesis. PMID:21541285

  4. Thyroid cancer

    MedlinePlus

    ... a family history of thyroid cancer and chronic goiter (enlarged thyroid). There are several types of thyroid ... Read More Anaplastic thyroid cancer Breathing difficulty Cancer Goiter - simple Metastasis Radiation therapy Thyroid cancer - papillary carcinoma ...

  5. Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction in female mice

    PubMed Central

    Birdsey, Nicholas; Huggins, Gordon S.; Svensson, Eric; Heppe, Daniel; Knaub, Leslie

    2010-01-01

    Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415–2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-γ coactivator-1α and estrogen-related receptor-α content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and

  6. Loss of the malignant phenotype of human neuroblastoma cells by a catalytically inactive dominant-negative hTERT mutant.

    PubMed

    Samy, Mona; Gattolliat, Charles-Henry; Pendino, Frédéric; Hillion, Josette; Nguyen, Eric; Bombard, Sophie; Douc-Rasy, Sétha; Bénard, Jean; Ségal-Bendirdjian, Evelyne

    2012-11-01

    Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. ©2012 AACR.

  7. Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.

    PubMed

    Hong, Sungkook; Hu, Ping; Marino, Juliana; Hufnagel, Sophia B; Hopkin, Robert J; Toromanović, Alma; Richieri-Costa, Antonio; Ribeiro-Bicudo, Lucilene A; Kruszka, Paul; Roessler, Erich; Muenke, Maximilian

    2016-05-15

    Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  8. Dominant-negative Sox18 function inhibits dermal papilla maturation and differentiation in all murine hair types.

    PubMed

    Villani, Rehan; Hodgson, Samantha; Legrand, Julien; Greaney, Jessica; Wong, Ho Yi; Pichol-Thievend, Cathy; Adolphe, Christelle; Wainwight, Brandon; Francois, Mathias; Khosrotehrani, Kiarash

    2017-05-15

    SOX family proteins SOX2 and SOX18 have been reported as being essential in determining hair follicle type; however, the role they play during development remains unclear. Here, we demonstrate that Sox18 regulates the normal differentiation of the dermal papilla of all hair types. In guard (primary) hair dermal condensate (DC) cells, we identified transient Sox18 in addition to SOX2 expression at E14.5, which allowed fate tracing of primary DC cells until birth. Similarly, expression of Sox18 was detected in the DC cells of secondary hairs at E16.5 and in tertiary hair at E18.5. Dominant-negative Sox18 mutation (opposum) did not prevent DC formation in any hair type. However, it affected dermal papilla differentiation, restricting hair formation especially in secondary and tertiary hairs. This Sox18 mutation also prevented neonatal dermal cells or dermal papilla spheres from inducing hair in regeneration assays. Microarray expression studies identified WNT5A and TNC as potential downstream effectors of SOX18 that are important for epidermal WNT signalling. In conclusion, SOX18 acts as a mesenchymal molecular switch necessary for the formation and function of the dermal papilla in all hair types. © 2017. Published by The Company of Biologists Ltd.

  9. Glassy-state stabilization of a dominant negative inhibitor anthrax vaccine containing aluminum hydroxide and glycopyranoside lipid A adjuvants.

    PubMed

    Hassett, Kimberly J; Vance, David J; Jain, Nishant K; Sahni, Neha; Rabia, Lilia A; Cousins, Megan C; Joshi, Sangeeta; Volkin, David B; Middaugh, C Russell; Mantis, Nicholas J; Carpenter, John F; Randolph, Theodore W

    2015-02-01

    During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, dominant negative inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide and glycopyranoside lipid A (GLA). Freeze-thawing of the liquid vaccine caused the adjuvants to aggregate and decreased its immunogenicity in mice. Immunogenicity of liquid vaccines also decreased when stored at 40°C for 8 weeks, as measured by decreases in neutralizing antibody titers in vaccinated mice. Concomitant with efficacy losses at elevated temperatures, changes in DNI structure were detected by fluorescence spectroscopy and increased deamidation was observed by capillary isoelectric focusing (cIEF) after only 1 week of storage of the liquid formulation at 40°C. In contrast, upon lyophilization, no additional deamidation after 4 weeks at 40°C and no detectable changes in DNI structure or reduction in immunogenicity after 16 weeks at 40°C were observed. Vaccines containing aluminum hydroxide and GLA elicited higher immune responses than vaccines adjuvanted with only aluminum hydroxide, with more mice responding to a single dose. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  10. Glassy-State Stabilization of a Dominant Negative Inhibitor Anthrax Vaccine Containing Aluminum Hydroxide and Glycopyranoside Lipid A Adjuvants

    PubMed Central

    Hassett, Kimberly J.; Vance, David J.; Jain, Nishant K.; Sahni, Neha; Rabia, Lilia A.; Cousins, Megan C.; Joshi, Sangeeta; Volkin, David B.; Middaugh, Russell; Mantis, Nicholas J.; Carpenter, John F.; Randolph, Theodore W.

    2014-01-01

    During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, Dominant Negative Inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide and glycopyranoside lipid A (GLA). Freeze-thawing of the liquid vaccine caused the adjuvants to aggregate and decreased its immunogenicity in mice. Immunogenicity of liquid vaccines also decreased when stored at 40 °C for 8 weeks, as measured by decreases in neutralizing antibody titers in vaccinated mice. Concomitant with efficacy losses at elevated temperatures, changes in DNI structure were detected by fluorescence spectroscopy and increased deamidation was observed by capillary isoelectric focusing (cIEF) after only 1 week of storage of the liquid formulation at 40 °C. In contrast, upon lyophilization, no additional deamidation after 4 weeks at 40 °C and no detectable changes in DNI structure or reduction in immunogenicity after 16 weeks at 40 °C was observed. Vaccines containing aluminum hydroxide and GLA elicited higher immune responses than vaccines adjuvanted with only aluminum hydroxide, with more mice responding to a single dose. PMID:25581103

  11. Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle

    PubMed Central

    Pelham, Christopher J.; Keen, Henry L.; Lentz, Steven R.

    2013-01-01

    Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with Type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPARγ that render the transcription factor dominant negative (DN) cause early-onset hypertension and Type II diabetes. We tested the hypothesis that DN PPARγ-mediated interference of endogenous wild-type PPARγ in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice. Endothelium-specific expression of DN PPARγ on the ApoE−/− background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g., Cd36, Mcp1, Catalase), and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPARγ, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE−/− background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g., Cd36, Mcp1, Osteopontin, Vcam1). In particular, induction of Osteopontin expression by smooth muscle-specific DN PPARγ correlated with increased plaque calcification. These data demonstrate that inhibition of PPARγ function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease. PMID:23447133

  12. Expression of a mutant form of cellulose synthase AtCesA7 causes dominant negative effect on cellulose biosynthesis.

    PubMed

    Zhong, Ruiqin; Morrison, W Herbert; Freshour, Glenn D; Hahn, Michael G; Ye, Zheng-Hua

    2003-06-01

    Cellulose synthase catalytic subunits (CesAs) have been implicated in catalyzing the biosynthesis of cellulose, the major component of plant cell walls. Interactions between CesA subunits are thought to be required for normal cellulose synthesis, which suggests that incorporation of defective CesA subunits into cellulose synthase complex could potentially cause a dominant effect on cellulose synthesis. However, all CesA mutants so far reported have been shown to be recessive in terms of cellulose synthesis. In the course of studying the molecular mechanisms regulating secondary wall formation in fibers, we have found that a mutant allele of AtCesA7 gene in the fra5 (fragile fiber 5) mutant causes a semidominant phenotype in the reduction of fiber cell wall thickness and cellulose content. The fra5 missense mutation occurred in a conserved amino acid located in the second cytoplasmic domain of AtCesA7. Overexpression of the fra5 mutant cDNA in wild-type plants not only reduced secondary wall thickness and cellulose content but also decreased primary wall thickness and cell elongation. In contrast, overexpression of the fra6 mutant form of AtCesA8 did not cause any reduction in cell wall thickness and cellulose content. These results suggest that the fra5 mutant protein may interfere with the function of endogenous wild-type CesA proteins, thus resulting in a dominant negative effect on cellulose biosynthesis.

  13. Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma.

    PubMed

    Yvon, Eric S; Burga, Rachel; Powell, Allison; Cruz, Conrad R; Fernandes, Rohan; Barese, Cecilia; Nguyen, Tuongvan; Abdel-Baki, Mohamed S; Bollard, Catherine M

    2017-03-01

    Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-β). We observed that TGF-β inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-β, we engrafted a dominant negative TGF-β receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-β. After manufacture using Good Manufacturing Practice-compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-β allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-β-secreting tumors and may be an important therapeutic approach for patients with cancer. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. Modulation of calcium signalling by dominant negative splice variant of ryanodine receptor subtype 3 in native smooth muscle cells.

    PubMed

    Dabertrand, Fabrice; Morel, Jean-Luc; Sorrentino, Vincenzo; Mironneau, Jean; Mironneau, Chantal; Macrez, Nathalie

    2006-07-01

    The ryanodine receptor subtype 3 (RYR3) is expressed ubiquitously but its physiological function varies from cell to cell. Here, we investigated the role of a dominant negative RYR3 isoform in Ca2+ signalling in native smooth muscle cells. We used intranuclear injection of antisense oligonucleotides to specifically inhibit endogenous RYR3 isoform expression. In mouse duodenum myocytes expressing RYR2 subtype and both spliced and non-spliced RYR3 isoforms, RYR2 and non-spliced RYR3 were activated by caffeine whereas the spliced RYR3 was not. Only RYR2 was responsible for the Ca2+-induced Ca2+ release mechanism that amplified Ca2+ influx- or inositol 1,4,5-trisphosphate-induced Ca2+ signals. However, the spliced RYR3 negatively regulated RYR2 leading to the decrease of amplitude and upstroke velocity of Ca2+ signals. Immunostaining in injected cells showed that the spliced RYR3 was principally expressed near the plasma membrane whilst the non-spliced isoform was revealed around the nucleus. This study shows for the first time that the short isoform of RYR3 controls Ca2+ release through RYR2 in native smooth muscle cells.

  15. Inhibition of telomerase activity by dominant-negative hTERT retards the growth of breast cancer cells.

    PubMed

    Rao, Yaojian; Xiong, Wei; Liu, Huijuan; Jia, Chunxia; Zhang, Hongxing; Cui, Zesheng; Zhang, Ya; Cui, Jiawei

    2016-03-01

    Telomerase, a ribonucleoprotein enzyme mainly consisted of a catalytic protein subunit human telomerase reverse transcriptase (hTERT) and a human telomerase RNA component, is responsible for maintaining telomeres. Telomerase over-expression correlates significantly with tumors and is a prognostic marker. However, telomerase over-expression in breast cancers and the effect of telomerase inhibition as a candidate cancer therapy are unknown. We used the dominant-negative mutant of hTERT (DN-hTERT) to inhibit telomerase activity on human breast adenocarcinoma cell line MCF-7 by transfection. Telomeric repeat amplification protocol assays and real-time quantitative RT-PCR were performed to investigate telomerase activity as well as expression of hTERT. Telomere length was measured by the flow-fluorescence in situ hybridization assay. Cell proliferation was assessed by the WST-8 assay, and apoptosis was evaluated by flow cytometry. The tumor formation ability of MCF-7 cells was investigated by transplanting cells subcutaneously into BALB/c nude mice. Ectopic expression of DN-hTERT caused dramatically inhibition of telomerase activity and reduction of telomere length. Telomerase inhibition induced growth arrest and apoptosis of MCF7 cells in vitro and loss of tumorigenic properties in vivo. This study shows that telomerase inhibition by DN-hTERT can effectively inhibit the cell viability and tumorigenicity of MCF7 cells and is an attractive approach for breast cancer therapy.

  16. Dominant Negative Mutants of the Murine Cytomegalovirus M53 Gene Block Nuclear Egress and Inhibit Capsid Maturation▿ †

    PubMed Central

    Popa, Mirela; Ruzsics, Zsolt; Lötzerich, Mark; Dölken, Lars; Buser, Christopher; Walther, Paul; Koszinowski, Ulrich H.

    2010-01-01

    The alphaherpesvirus proteins UL31 and UL34 and their homologues in other herpesvirus subfamilies cooperate at the nuclear membrane in the export of nascent herpesvirus capsids. We studied the respective betaherpesvirus proteins M53 and M50 in mouse cytomegalovirus (MCMV). Recently, we established a random approach to identify dominant negative (DN) mutants of essential viral genes and isolated DN mutants of M50 (B. Rupp, Z. Ruzsics, C. Buser, B. Adler, P. Walther and U. H. Koszinowski, J. Virol 81:5508-5517). Here, we report the identification and phenotypic characterization of DN alleles of its partner, M53. While mutations in the middle of the M53 open reading frame (ORF) resulted in DN mutants inhibiting MCMV replication by ∼100-fold, mutations at the C terminus resulted in up to 1,000,000-fold inhibition of virus production. C-terminal DN mutants affected nuclear distribution and steady-state levels of the nuclear egress complex and completely blocked export of viral capsids. In addition, they induced a marked maturation defect of viral capsids, resulting in the accumulation of nuclear capsids with aberrant morphology. This was associated with a two-thirds reduction in the total amount of unit length genomes, indicating an accessory role for M53 in DNA packaging. PMID:20610730

  17. Dominant negative mutants of the murine cytomegalovirus M53 gene block nuclear egress and inhibit capsid maturation.

    PubMed

    Popa, Mirela; Ruzsics, Zsolt; Lötzerich, Mark; Dölken, Lars; Buser, Christopher; Walther, Paul; Koszinowski, Ulrich H

    2010-09-01

    The alphaherpesvirus proteins UL31 and UL34 and their homologues in other herpesvirus subfamilies cooperate at the nuclear membrane in the export of nascent herpesvirus capsids. We studied the respective betaherpesvirus proteins M53 and M50 in mouse cytomegalovirus (MCMV). Recently, we established a random approach to identify dominant negative (DN) mutants of essential viral genes and isolated DN mutants of M50 (B. Rupp, Z. Ruzsics, C. Buser, B. Adler, P. Walther and U. H. Koszinowski, J. Virol 81:5508-5517). Here, we report the identification and phenotypic characterization of DN alleles of its partner, M53. While mutations in the middle of the M53 open reading frame (ORF) resulted in DN mutants inhibiting MCMV replication by approximately 100-fold, mutations at the C terminus resulted in up to 1,000,000-fold inhibition of virus production. C-terminal DN mutants affected nuclear distribution and steady-state levels of the nuclear egress complex and completely blocked export of viral capsids. In addition, they induced a marked maturation defect of viral capsids, resulting in the accumulation of nuclear capsids with aberrant morphology. This was associated with a two-thirds reduction in the total amount of unit length genomes, indicating an accessory role for M53 in DNA packaging.

  18. A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: a new mechanism to regulate water permeability.

    PubMed

    De Bellis, Manuela; Pisani, Francesco; Mola, Maria Grazia; Basco, Davide; Catalano, Francesco; Nicchia, Grazia Paola; Svelto, Maria; Frigeri, Antonio

    2014-02-01

    Two major isoforms of aquaporin-4 (AQP4) have been described in human tissue. Here we report the identification and functional analysis of an alternatively spliced transcript of human AQP4, AQP4-Δ4, that lacks exon 4. In transfected cells AQP4-Δ4 is mainly retained in the endoplasmic reticulum and shows no water transport properties. When AQP4-Δ4 is transfected into cells stably expressing functional AQP4, the surface expression of the full-length protein is reduced. Furthermore, the water transport activity of the cotransfectants is diminished in comparison to transfectants expressing only AQP4. The observed down-regulation of both the expression and water channel activity of AQP4 is likely to originate from a dominant-negative effect caused by heterodimerization between AQP4 and AQP4-Δ4, which was detected in coimmunoprecipitation studies. In skeletal muscles, AQP4-Δ4 mRNA expression inversely correlates with the level of AQP4 protein and is physiologically associated with different types of skeletal muscles. The expression of AQP4-Δ4 may represent a new regulatory mechanism through which the cell-surface expression and therefore the activity of AQP4 can be physiologically modulated.

  19. Regression/Eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide

    PubMed Central

    Cates, Charles C.; Arias, Angelo D.; Wong, Lynn S. Nakayama; Lamé, Michael W.; Sidorov, Maxim; Cayanan, Geraldine; Rowland, Douglas J.; Fung, Jennifer; Karpel-Massler, Georg; Siegelin, Markus D.; Greene, Lloyd A.; Angelastro, James M.

    2016-01-01

    Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas. PMID:26863637

  20. A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: a new mechanism to regulate water permeability

    PubMed Central

    De Bellis, Manuela; Pisani, Francesco; Mola, Maria Grazia; Basco, Davide; Catalano, Francesco; Nicchia, Grazia Paola; Svelto, Maria; Frigeri, Antonio

    2014-01-01

    Two major isoforms of aquaporin-4 (AQP4) have been described in human tissue. Here we report the identification and functional analysis of an alternatively spliced transcript of human AQP4, AQP4-Δ4, that lacks exon 4. In transfected cells AQP4-Δ4 is mainly retained in the endoplasmic reticulum and shows no water transport properties. When AQP4-Δ4 is transfected into cells stably expressing functional AQP4, the surface expression of the full-length protein is reduced. Furthermore, the water transport activity of the cotransfectants is diminished in comparison to transfectants expressing only AQP4. The observed down-regulation of both the expression and water channel activity of AQP4 is likely to originate from a dominant-negative effect caused by heterodimerization between AQP4 and AQP4-Δ4, which was detected in coimmunoprecipitation studies. In skeletal muscles, AQP4-Δ4 mRNA expression inversely correlates with the level of AQP4 protein and is physiologically associated with different types of skeletal muscles. The expression of AQP4-Δ4 may represent a new regulatory mechanism through which the cell-surface expression and therefore the activity of AQP4 can be physiologically modulated. PMID:24356448

  1. Identification of dominant negative human immunodeficiency virus type 1 Vif mutants that interfere with the functional inactivation of APOBEC3G by virus-encoded Vif.

    PubMed

    Walker, Robert C; Khan, Mohammad A; Kao, Sandra; Goila-Gaur, Ritu; Miyagi, Eri; Strebel, Klaus

    2010-05-01

    APOBEC3G (A3G) is a host cytidine deaminase that serves as a potent intrinsic inhibitor of retroviral replication. A3G is packaged into human immunodeficiency virus type 1 virions and deaminates deoxycytidine to deoxyuridine on nascent minus-strand retroviral cDNA, leading to hyper-deoxyguanine-to-deoxyadenine mutations on positive-strand cDNA and inhibition of viral replication. The antiviral activity of A3G is suppressed by Vif, a lentiviral accessory protein that prevents encapsidation of A3G. In this study, we identified dominant negative mutants of Vif that interfered with the ability of wild-type Vif to inhibit the encapsidation and antiviral activity of A3G. These mutants were nonfunctional due to mutations in the highly conserved HCCH and/or SOCS box motifs, which are required for assembly of a functional Cul5-E3 ubiquitin ligase complex. Similarly, mutation or deletion of a PPLP motif, which was previously reported to be important for Vif dimerization, induced a dominant negative phenotype. Expression of dominant negative Vif counteracted the Vif-induced reduction of intracellular A3G levels, presumably by preventing Vif-induced A3G degradation. Consequently, dominant negative Vif interfered with wild-type Vif's ability to exclude A3G from viral particles and reduced viral infectivity despite the presence of wild-type Vif. The identification of dominant negative mutants of Vif presents exciting possibilities for the design of novel antiviral strategies.

  2. A dominant-negative needle mutant blocks type III secretion of early but not late substrates in Yersinia.

    PubMed

    Davis, Alison J; Díaz, Dennise A De Jesús; Mecsas, Joan

    2010-04-01

    Yersinia pseudotuberculosis uses a type III secretion system (T3SS) to deliver effectors into host cells. A key component of the T3SS is the needle, which is a hollow tube on the bacterial surface through which effectors are secreted, composed of the YscF protein. To study needle assembly, we performed a screen for dominant-negative yscF alleles that prevented effector secretion in the presence of wild-type (WT) YscF. One allele, yscF-L54V, prevents WT YscF secretion and needle assembly, although purified YscF-L54V polymerizes in vitro. YscF-L54V binds to its chaperones YscE and YscG, and the YscF-L54V-EG complex targets to the T3SS ATPase, YscN. We propose that YscF-L54V stalls at a binding site in the needle assembly pathway following its release from the chaperones, which blocks the secretion of WT YscF and other early substrates required for building a needle. Interestingly, YscF-L54V does not affect the activity of pre-assembled actively secreting machines, indicating that a factor and/or binding site required for YscF secretion is absent from T3SS machines already engaged in effector secretion. Thus, substrate switching may involve the removal of an early substrate-specific binding site as a mechanism to exclude early substrates from Yop-secreting machines.

  3. POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity

    PubMed Central

    Young, Matthew J.; Humble, Margaret M.; DeBalsi, Karen L.; Sun, Kathie Y.; Copeland, William C.

    2015-01-01

    Human mitochondrial DNA (mtDNA) is replicated and repaired by the mtDNA polymerase gamma, polγ. Polγ is composed of three subunits encoded by two nuclear genes: (1) POLG codes for the 140-kilodalton (kDa) catalytic subunit, p140 and (2) POLG2 encodes the ∼110-kDa homodimeric accessory subunit, p55. Specific mutations are associated with POLG- or POLG2-related disorders. During DNA replication the p55 accessory subunit binds to p140 and increases processivity by preventing polγ's dissociation from the template. To date, studies have demonstrated that homodimeric p55 disease variants are deficient in the ability to stimulate p140; however, all patients currently identified with POLG2-related disorders are heterozygotes. In these patients, we expect p55 to occur as 25% wild-type (WT) homodimers, 25% variant homodimers and 50% heterodimers. We report the development of a tandem affinity strategy to isolate p55 heterodimers. The WT/G451E p55 heterodimer impairs polγ function in vitro, demonstrating that the POLG2 c.1352G>A/p.G451E mutation encodes a dominant negative protein. To analyze the subcellular consequence of disease mutations in HEK293 cells, we designed plasmids encoding p55 disease variants tagged with green fluorescent protein (GFP). P205R and L475DfsX2 p55 variants exhibit irregular diffuse mitochondrial fluorescence and unlike WT p55, they fail to form distinct puncta associated with mtDNA nucleoids. Furthermore, homogenous preparations of P205R and L475DfsX2 p55 form aberrant reducible multimers. We predict that abnormal protein folding or aggregation or both contribute to the pathophysiology of these disorders. Examination of mitochondrial bioenergetics in stable cell lines overexpressing GFP-tagged p55 variants revealed impaired mitochondrial reserve capacity. PMID:26123486

  4. [Effect of dominant negative HIF-1alpha (dn HIF-1alpha) on biological characteristics of uterine cervix cancer cells].

    PubMed

    Tang, Bin-Zhi; Zhao, Feng-Yan; Wei, Ting; Mu, De-Zhi; Mao, Meng; Fu, Qiang; Zhang, Lin; Qu, Yia

    2008-05-01

    To explore the effect of dominant negative HIF-1alpha (dn HIF-1alpha) on biological characteristics of uterine cervix cancer cell SiHa and elucidate the related mechanism. pcDNA3. 1-dn HIF-1alpha was transfected into SiHa cells. The expression of HIF-1alpha and VEGF protein were detected by immunocytochemical method and Western Blotting. The growth proliferation of cells was surveyed by the MTT assay and cell apoptosis was detected through TUNEL after treated with CoCl2, meanwhile the results were compared with the group transfected with mock plasmid and untransfected group. After successfully transfected with relevant plasmid, there's no obvious difference of expression of HIF-1alpha among dn HIF-1alpha group, pcDNA3. 1 group, and untransfected group, however the expression of VEGF of dn HIF-1alpha group was significantly lower than that of the others (P < 0. 05). The proliferation ability of dn HIF-1alpha group was obviously lower than that of the other two (P < 0.05), whether it was under normoxia or chemical hypoxia induced by CoCl2. The characteristic apoptotic morphology was most significantly apparent in dn HIF-1alpha group among these three (P < 0.05). Domain negative HIF-1alpha can inhibit the proliferation of uterine cervix cancer cell and accelerate its apoptosis under hypoxia induced by CoCl2, as well as decrease the expression of VEGF protein. The implications of all this were that the domain negative HIF-1alpha may play an important role in the therapy of uterine cervix cancer.

  5. Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.

    PubMed

    Campbell, Matthew D; Witcher, Marc; Gopal, Anoop; Michele, Daniel E

    2016-05-01

    Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.

  6. Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance.

    PubMed

    Stump, Madeliene; Guo, Deng-Fu; Lu, Ko-Ting; Mukohda, Masashi; Liu, Xuebo; Rahmouni, Kamal; Sigmund, Curt D

    2016-07-01

    Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMC(Cre)/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

  7. A dominant-negative needle mutant blocks type III secretion of early but not late substrates in Yersinia

    PubMed Central

    Davis, Alison J.; De Jesús Díaz, Dennise A.; Mecsas, Joan

    2010-01-01

    Summary Yersinia pseudotuberculosis uses a Type III Secretion System (T3SS) to deliver effectors into host cells. A key component of the T3SS is the needle, which is a hollow tube on the bacterial surface through which effectors are secreted, composed of the YscF protein. To study needle assembly, we performed a screen for dominant-negative yscF alleles that prevented effector secretion in the presence of wild-type (WT) YscF. One allele, yscF-L54V, prevents WT YscF secretion and needle assembly, although purified YscF-L54V polymerizes in vitro. YscF-L54V binds to its chaperones YscE and YscG, and the YscF-L54V-EG complex targets to the T3SS ATPase, YscN. We propose that YscF-L54V stalls at a binding site in the needle assembly pathway following its release from the chaperones, which blocks the secretion of WT YscF and other early substrates required for building a needle. Interestingly, YscF-L54V does not affect the activity of pre-assembled actively secreting machines, indicating that a factor and/or binding site required for YscF secretion is absent from T3SS machines already engaged in effector secretion. Thus, substrate switching may involve the removal of an early substrate-specific binding site as a mechanism to exclude early substrates from Yop-secreting machines. PMID:20199604

  8. A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy.

    PubMed

    Fahrner, Jill A; Liu, Raymond; Perry, Michael Scott; Klein, Jessica; Chan, David C

    2016-08-01

    DNM1L encodes dynamin-related protein 1 (DRP1/DLP1), a key component of the mitochondrial fission machinery that is essential for proper functioning of the mammalian brain. Previously reported probands with de novo missense mutations in DNM1L presented in the first year of life with severe encephalopathy and refractory epilepsy, with several dying within the first several weeks after birth. In contrast, we report identical novel missense mutations in DNM1L in two unrelated probands who experienced normal development for several years before presenting with refractory focal status epilepticus and subsequent rapid neurological decline. We expand the phenotype of DNM1L-related mitochondrial fission defects, reveal common unique clinical characteristics and imaging findings, and compare the cellular impact of this novel mutation to the previously reported A395D lethal variant. We demonstrate that our R403C mutation, which resides in the assembly region of DRP1, acts by a dominant-negative mechanism and reduces oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent compared to the A395D mutation. In contrast to the initial report of neonatal lethality resulting from DNM1L mutation and DRP1 dysfunction, our results show that milder DRP1 impairment is compatible with normal early development and subsequently results in a distinct set of neurological findings. In addition, we identify a common pathogenic mechanism whereby DNM1L mutations impair mitochondrial fission. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. A dominant-negative form of Arabidopsis AP-3 β-adaptin improves intracellular pH homeostasis.

    PubMed

    Niñoles, Regina; Rubio, Lourdes; García-Sánchez, María J; Fernández, José A; Bueso, Eduardo; Alejandro, Santiago; Serrano, Ramón

    2013-05-01

    Intracellular pH (pHi ) is a crucial parameter in cellular physiology but its mechanisms of homeostasis are only partially understood. To uncover novel roles and participants of the pHi regulatory system, we have screened an Arabidopsis mutant collection for resistance of seed germination to intracellular acidification induced by weak organic acids (acetic, propionic, sorbic). The phenotypes of one identified mutant, weak acid-tolerant 1-1D (wat1-1D) are due to the expression of a truncated form of AP-3 β-adaptin (encoded by the PAT2 gene) that behaves as a as dominant-negative. During acetic acid treatment the root epidermal cells of the mutant maintain a higher pHi and a more depolarized plasma membrane electrical potential than wild-type cells. Additional phenotypes of wat1-1D roots include increased rates of acetate efflux, K(+) uptake and H(+) efflux, the latter reflecting the in vivo activity of the plasma membrane H(+) -ATPase. The in vitro activity of the enzyme was not increased but, as the H(+) -ATPase is electrogenic, the increased ion permeability would allow a higher rate of H(+) efflux. The AP-3 adaptor complex is involved in traffic from Golgi to vacuoles but its function in plants is not much known. The phenotypes of the wat1-1D mutant can be explained if loss of function of the AP-3 β-adaptin causes activation of channels or transporters for organic anions (acetate) and for K(+) at the plasma membrane, perhaps through miss-localization of tonoplast proteins. This suggests a role of this adaptin in trafficking of ion channels or transporters to the tonoplast. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

  10. An Engineered TGF-β Monomer that Functions as a Dominant Negative to Block TGF-β Signaling.

    PubMed

    Kim, Sun Kyung; Barron, Lindsey; Hinck, Cynthia S; Petrunak, Elyse M; Cano, Kristin E; Thangirala, Avinash; Iskra, Brian; Brothers, Molly; Vonberg, Machell; Leal, Belinda; Richter, Blair; Kodali, Ravindra; Taylor, Alex B; Du, Shoucheng; Barnes, Christopher O; Sulea, Traian; Calero, Guillermo; Hart, P John; Hart, Matthew J; Demeler, Borries; Hinck, Andrew P

    2017-02-22

    The transforming growth factor beta isoforms, TGF-β1, -β2, and -β3 are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor, TβRI, but dispensible for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor, TβRII, as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a Ki of 20 - 70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI, enabled it to bind endogenous TβRII, but prevented it from binding and recruiting TβRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-β signaling, and may inform similar modifications of other TGF-β family members.

  11. Dominant negative mutation in cell surface beta 1,4- galactosyltransferase inhibits cell-cell and cell-matrix interactions

    PubMed Central

    1993-01-01

    In addition to its traditional location within the Golgi complex, beta 1,4-galactosyltransferase (GalTase) is also present on the cell surface, where it is thought to function as a cell adhesion molecule by binding to extracellular oligosaccharide ligands. Recent studies suggest that cells contain two forms of GalTase with distinct cytoplasmic domains. The longer form of GalTase contains a 13-amino acid cytoplasmic extension and is preferentially targeted to the plasma membrane, relative to the shorter GalTase protein that is confined primarily to the Golgi compartment. In this study, we created a dominant negative mutation that interferes with the function of cell surface GalTase by transfecting into cells cDNAs encoding truncated versions of the long form of GalTase containing the complete cytoplasmic and transmembrane domains, but devoid of the catalytic domain. In both F9 embryonal carcinoma cells and Swiss 3T3 fibroblasts, overexpressing the truncated long GalTase (TLGT) protein displaced the endogenous cell surface GalTase from its association with the cytoskeleton, resulting in a loss of intercellular adhesion and cell spreading specifically on matrices that use GalTase as a cell surface receptor. In contrast, overexpressing the analogous truncated short GalTase (TSGT) protein did not affect cell morphology or GalTase activity. In control assays, inducing the TLGT protein had no effect on cell interactions with fibronectin (which is independent of GalTase), or on the cytoskeleton attachment of another matrix receptor (beta 1 integrin), or on overall glycoprotein synthesis, thus eliminating nonspecific effects of the TLGT protein on cellular adhesion and metabolism. These results represent the first molecular manipulation of cell surface GalTase expression and confirm its function as a cell adhesion molecule. These studies further suggest that the cytoskeleton contains a defined, saturable number of binding sites for GalTase, which enables it to function as

  12. Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant.

    PubMed

    Soucek, Radim; Thomas, Dierk; Kelemen, Kamilla; Bikou, Olympia; Seyler, Claudia; Voss, Frederik; Becker, Rüdiger; Koenen, Michael; Katus, Hugo A; Bauer, Alexander

    2012-02-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapy-dependent modulation of atrial electrophysiology may provide a more specific alternative to pharmacological and ablative treatment strategies. We hypothesized that genetic inactivation of atrial repolarizing ether-a-go-go-related gene (ERG) K(+) currents using a dominant-negative mutant would provide rhythm control in AF. Ten domestic swine underwent pacemaker implantation and were subjected to atrial burst pacing to induce persistent AF. Animals were then randomized to receive either AdCERG-G627S to suppress ERG/I(Kr) currents or green fluorescent protein (AdGFP) as control. Adenoviruses were applied using a novel hybrid technique combining atrial virus injection and epicardial electroporation to increase transgene expression. In pigs treated with AdCERG-G627S, the onset of persistent AF was prevented (n = 2) or significantly delayed compared with AdGFP controls (12 ± 2.1 vs. 6.2 ± 1.3 days; P < .001) during 14-day follow-up. Effective refractory periods were prolonged in the AdCERG-G627S group compared with AdGFP animals (221.5 ± 4.7 ms vs. 197.0 ± 4.7 ms; P < .006). Impairment of left ventricular ejection fraction (LVEF) during AF was prevented by AdCERG-G627S application (LVEF(CERG-G627S) = 62.1% ± 4.0% vs. LVEF(GFP) = 30.3% ± 9.1%; P < .001). Inhibition of ERG function using atrial AdCERG-G627S gene transfer suppresses or delays the onset of persistent AF by prolongation of atrial refractoriness in a porcine model. Targeted gene therapy represents an alternative to pharmacological or ablative treatment of AF. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  13. Postpartum Thyroiditis

    MedlinePlus

    ... high thyroid hormone levels in the blood) and hypothyroidism (low thyroid hormone levels in the blood). In postpartum thyroiditis, thyrotoxicosis occurs first followed by hypothyroidism. What causes postpartum thyroiditis? The exact cause is ...

  14. Postpartum Thyroiditis

    MedlinePlus

    ... high thyroid hormone levels in the blood) and hypothyroidism (low thyroid hormone levels in the blood). In postpartum thyroiditis, thyrotoxicosis occurs first followed by hypothyroidism. What causes postpartum thyroiditis? The exact cause is ...

  15. Use of dominant-negative HrpA mutants to dissect Hrp pilus assembly and type III secretion in Pseudomonas syringae pv. tomato.

    PubMed

    Lee, Yong Hoon; Kolade, Olatomirin O; Nomura, Kinya; Arvidson, Dennis N; He, Sheng Yang

    2005-06-03

    The Hrp pilus plays an essential role in the long-distance type III translocation of effector proteins from bacteria into plant cells. HrpA is the structural subunit of the Hrp pilus in Pseudomonas syringae pv. tomato (Pst) DC3000. Little is known about the molecular features in the HrpA protein for pilus assembly or for transporting effector proteins. From previous collections of nonfunctional HrpA derivatives that carry random pentapeptide insertions or single amino acid mutations, we identified several dominant-negative mutants that blocked the ability of wild-type Pst DC3000 to elicit host responses. The dominant-negative phenotype was correlated with the disappearance of the Hrp pilus in culture and inhibition of wild-type HrpA protein self-assembly in vitro. Dominant-negative HrpA mutants can be grouped into two functional classes: one class exerted a strong dominant-negative effect on the secretion of effector proteins AvrPto and HopPtoM in culture, and the other did not. The two classes of mutant HrpA proteins carry pentapeptide insertions in discrete regions, which are interrupted by insertions without a dominant-negative effect. These results enable prediction of possible subunit-subunit interaction sites in the assembly of the Hrp pilus and suggest the usefulness of dominant-negative mutants in dissection of the role of the wild-type HrpA protein in various stages of type III translocation: protein exit across the bacterial cell wall, the assembly and/or stabilization of the Hrp pilus in the extracellular space, and Hrp pilus-mediated long-distance transport beyond the bacterial cell wall.

  16. A dominantly negative mutation in cardiac troponin I at the interface with troponin T causes early remodeling in ventricular cardiomyocytes.

    PubMed

    Wei, Hongguang; Jin, J-P

    2014-08-15

    We previously reported a point mutation substituting Cys for Arg(111) in the highly conserved troponin T (TnT)-contacting helix of cardiac troponin I (cTnI) in wild turkey hearts (Biesiadecki et al. J Biol Chem 279: 13825-13832, 2004). This dominantly negative TnI-TnT interface mutation decreases the binding affinity of cTnI for TnT, impairs diastolic function, and blunts the β-adrenergic response of cardiac muscle (Wei et al. J Biol Chem 285: 27806-27816, 2010). Here we further investigate cellular phenotypes of transgenic mouse cardiomyocytes expressing the equivalent mutation cTnI-K118C. Functional studies were performed on single adult cardiomyocytes after recovery in short-term culture from isolation stress. The amplitude of contraction and the velocities of shortening and relengthening were lower in cTnI-K118C cardiomyocytes than wild-type controls. The intracellular Ca(2+) transient was slower in cTnI-K118C cardiomyocytes than wild-type cells. cTnI-K118C cardiomyocytes also showed a weaker β-adrenergic response. The resting length of cTnI-K118C cardiomyocytes was significantly greater than that of age-matched wild-type cells, with no difference in cell width. The resting sarcomere was not longer, but slightly shorter, in cTnI-K118C cardiomyocytes than wild-type cells, indicating longitudinal addition of sarcomeres. More tri- and quadrinuclei cardiomyocytes were found in TnI-K118C than wild-type hearts, suggesting increased nuclear divisions. Whole-genome mRNA array and Western blots detected an increased expression of leukemia inhibitory factor receptor-β in the hearts of 2-mo-old cTnI-K118C mice, suggesting a signaling pathway responsible for the potent effect of cTnI-K118C mutation on early remodeling in cardiomyocytes.

  17. Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

    PubMed

    Puschmann, Andreas; Fiesel, Fabienne C; Caulfield, Thomas R; Hudec, Roman; Ando, Maya; Truban, Dominika; Hou, Xu; Ogaki, Kotaro; Heckman, Michael G; James, Elle D; Swanberg, Maria; Jimenez-Ferrer, Itzia; Hansson, Oskar; Opala, Grzegorz; Siuda, Joanna; Boczarska-Jedynak, Magdalena; Friedman, Andrzej; Koziorowski, Dariusz; Aasly, Jan O; Lynch, Timothy; Mellick, George D; Mohan, Megha; Silburn, Peter A; Sanotsky, Yanosh; Vilariño-Güell, Carles; Farrer, Matthew J; Chen, Li; Dawson, Valina L; Dawson, Ted M; Wszolek, Zbigniew K; Ross, Owen A; Springer, Wolfdieter

    2017-01-01

    by a partial dominant-negative function phenotype.

  18. A dominantly negative mutation in cardiac troponin I at the interface with troponin T causes early remodeling in ventricular cardiomyocytes

    PubMed Central

    Wei, Hongguang

    2014-01-01

    We previously reported a point mutation substituting Cys for Arg111 in the highly conserved troponin T (TnT)-contacting helix of cardiac troponin I (cTnI) in wild turkey hearts (Biesiadecki et al. J Biol Chem 279: 13825–13832, 2004). This dominantly negative TnI-TnT interface mutation decreases the binding affinity of cTnI for TnT, impairs diastolic function, and blunts the β-adrenergic response of cardiac muscle (Wei et al. J Biol Chem 285: 27806–27816, 2010). Here we further investigate cellular phenotypes of transgenic mouse cardiomyocytes expressing the equivalent mutation cTnI-K118C. Functional studies were performed on single adult cardiomyocytes after recovery in short-term culture from isolation stress. The amplitude of contraction and the velocities of shortening and relengthening were lower in cTnI-K118C cardiomyocytes than wild-type controls. The intracellular Ca2+ transient was slower in cTnI-K118C cardiomyocytes than wild-type cells. cTnI-K118C cardiomyocytes also showed a weaker β-adrenergic response. The resting length of cTnI-K118C cardiomyocytes was significantly greater than that of age-matched wild-type cells, with no difference in cell width. The resting sarcomere was not longer, but slightly shorter, in cTnI-K118C cardiomyocytes than wild-type cells, indicating longitudinal addition of sarcomeres. More tri- and quadrinuclei cardiomyocytes were found in TnI-K118C than wild-type hearts, suggesting increased nuclear divisions. Whole-genome mRNA array and Western blots detected an increased expression of leukemia inhibitory factor receptor-β in the hearts of 2-mo-old cTnI-K118C mice, suggesting a signaling pathway responsible for the potent effect of cTnI-K118C mutation on early remodeling in cardiomyocytes. PMID:24898585

  19. Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage.

    PubMed

    Wijnhoven, Susan W P; Speksnijder, Ewoud N; Liu, Xiaoling; Zwart, Edwin; vanOostrom, Conny Th M; Beems, Rudolf B; Hoogervorst, Esther M; Schaap, Mirjam M; Attardi, Laura D; Jacks, Tyler; van Steeg, Harry; Jonkers, Jos; de Vries, Annemieke

    2007-05-15

    p53 alterations in human tumors often involve missense mutations that may confer dominant-negative or gain-of-function properties. Dominant-negative effects result in inactivation of wild-type p53 protein in heterozygous mutant cells and as such in a p53 null phenotype. Gain-of-function effects can directly promote tumor development or metastasis through antiapoptotic mechanisms or transcriptional activation of (onco)genes. Here, we show, using conditional mouse technology, that epithelium-specific heterozygous expression of mutant p53 (i.e., the p53.R270H mutation that is equivalent to the human hotspot R273H) results in an increased incidence of spontaneous and UVB-induced skin tumors. Expression of p53.R270H exerted dominant-negative effects on latency, multiplicity, and progression status of UVB-induced but not spontaneous tumors. Surprisingly, gain-of-function properties of p53.R270H were not detected in skin epithelium. Apparently, dominant-negative and gain-of-function effects of mutant p53 are highly tissue specific and become most manifest upon stabilization of p53 after DNA damage.

  20. Dominant-Negative Mutants Identify a Role for Girk Channels in D3 Dopamine Receptor-Mediated Regulation of Spontaneous Secretory Activity

    PubMed Central

    Kuzhikandathil, Eldo V.; Oxford, Gerry S.

    2000-01-01

    The human D3 dopamine receptor can activate G-protein–coupled inward rectifier potassium channels (GIRKs), inhibit P/Q-type calcium channels, and inhibit spontaneous secretory activity in AtT-20 neuroendocrine cells (Kuzhikandathil, E.V., W. Yu, and G.S. Oxford. 1998. Mol. Cell. Neurosci. 12:390–402; Kuzhikandathil, E.V., and G.S. Oxford. 1999. J. Neurosci. 19:1698–1707). In this study, we evaluate the role of GIRKs in the D3 receptor-mediated inhibition of secretory activity in AtT-20 cells. The absence of selective blockers for GIRKs has precluded a direct test of the hypothesis that they play an important role in inhibiting secretory activity. However, the tetrameric structure of these channels provides a means of disrupting endogenous GIRK function using a dominant negative approach. To develop a dominant-negative GIRK mutant, the K+ selectivity amino acid sequence -GYG- in the putative pore domain of the human GIRK2 channels was mutated to -AAA-, -GLG-, or -GFG-. While the mutation of -GYG- to -GFG- did not affect channel function, both the -AAA- and -GLG- GIRK2 mutants were nonfunctional. This suggests that the aromatic ring of the tyrosine residue rather than its hydroxyl group is involved in maintaining the pore architecture of human GIRK2 channels. When expressed in AtT-20 cells, the nonfunctional AAA-GIRK2 and GLG-GIRK2 acted as effective dominant-negative mutants and significantly attenuated endogenous GIRK currents. Furthermore, these dominant-negative mutants interfered with the D3 receptor-mediated inhibition of secretion in AtT-20 cells, suggesting they are centrally involved in the signaling pathway of this secretory response. These results indicate that dominant-negative GIRK mutants are effective molecular tools to examine the role of GIRK channels in vivo. PMID:10828244

  1. The structural basis of the dominant negative phenotype of the Gαi1β1γ2 G203A/A326S heterotrimer

    PubMed Central

    Liu, Ping; Jia, Ming-zhu; Zhou, X Edward; De Waal, Parker W; Dickson, Bradley M; Liu, Bo; Hou, Li; Yin, Yan-ting; Kang, Yan-yong; Shi, Yi; Melcher, Karsten; Xu, H Eric; Jiang, Yi

    2016-01-01

    Aim: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Gαi1β1γ2 G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Gαi1β1γ2. Methods: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. Results: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Gα-Gβγ interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of Gαi and the N-termini of both the Gβ and Gγ subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. Conclusion: Overall, the results suggest that the mutations impede guanine nucleotide binding and Gα-Gβγ protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations. PMID:27498775

  2. Probing the structure, function, and interactions of the Escherichia coli H-NS and StpA proteins by using dominant negative derivatives.

    PubMed

    Williams, R M; Rimsky, S; Buc, H

    1996-08-01

    Twelve different dominant negative mutants of the Escherichia coli nucleoid-associated protein, H-NS, have been selected and characterized in vivo. The mutants are all severely defective in promoter repression activity in a strain lacking H-NS, and they all disrupt the repression normally exerted by H-NS at two of its target promoters. From the locations of the alterations in these mutants, which result in both large truncations and amino acid substitutions, we propose that H-NAS contains at least two distinct domains. The in vitro protein-protein cross-linking data presented in this report indicate that the proposed N-terminal domain of H-NS has a role in H-NS multimerization. StpA is a protein with known structural and functional homologies to H-NS. We have analyzed the extent of these homologies by constructing and studying StpA mutants predicted to be dominant negative. Our data indicate that the substitutions and deletions found in dominant negative H-NS have similar effects in the context of StpA. We conclude that the domain organizations and functions in StpA and H-NS are closely related. Furthermore, dominant negative H-NS can disrupt the activity of native StpA, and reciprocally, dominant negative StpA can disrupt the activity of native H-NS. We demonstrate that the N-terminal domain of H-NS can be chemically cross-linked to both full-length H-NS and StpA. We account for these observations by proposing that H-NS and StpA have the ability to form hybrid species.

  3. Thyroid Storm with Heart Failure Treated with a Short-acting Beta-adrenoreceptor Blocker, Landiolol Hydrochloride.

    PubMed

    Yamashita, Yugo; Iguchi, Moritake; Nakatani, Rieko; Usui, Takeshi; Takagi, Daisuke; Hamatani, Yasuhiro; Unoki, Takashi; Ishii, Mitsuru; Ogawa, Hisashi; Masunaga, Nobutoyo; Abe, Mitsuru; Akao, Masaharu

    2015-01-01

    Beta-adrenoreceptor blockers are essential in controlling the peripheral actions of thyroid hormones and a rapid heart rate in patients with thyroid storm, although they should be used with great caution when there is the potential for heart failure. A 67-year-old woman was diagnosed as having thyroid storm in addition to marked tachycardia with atrial fibrillation and heart failure associated with a reduced left ventricular function. The administration of an oral beta blocker, bisoprolol fumarate, induced hypotension and was not tolerable for the patient, whereas landiolol hydrochloride, a short-acting intravenous beta-adrenoreceptor blocker with high cardioselectivity and a short elimination half-life, was useful for controlling the patient's tachycardia and heart failure without causing hemodynamic deterioration.

  4. Silent thyroiditis

    MedlinePlus

    ... gland. The disorder can cause hyperthyroidism, followed by hypothyroidism. The thyroid gland is located in the neck, ... Later symptoms may be of an underactive thyroid ( hypothyroidism ), including fatigue and cold intolerance, until the thyroid ...

  5. Thyroid Disease

    MedlinePlus

    ... your menstrual period. Your thyroid helps control your menstrual cycle. Too much or too little thyroid hormone can ... Problems getting pregnant. When thyroid disease affects the menstrual cycle, it also affects ovulation. This can make it ...

  6. Dominant-negative mutation in the beta2 and beta6 proteasome subunit genes affect alternative cell fate decisions in the Drosophila sense organ lineage.

    PubMed

    Schweisguth, F

    1999-09-28

    In Drosophila, dominant-negative mutations in the beta2 and beta6 proteasome catalytic subunit genes have been identified as dominant temperature-sensitive (DTS) mutations. At restrictive temperature, beta2 and beta6 DTS mutations confer lethality at the pupal stage. I investigate here the role of proteasome activity in regulating cell fate decisions in the sense organ lineage at the early pupal stage. Temperature-shift experiments in beta2 and beta6 DTS mutant pupae occasionally resulted in external sense organs with two sockets and no shaft. This double-socket phenotype was strongly enhanced in conditions in which Notch signaling was up-regulated. Furthermore, conditional overexpression of the beta6 dominant-negative mutant subunit led to shaft-to-socket and to neuron-to-sheath cell fate transformations, which are both usually associated with increased Notch signaling activity. Finally, expression of the beta6 dominant-negative mutant subunit led to the stabilization of an ectopically expressed nuclear form of Notch in imaginal wing discs. This study demonstrates that mutations affecting two distinct proteasome catalytic subunits affect two alternative cell fate decisions and enhance Notch signaling activity in the sense organ lineage. These findings raise the possibility that the proteasome targets an active form of the Notch receptor for degradation in Drosophila.

  7. Thyroid Cancer

    MedlinePlus

    ... are here Home > Types of Cancer > Thyroid Cancer Thyroid Cancer This is Cancer.Net’s Guide to Thyroid Cancer. Use the menu below to choose the ... social workers, and patient advocates. Cancer.Net Guide Thyroid Cancer Introduction Statistics Medical Illustrations Risk Factors Symptoms ...

  8. Thyroid ultrasound

    PubMed Central

    Chaudhary, Vikas; Bano, Shahina

    2013-01-01

    Thyroid ultrasonography has established itself as a popular and useful tool in the evaluation and management of thyroid disorders. Advanced ultrasound techniques in thyroid imaging have not only fascinated the radiologists but also attracted the surgeons and endocrinologists who are using these techniques in their daily clinical and operative practice. This review provides an overview of indications for ultrasound in various thyroid diseases, describes characteristic ultrasound findings in these diseases, and illustrates major diagnostic pitfalls of thyroid ultrasound. PMID:23776892

  9. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    PubMed Central

    Barmashenko, Gleb; Buttgereit, Jens; Herring, Neil; Bader, Michael; Özcelik, Cemil; Manahan-Vaughan, Denise; Braunewell, Karl H.

    2014-01-01

    The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1–100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning. PMID:25520616

  10. Response to Multiple Radiation Doses of Human Colorectal Carcinoma Cells Infected With Recombinant Adenovirus Containing Dominant-Negative Ku70 Fragment

    SciTech Connect

    Urano, Muneyasu; He Fuqiu; Minami, Akiko; Ling, C. Clifton; Li, Gloria C.

    2010-07-01

    Purpose: To investigate the effect of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment on the response of tumor cells to multiple small radiation doses. Our ultimate goal is to demonstrate the feasibility of using this virus in gene-radiotherapy to enhance the radiation response of tumor cells. Methods and Materials: Human colorectal HCT8 and HT29 carcinoma cells were plated in glass tubes, infected with virus (25 multiplicity of infection), and irradiated with a single dose or zero to five doses of 3 Gy each at 6-h intervals. Hypoxia was induced by flushing with 100% nitrogen gas. The cells were trypsinized 0 or 6 h after the final irradiation, and cell survival was determined by colony formation. The survival data were fitted to linear-quadratic model or exponential line. Results: Virus infection enhanced the radiation response of the HCT8 and HT29 cells. The virus enhancement ratio for single-dose irradiation at a surviving fraction of 0.1 was {approx}1.3 for oxic and hypoxic HCT8 and 1.4 and 1.1 for oxic and hypoxic HT29, respectively. A similar virus enhancement ratio of 1.2-1.3 was observed for both oxic and hypoxic cells irradiated with multiple doses; however, these values were smaller than the values found for dominant-negative Ku70-transfected Rat-1 cells. This difference has been discussed. The oxygen enhancement ratio for HCT8 and HT29 receiving fractionated doses was 1.2 and 2.0, respectively, and virus infection altered them slightly. Conclusion: Infection of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment enhanced the response of human colorectal cancer cells to single and multiple radiation doses.

  11. The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of Rift Valley fever virus MP-12 vaccine.

    PubMed

    Lihoradova, Olga; Kalveram, Birte; Indran, Sabarish V; Lokugamage, Nandadeva; Juelich, Terry L; Hill, Terence E; Tseng, Chien-Te K; Gong, Bin; Fukushi, Shuetsu; Morikawa, Shigeru; Freiberg, Alexander N; Ikegami, Tetsuro

    2012-07-01

    Rift Valley fever virus (RVFV), belonging to the genus Phlebovirus, family Bunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-α) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-α nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans.

  12. The Dominant-Negative Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR Increases the Efficacy of Rift Valley Fever Virus MP-12 Vaccine

    PubMed Central

    Lihoradova, Olga; Kalveram, Birte; Indran, Sabarish V.; Lokugamage, Nandadeva; Juelich, Terry L.; Hill, Terence E.; Tseng, Chien-Te K.; Gong, Bin; Fukushi, Shuetsu; Morikawa, Shigeru; Freiberg, Alexander N.

    2012-01-01

    Rift Valley fever virus (RVFV), belonging to the genus Phlebovirus, family Bunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-α) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-α nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans. PMID:22573861

  13. Selective expression of a dominant-negative type Iα PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity.

    PubMed

    Yang, Linghai; Gilbert, Merle L; Zheng, Ruimao; McKnight, G Stanley

    2014-04-02

    Striatal medium spiny neurons (MSNs) mediate many of the physiological effects of dopamine, including the regulation of feeding and motor behaviors. Dopaminergic inputs from the midbrain modulate MSN excitability through pathways that involve cAMP and protein kinase A (PKA), but the physiological role of specific PKA isoforms in MSN neurons remains poorly understood. One of the major PKA regulatory (R) subunit isoforms expressed in MSNs is RIIβ, which localizes the PKA holoenzyme primarily to dendrites by interaction with AKAP5 and other scaffolding proteins. However, RI (RIα and RIβ) subunits are also expressed in MSNs and the RI holoenzyme has a weaker affinity for most scaffolding proteins and tends to localize in the cell body. We generated mice with selective expression of a dominant-negative RI subunit (RIαB) in striatal MSNs and show that this dominant-negative RIαB localizes to the cytoplasm and specifically inhibits type I PKA activity in the striatum. These mice are normal at birth; however, soon after weaning they exhibit growth retardation and the adult mice are hypophagic, lean, and resistant to high-fat diet-induced hyperphagia and obesity. The RIαB-expressing mice also exhibit decreased locomotor activity and decreased dopamine-regulated CREB phosphorylation and c-fos gene expression in the striatum. Our results demonstrate a critical role for cytoplasmic RI-PKA holoenzyme in gene regulation and the overall physiological function of MSNs.

  14. Missense Mutations in Pyruvate Kinase M2 Promote Cancer Metabolism, Oxidative Endurance, Anchorage Independence, and Tumor Growth in a Dominant Negative Manner

    PubMed Central

    Iqbal, Mohd Askandar; Siddiqui, Farid Ahmad; Chaman, Noor; Gupta, Vibhor; Kumar, Bhupender; Gopinath, Prakasam; Bamezai, Rameshwar N. K.

    2014-01-01

    The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in the Bloom syndrome condition. Cells stably expressing exogenous wild-type or mutant PKM2 (K422R or H391Y) or co-expressing both wild type and mutant (PKM2-K422R or PKM2-H391Y) were assessed for cancer metabolism and tumorigenic potential. Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either wild-type or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation, and tumor growth. These observations signify the dominant negative nature of mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; this study demonstrates for the first time the possible predisposition of Bloom syndrome patients with impaired PKM2 activity to cancer and the importance of studying genetic variations in PKM2 in the future to understand their relevance in cancer in general. PMID:24492614

  15. Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner.

    PubMed

    Iqbal, Mohd Askandar; Siddiqui, Farid Ahmad; Chaman, Noor; Gupta, Vibhor; Kumar, Bhupender; Gopinath, Prakasam; Bamezai, Rameshwar N K

    2014-03-21

    The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in the Bloom syndrome condition. Cells stably expressing exogenous wild-type or mutant PKM2 (K422R or H391Y) or co-expressing both wild type and mutant (PKM2-K422R or PKM2-H391Y) were assessed for cancer metabolism and tumorigenic potential. Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either wild-type or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation, and tumor growth. These observations signify the dominant negative nature of mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; this study demonstrates for the first time the possible predisposition of Bloom syndrome patients with impaired PKM2 activity to cancer and the importance of studying genetic variations in PKM2 in the future to understand their relevance in cancer in general.

  16. A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia.

    PubMed

    Devlin, Emily E; Dacosta, Lydie; Mohandas, Narla; Elliott, Gene; Bodine, David M

    2010-10-14

    Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.

  17. A heterozygous dominant-negative mutation in the coiled-coil domain of STAT1 is the cause of autosomal-dominant Mendelian susceptibility to mycobacterial diseases.

    PubMed

    Ueki, Masahiro; Yamada, Masafumi; Ito, Kenta; Tozawa, Yusuke; Morino, Saeko; Horikoshi, Yuho; Takada, Hidetoshi; Abdrabou, Shimaa Said Mohamed Ali; Takezaki, Shunichiro; Kobayashi, Ichiro; Ariga, Tadashi

    2017-01-01

    Heterozygous dominant-negative mutations of STAT1 are responsible for autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD). So far, only 7 mutations have been previously described and are localized to 3 domains: the DNA-binding domain, the SH2 domain, and the tail segment. In this study, we demonstrated the first coiled-coil domain (CCD) mutation of c.749G>C, p.G250A (G250A) in STAT1 as a genetic cause of AD-MSMD in a patient with mycobacterial multiple osteomyelitis. This de novo heterozygous mutation was shown to have a dominant-negative effect on the gamma-activated sequence (GAS) transcriptional activity following IFN-γ stimulation, which could be attributable to the abolished phosphorylation of STAT1 from the wild-type (WT) allele. The three-dimensional structure of STAT1 revealed the G250 residue was located distant from a cluster of residues affected by gain-of-function mutations responsible for chronic mucocutaneous candidiasis.

  18. Dominant negative mutants of human T-cell leukemia virus type I Rex and human immunodeficiency virus type 1 Rev fail to multimerize in vivo.

    PubMed Central

    Bogerd, H; Greene, W C

    1993-01-01

    Human T-cell leukemia virus type I (HTLV-I) Rex and human immunodeficiency virus type 1 (HIV-1) Rev are essential gene products required for the replication of these two pathogenic human retroviruses. Both Rex and Rev act at a posttranscriptional level by binding to highly structured RNA-response elements, the Rex-response element in HTLV-I and the Rev-response element in HIV-1. Using a sensitive in vivo assay of protein-protein interaction, we now demonstrate that the HTLV-I Rex and HIV-1 Rev proteins readily form homomultimeric complexes in the absence of their cognate RNA-response elements yet fail to form heteromultimeric complexes with each other. Dominant negative mutations have been identified in both the rex and rev genes which presumably specify a critical activation or effector domain in each of these viral transactivators. Surprisingly, these dominant negative mutants of Rex and Rev fail to interact in vivo. These findings raise the possibility that the binding of nonfunctional monomers rather than functional multimers underlies the transdominant phenotype of these Rex and Rev mutants. Further, it seems likely that the assembly of functional and stable multimers of Rex and Rev in vivo may depend not only on the intrinsic multimerization domains of these proteins but also on the binding of a bridging cellular cofactor to the related activation domains present in each viral transactivator. Images PMID:8474155

  19. Thyroid hormone receptors in brain development and function.

    PubMed

    Bernal, Juan

    2007-03-01

    Thyroid hormones are important during development of the mammalian brain, acting on migration and differentiation of neural cells, synaptogenesis, and myelination. The actions of thyroid hormones are mediated through nuclear thyroid hormone receptors (TRs) and regulation of gene expression. The purpose of this article is to review the role of TRs in brain maturation. In developing humans maternal and fetal thyroid glands provide thyroid hormones to the fetal brain, but the timing of receptor ontogeny agrees with clinical data on the importance of the maternal thyroid gland before midgestation. Several TR isoforms, which are encoded by the THRA and THRB genes, are expressed in the brain, with the most common being TRalpha1. Deletion of TRalpha1 in rodents is not, however, equivalent to hormone deprivation and, paradoxically, even prevents the effects of hypothyroidism. Unliganded receptor activity is, therefore, probably an important factor in causing the harmful effects of hypothyroidism. Accordingly, expression of a mutant receptor with impaired triiodothyronine (T(3)) binding and dominant negative activity affected cerebellar development and motor performance. TRs are also involved in adult brain function. TRalpha1 deletion, or expression of a dominant negative mutant receptor, induces consistent behavioral changes in adult mice, leading to severe anxiety and morphological changes in the hippocampus.

  20. Thyroid ultrasound

    MedlinePlus

    ... D, Davies TF, Schlumberger MJ, Hay ID, Larsen PR. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology . 13th ...

  1. Thyroid Antibodies

    MedlinePlus

    ... blocking production of thyroid hormones and resulting in hypothyroidism . TBII is not routinely tested, but TSI is ... autoimmune disease . A low level of thyroid hormones ( hypothyroidism ) can cause symptoms, such as: Weight gain Fatigue ...

  2. Thyroid Problems

    MedlinePlus

    ... treated differently. Common thyroid disorders and problems include: Hypothyroidism Hypothyroidism is a disorder in which your thyroid doesn’ ... normal after you get better. If you have hypothyroidism, however, the levels of T4 in your blood ...

  3. Thyroid disease

    SciTech Connect

    Falk, S.

    1990-01-01

    Presenting a multidisciplinary approach to the diagnosis and treatment of thyroid disease, this volume provides a comprehensive picture of current thyroid medicine and surgery. The book integrates the perspectives of the many disciplines that deal with the clinical manifestations of thyroid disorders. Adding to the clinical usefulness of the book is the state-of-the-art coverage of many recent developments in thyroidology, including the use of highly sensitive two-site TSH immunoradionetric measurements to diagnose thyroid activity; thyroglobulin assays in thyroid cancer and other diseases; new diagnostic applications of MRI and CT; treatment with radionuclides and chemotherapy; new developments in thyroid immunology, pathology, and management of hyperthyroidism; suppressive treatment with thyroid hormone; and management of Graves' ophthalmopathy. The book also covers all aspects of thyroid surgery, including surgical treatment of hyperthyroidism; papillary, follicular, and other carcinomas; thyroidectomy; and prevention and management of complications.

  4. Thyroid Tests

    MedlinePlus

    ... the thyroid, a computerized tomography (CT) scan, or nuclear medicine tests, to diagnose and find the cause ... is having the scan for other health problems. Nuclear medicine tests. Nuclear medicine tests of the thyroid ...

  5. Thyroid Surgery

    MedlinePlus

    ... panel of genetic mutations linked to follicular or papillary thyroid cancer… Read More June 10, 2012 6 Cirugia De ... 2011 0 Gene Mutation Increases Risk of Recurrent Papillary Thyroid Cancer in Some Patients By admin | 2011 News Releases , ...

  6. Thyroid Cancer

    MedlinePlus

    ... body work normally. There are several types of cancer of the thyroid gland. You are at greater ... imaging tests, and a biopsy to diagnose thyroid cancer. Treatment depends on the type of cancer you ...

  7. Thyroid hemiagenesis.

    PubMed

    Shaha, A R; Gujarati, R

    1997-06-01

    Thyroid hemiagenesis is a rare embryological condition, predominantly in females (3:1) with a left lobe being absent. The associated diseases in the remaining thyroid lobe include benign adenoma, multinodular goiter, hyperthyroidism, chronic thyroiditis, and rarely carcinoma. The most common pathology involved in thyroid hemiagenesis is hyperthyroidism. Presence of carcinoma in a patient with hemiagenesis is quite rare and very few cases are reported in the world literature. We report a 30-year-old female who presented with left thyroid mass gradually increasing in size over a period of 3 months. The patient's pre-operative workup included a thyroid scan, which revealed a cold nodule in the left lobe with absent right lobe. A fine-needle aspiration biopsy was suspicious for papillary thyroid carcinoma. The patient underwent thyroid exploration and left thyroid lobectomy. The operative findings confirmed hemiagenesis of the right lobe and papillary carcinoma in the left lobe. All four parathyroids were in normal position. The purpose of this presentation is to discuss and review the literature on thyroid hemiagenesis and present a rare case of absent right thyroid lobe with carcinoma in the remaining left thyroid lobe.

  8. Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism

    SciTech Connect

    Spritz, R.A.; Giebel, L.B.; Holmes, S.A. )

    1992-02-01

    Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white parches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, 'dominant white spotting' (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinases receptor for the mast/stem cell growth factor. The authors have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe[r arrow]Leu) at codon 584, within the tyrosine kinases domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associated with a variable and relatively mild piebald phenotype. This is consistent with a possible 'dominant negative' effect of missense c-kit polypeptides on the function of the dimeric receptor.

  9. The new and recurrent FLT3 juxtamembrane deletion mutation shows a dominant negative effect on the wild-type FLT3 receptor

    PubMed Central

    Sandhöfer, Nadine; Bauer, Julia; Reiter, Katrin; Dufour, Annika; Rothenberg, Maja; Konstandin, Nikola P.; Zellmeier, Evelyn; Tizazu, Belay; Greif, Philipp A.; Metzeler, Klaus H.; Hiddemann, Wolfgang; Polzer, Harald; Spiekermann, Karsten

    2016-01-01

    In acute myeloid leukemia (AML), the Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes. Recently, a new and recurrent juxtamembrane deletion mutation (p.Q569Vfs*2) resulting in a truncated receptor was identified. The mutated receptor is expressed on the cell surface and still binds its ligand but loses the ability to activate ERK signaling. FLT3 p.Q569fs-expressing Ba/F3 cells show no proliferation after ligand stimulation. Furthermore, coexpressed with the FLT3 wild-type (WT) receptor, the truncated receptor suppresses stimulation and activation of the WT receptor. Thus, FLT3 p.Q569Vfs*2, to our knowledge, is the first FLT3 mutation with a dominant negative effect on the WT receptor. PMID:27346558

  10. Caveolin-1 mutants P132L and Y14F are dominant negative regulators of invasion, migration and aggregation in H1299 lung cancer cells

    SciTech Connect

    Shatz, Maria; Lustig, Gila; Reich, Reuven; Liscovitch, Mordechai

    2010-06-10

    Caveolin-1 is an essential protein constituent of caveolae. Accumulating evidence indicates that caveolin-1 may act as a positive regulator of cancer progression. In this study, we investigated the function of caveolin-1 in human lung cancer cells. Caveolin-1 knockdown inhibited cell proliferation and reduced focal adhesion kinase (Fak) phosphorylation. Matrix invasion and cell migration as well as expression and activity of matrix metalloproteases were attenuated following caveolin-1 RNAi-mediated knockdown or overexpression of Y14F and P132L mutants, demonstrating dominant-negative activity of these mutants. Time-lapse fluorescence microscopy revealed that caveolin-1 and its mutants P132L and Y14F are localized to the trailing edge of migrating cells during both random and directed cell movement, implying an active role of caveolin-1 in the migration process. Suppression of caveolin-1 function greatly elevated the percentage of H1299 cells exhibiting focal adhesions. In addition, cell aggregation was increased by wild type caveolin-1 and attenuated by both P132L and Y14F mutants. Overexpression of wild type caveolin-1 increased caveolae density, however, P132L and Y14F mutants did not affect caveolae formation, suggesting that in this respect that the mutants do not act in a dominant negative manner, and that effects of caveolin-1 on caveolae and cell invasion, migration, focal adhesion and aggregation, are separable. Our data provide novel mechanistic insights into the role of caveolin-1 in cell motility, invasiveness and aggregation, therefore, expanding our understanding of the tumor-promoting activities of caveolin-1 in advanced-stage cancer.

  11. Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.

    PubMed

    Minekawa, A; Abe, T; Inoshita, A; Iizuka, T; Kakehata, S; Narui, Y; Koike, T; Kamiya, K; Okamura, H-O; Shinkawa, H; Ikeda, K

    2009-12-15

    Mutations in the connexin26 gene (GJB2) are the most common genetic cause of congenital bilateral non-syndromic sensorineural hearing loss. Transgenic mice were established carrying human Cx26 with the R75W mutation that was identified in a deaf family with autosomal dominant negative inheritance [Kudo T et al. (2003) Hum Mol Genet 12:995-1004]. A dominant-negative Gjb2 R75W transgenic mouse model shows incomplete development of the cochlear supporting cells, resulting in profound deafness from birth [Inoshita A et al. (2008) Neuroscience 156:1039-1047]. The Cx26 defect in the Gjb2 R75W transgenic mouse is restricted to the supporting cells; it is unclear why the auditory response is severely disturbed in spite of the presence of outer hair cells (OHCs). The present study was designed to evaluate developmental changes in the in vivo and in vitro function of the OHC, and the fine structure of the OHC and adjacent supporting cells in the R75W transgenic mouse. No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development. A characteristic phenotype observed in these mice was the absence of the tunnel of Corti, Nuel's space, and spaces surrounding the OHC; the OHC were compressed and squeezed by the surrounding supporting cells. On the other hand, the OHC developed normally. Structural features of the lateral wall, such as the membrane-bound subsurface cisterna beneath the plasma membrane, were intact. Prestin, the voltage-dependent motor protein, was observed by immunohistochemistry in the OHC basolateral membranes of both transgenic and non-transgenic mice. No significant differences in electromotility of isolated OHCs during development was observed between transgenic and control mice. The present study indicates that normal development of the supporting cells is indispensable for proper cellular function of the OHC.

  12. Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF

    SciTech Connect

    Chen Xiaoli; Matsumoto, Hideko; Hinck, Cynthia S.; Al-Hasani, Hadi; St-Denis, Jean-Francois; Whiteheart, Sidney W.; Cushman, Samuel W. . E-mail: sam_cushman@nih.gov

    2005-07-22

    In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by {approx}50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-D1EQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins.

  13. LQT5 masquerading as LQT2: a dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current

    PubMed Central

    Nof, Eyal; Barajas-Martinez, Hector; Eldar, Michael; Urrutia, Janire; Caceres, Gabriel; Rosenfeld, Gail; Bar-Lev, David; Feinberg, Micha; Burashnikov, Elena; Casis, Oscar; Hu, Dan; Glikson, Michael; Antzelevitch, Charles

    2011-01-01

    Aims KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of-function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of IKs current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype. Methods and results An 11-year old competitive athlete presented with mild bradycardia and a QTc interval of 470 ms. An LQT2 phenotype, consisting of low-voltage bifid T waves, was evident in the right precordial electrocardiogram leads. During the tachycardia phase following adenosine, QTc increased to 620 ms. Genetic analysis revealed a rare heterozygous polymorphism in KCNE1 predicting the substitution of asparagine for aspartic acid at position 85 of minK (D85N). Patch clamp experiments showed that KCNE1-D85N, when co-expressed with KCNH2 in TSA201 cells, significantly reduced IKr. Homozygous co-expression of the mutant with KCNH2 reduced IKr tail current by 85%, whereas heterozygous co-expression reduced the current by 52%, demonstrating for the first time a dominant-negative effect of D85N to reduce IKr. Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in IKs. Conclusions Our results suggest that a rare polymorphism KCNE1-D85N underlies the development of an LQT2 phenotype in this young athlete by interacting with KCNH2 to cause a dominant-negative effect to reduce IKr. Our data provide further evidence in support of the promiscuity of potassium channel β subunits in modulating the function of multiple potassium channels leading to a diversity of clinical phenotypes. PMID:21712262

  14. The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors.

    PubMed

    Ota, Satoshi; Tonou-Fujimori, Noriko; Yamasu, Kyo

    2009-01-01

    The roles of the FGF family growth factors and their receptors (FGFRs) in zebrafish embryos were examined using variously modified versions of the four FGFR genes (fgfr1-4). Constitutively active forms of all of the examined FGFRs (ca-FGFRs) caused dorsalization, brain caudalization, and secondary axis formation, indicating that the main FGF signal transduction downstream of the receptor is highly similar among FGFRs. All of the membrane-bound type of dominant-negative FGFRs (mdn-FGFRs) derived from the four fgfr genes, which interfere with endogenous FGFRs, produced posterior truncation, as previously reported in both Xenopus and zebrafish. mdn-FGFR3c had the strongest effects on embryos, progressively disrupting the posterior structure as the dose increased. At the highest dose, only the forebrain was formed. At lower doses, mdn-FGFR3c mainly suppressed the paraxial mesoderm. The co-injection of mRNA for different mdn-FGFRs and FGFs resulted in diverse suppression spectra of the respective FGFRs against FGFs. Only mdn-FGFR3c severely suppressed all of the FGFs examined. We also examined the effects of the secretory type of dominant-negative FGFRs (sdn-FGFRs), which are released from cells and trap FGF ligands. Only sdn-FGFR3c resulted in the characteristic effect of selectively disrupting the isthmic development, as well as the tailbud. The co-injection of the mRNA for sdn-FGFRs and FGFs suggested that sdn-FGFR3c inhibits FGFs of the FGF8 subfamily, which is consistent with its specific effects on development. We discuss the implications of our findings obtained in the present study.

  15. Caveolin-1 mutants P132L and Y14F are dominant negative regulators of invasion, migration and aggregation in H1299 lung cancer cells.

    PubMed

    Shatz, Maria; Lustig, Gila; Reich, Reuven; Liscovitch, Mordechai

    2010-06-10

    Caveolin-1 is an essential protein constituent of caveolae. Accumulating evidence indicates that caveolin-1 may act as a positive regulator of cancer progression. In this study, we investigated the function of caveolin-1 in human lung cancer cells. Caveolin-1 knockdown inhibited cell proliferation and reduced focal adhesion kinase (Fak) phosphorylation. Matrix invasion and cell migration as well as expression and activity of matrix metalloproteases were attenuated following caveolin-1 RNAi-mediated knockdown or overexpression of Y14F and P132L mutants, demonstrating dominant-negative activity of these mutants. Time-lapse fluorescence microscopy revealed that caveolin-1 and its mutants P132L and Y14F are localized to the trailing edge of migrating cells during both random and directed cell movement, implying an active role of caveolin-1 in the migration process. Suppression of caveolin-1 function greatly elevated the percentage of H1299 cells exhibiting focal adhesions. In addition, cell aggregation was increased by wild type caveolin-1 and attenuated by both P132L and Y14F mutants. Overexpression of wild type caveolin-1 increased caveolae density, however, P132L and Y14F mutants did not affect caveolae formation, suggesting that in this respect that the mutants do not act in a dominant negative manner, and that effects of caveolin-1 on caveolae and cell invasion, migration, focal adhesion and aggregation, are separable. Our data provide novel mechanistic insights into the role of caveolin-1 in cell motility, invasiveness and aggregation, therefore, expanding our understanding of the tumor-promoting activities of caveolin-1 in advanced-stage cancer.

  16. [Thyroid cancer].

    PubMed

    Nagayama, Yuji

    2012-03-01

    The thyroid glands are a vulnerable organ to ionizing radiation. Indeed the epidemiological studies have revealed an increase in the incidences of thyroid cancer among atomic bomb survivors in Hiroshima and Nagasaki and radiation casualties in Chernobyl. The carcinogenic risk for the thyroids is dependent on radiation dose, and higher in younger people. Recent advances in molecular biology contribute to clarify the mechanisms for thyroid carcinogenesis at genetic and molecular levels. Here radiation-induced thyroid carcinogenesis is reviewed from epidemiological data to basic research.

  17. What Is Thyroid Cancer?

    MedlinePlus

    ... Treatment? Thyroid Cancer About Thyroid Cancer What Is Thyroid Cancer? Cancer starts when cells in the body begin ... cell) Medullary Anaplastic (an aggressive undifferentiated tumor) Differentiated thyroid cancers Most thyroid cancers are differentiated cancers. The cells ...

  18. Thyroid Disorders (For Kids)

    MedlinePlus

    ... Emergency Room? What Happens in the Operating Room? Thyroid Disorders KidsHealth > For Kids > Thyroid Disorders A A ... the world is a thyroid? What Is the Thyroid? The thyroid (say: THYE-royd) is a gland, ...

  19. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype–phenotype correlations, codon bias and dominant-negative effects

    PubMed Central

    Hannan, Fadil M.; Howles, Sarah A.; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M.; Babinsky, Valerie N.; Reed, Anita A.; Thakker, Clare E.; Bockenhauer, Detlef; Brown, Rosalind S.; Connell, John M.; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J.; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J.; McKnight, John A.; Morrison, Patrick J.; Mughal, M. Zulf; O'Halloran, Domhnall; Pearce, Simon H.; Porteous, Mary E.; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; van't Hoff, William G.; Wang, Timothy; Whyte, Michael P.; Nesbit, M. Andrew; Thakker, Rajesh V.

    2015-01-01

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. PMID:26082470

  20. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

    PubMed

    Hannan, Fadil M; Howles, Sarah A; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M; Babinsky, Valerie N; Reed, Anita A; Thakker, Clare E; Bockenhauer, Detlef; Brown, Rosalind S; Connell, John M; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J; McKnight, John A; Morrison, Patrick J; Mughal, M Zulf; O'Halloran, Domhnall; Pearce, Simon H; Porteous, Mary E; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; Van't Hoff, William G; Wang, Timothy; Whyte, Michael P; Nesbit, M Andrew; Thakker, Rajesh V

    2015-09-15

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. © The Author 2015. Published by Oxford University Press.

  1. A dominant negative form of inositol 1,4,5-trisphosphate receptor induces metacyclogenesis and increases mitochondrial density in Trypanosoma cruzi

    SciTech Connect

    Hashimoto, Muneaki; Nara, Takeshi; Enomoto, Masahiro; Kurebayashi, Nagomi; Yoshida, Mitsutaka; Sakurai, Takashi; Mita, Toshihiro; Mikoshiba, Katsuhiko

    2015-10-23

    Inositol 1,4,5-trisphosphate receptor (IP{sub 3}R) is a key regulator of intracellular Ca{sup 2+} concentration that release Ca{sup 2+} from Ca{sup 2+} stores in response to various external stimuli. IP{sub 3}R also works as a signal hub which form a platform for interacting with various proteins involved in diverse cell signaling. Previously, we have identified an IP{sub 3}R homolog in the parasitic protist, Trypanosoma cruzi (TcIP{sub 3}R). Parasites expressing reduced or increased levels of TcIP{sub 3}R displayed defects in growth, transformation, and infectivity. In the present study, we established parasitic strains expressing a dominant negative form of TcIP{sub 3}R, named DN-TcIP{sub 3}R, to further investigate the physiological role(s) of TcIP{sub 3}R. We found that the growth of epimastigotes expressing DN-TcIP{sub 3}R was significantly slower than that of parasites with TcIP{sub 3}R expression levels that were approximately 65% of wild-type levels. The expression of DN-TcIP{sub 3}R in epimastigotes induced metacyclogenesis even in the normal growth medium. Furthermore, these epimastigotes showed the presence of dense mitochondria under a transmission electron microscope. Our findings confirm that TcIP{sub 3}R is crucial for epimastigote growth, as previously reported. They also suggest that a strong inhibition of the IP{sub 3}R-mediated signaling induces metacyclogenesis and that mitochondrial integrity is closely associated with this signaling. - Highlights: • We established T. cruzi strains expressing a dominant negative form of the TcIP{sub 3}R. • DN-TcIP{sub 3}R expression inhibits epimastigote growth and induces metacyclogenesis. • Microscopic analysis indicated TcIP{sub 3}R role in maintaining mitochondrial integrity. • Growth, but not microbial density, was altered by mammalian IP{sub 3}R inhibitor (2-APB).

  2. Human Colon Tumors Express a Dominant-negative Form of SIGIRR That Promotes Inflammation and Colitis-associated Colon Cancer in Mice

    PubMed Central

    Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet Fatih; Zepp, Jarod A.; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L.; Kalady, Matthew F.; Markowitz, Sanford D.; Li, Xiaoxia

    2016-01-01

    Background & Aims Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. Methods We performed RNA sequence analyses of pairs of colon tumor and non-tumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRRN86/102S, which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. Results RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRRΔE8, in colorectal cancer tissues compared to paired non-tumor tissues. SIGIRRΔE8 is not modified by complex glycans and is therefore retained in the cytoplasm—it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRRΔE8 interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in non-tumor tissues it was found at the cell membrane. Mice that expressed SIGIRRN86/102S developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant

  3. [Inhibition Function of Dominant-negative Mutant Gene Survivin-D53A to SPC-A1 Lung Adenocarcinoma Xenograft in Nude Mice Models].

    PubMed

    Yu, Min; Peng, Xingchen; Lu, You; Huang, Meijuan

    2015-06-01

    Survivin-D53A (SVV-D53A) is a dominant-negative mutant survivin, which represents a potential promising target for cancer gene therapy. The present study was designed to determine whether SVV-D53A plasmid encapsuled by DOTAP: Chol liposome would have the anti-tumor activity against SPC-A1 lung adenocarcinoma, and to detect the possible mechanisms. In our experiment, SPC-A1 cells were transfected in vitro with SVV-D53A plasmid and examined for protein expression by Western blot, then flow cytometric analysis was used to detect apoptosis. SPC-A1 lung adenocarcinoma xenografts were established in vivo in the nude mice, which received the i. v. administrations of SVV-D53A plasmid/liposome complexes. After mice were sacrificed, the paraffin-embedded tumor tissue sections were used for proliferating cell nuclear antigen (PCNA) expression and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Compared with the control group, the mice treated with SVV-D53A plasmid had an obviously reduced tumor volume, with high level of apoptosis and decreased cell proliferation in tumor tissue. The research results proved that the administration of SVV-D53A plasmid resulted in significant inhibition of SPC-A1 cells both in vitro and in vivo. The functional mechanism is that the anti-tumor response causes and induces tumor cell apoptosis.

  4. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease.

    PubMed

    Harms, Ashley S; Barnum, Christopher J; Ruhn, Kelly A; Varghese, Steve; Treviño, Isaac; Blesch, Armin; Tansey, Malú G

    2011-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD.

  5. Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease

    PubMed Central

    Harms, Ashley S; Barnum, Christopher J; Ruhn, Kelly A; Varghese, Steve; Treviño, Isaac; Blesch, Armin; Tansey, Malú G

    2011-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD. PMID:20959812

  6. Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant

    PubMed Central

    Shimizu, Y; Kinoshita, I; Kikuchi, J; Yamazaki, K; Nishimura, M; Birrer, M J; Dosaka-Akita, H

    2008-01-01

    cJun, a major constituent of AP-1 transcription factor transducing multiple mitogen growth signals, is frequently overexpressed in non-small cell lung cancers (NSCLCs). The purpose of this study is to determine the effects of AP-1 blockade on the growth of NSCLC cells using a cJun dominant-negative mutant, TAM67. Transiently transfected TAM67 inhibited AP-1 transcriptional activity in NSCLC cell lines, NCI-H1299 (H1299), A549 and NCI-H520 (H520). The colony-forming efficiency of H1299 and A549 was reduced by TAM67, while that of H520 was not. To elucidate the effects of TAM67 on the growth of H1299, we established H1299 clone cells that expressed TAM67 under the control of a doxycycline-inducible promoter. In the H1299 clone cells, the induced TAM67 inhibited anchorage-dependent growth by promoting G1 cell-cycle block, but not by apoptosis. The induced TAM67 decreased the expression of a cell-cycle regulatory protein, cyclin A. TAM67 also inhibited anchorage-independent growth of these cells. Furthermore, TAM67 reduced growth of established xenograft tumours from these cells in nude mice. These results suggest that AP-1 plays an essential role in the growth of at least some of NSCLC cells. PMID:18283312

  7. A Dominant Negative Mutant of Cyclin-Dependent Kinase A Reduces Endoreduplication but Not Cell Size or Gene Expression in Maize Endosperm

    PubMed Central

    Leiva-Neto, João T.; Grafi, Gideon; Sabelli, Paolo A.; Dante, Ricardo A.; Woo, Young-min; Maddock, Sheila; Gordon-Kamm, William J.; Larkins, Brian A.

    2004-01-01

    Cells in maize (Zea mays) endosperm undergo multiple cycles of endoreduplication, with some attaining DNA contents as high as 96C and 192C. Genome amplification begins around 10 d after pollination, coincident with cell enlargement and the onset of starch and storage protein accumulation. Although the role of endoreduplication is unclear, it is thought to provide a mechanism that increases cell size and enhances gene expression. To investigate this process, we reduced endoreduplication in transgenic maize endosperm by ectopically expressing a gene encoding a dominant negative mutant form of cyclin-dependent kinase A. This gene was regulated by the 27-kD γ-zein promoter, which restricted synthesis of the defective enzyme to the endoreduplication rather than the mitotic phase of endosperm development. Overexpression of a wild-type cyclin-dependent kinase A increased enzyme activity but had no effect on endoreduplication. By contrast, ectopic expression of the defective enzyme lowered kinase activity and reduced by half the mean C-value and total DNA content of endosperm nuclei. The lower level of endoreduplication did not affect cell size and only slightly reduced starch and storage protein accumulation. There was little difference in the level of endosperm gene expression with high and low levels of endoreduplication, suggesting that this process may not enhance transcription of genes associated with starch and storage protein synthesis. PMID:15208390

  8. Rapid screening for dominant negative mutations in the beet necrotic yellow vein virus triple gene block proteins P13 and P15 using a viral replicon.

    PubMed

    Lauber, E; Janssens, L; Weyens, G; Jonard, G; Richards, K E; Lefèbvre, M; Guilley, H

    2001-08-01

    Point mutations were introduced into the genes encoding the triple gene bock movement proteins P13 and P15 of beet necrotic yellow vein virus (BNYVV). Mutations which disabled viral cell-to-cell movement in Chenopodium quinoa were then tested for their ability to act as dominant negative inhibiters of movement of wild-type BNYVV when expressed from a co-inoculated BNYVV RNA 3-based replicon. For P13, three types of mutation inhibited the movement function: non-synomynous mutations in the N- and C-terminal hydrophobic domains, a mutation at the boundary between the N-terminal hydrophobic domain and the central hydrophilic domain (mutant P13-A12), and mutations in the conserved sequence motif in the central hydrophilic domain. However, only the 'boundary' mutant P13-A12 strongly inhibited movement of wild-type virus when expressed from the co-inoculated replicon. Similar experiments with P15 detected four movement-defective mutants which strongly inhibited cell-to-cell movement of wild-type BNYVV when the mutants were expressed from a co-inoculated replicon. Beta vulgaris transformed with two of these P15 mutants were highly resistant to fungus-mediated infection with BNYVV.

  9. The effect of DN (dominant-negative) Ku70 and reoxygenation on hypoxia cell-kill: evidence of hypoxia-induced potentially lethal damage.

    PubMed

    Urano, Muneyasu; Li, Gloria C; He, Fuqiu; Minami, Akiko; Burgman, Paul; Ling, C Clifton

    2012-07-01

    To study the effect of DN (dominant-negative) Ku70 and reoxygenation on the hypoxia-induced cell-kill. Cell lines were human colorectal carcinoma HCT8 and HT29 cells and their respective derivatives, v-HCT8 and v-HT29 infected with DNKu70-containing adenovirus. Cells were plated in glass tubes and made hypoxic by flushing N(2) gas containing 0, 0.1 or 0.5% O(2). Cell survival was determined by colony formation assay immediately after 0-96 h hypoxia. To reoxygenate medium were replaced fresh following 48 or 72 h in hypoxia and cells were incubated in aerobic environment for 2-24 h before survival assay. When incubated in hypoxia, cells lost reproductive capability ∼ exponentially as a function of time in hypoxia, and depending on the O(2) concentration. DNKu70 rendered cells more prone to hypoxia-induced cell-kill. Following reoxygenation cell survival increased rapidly but without detectable cell proliferation during first 24 hours. This evinced hypoxia-induced potentially lethal damage (PLD) that was repairable upon reoxygenation. DNKu70 did not significantly inhibit this repair. Hypoxia-induced cell lethality was facilitated by DNKu70, but substantially repaired upon reoxygenation. This may have negative impact on the effect of reoxygenation in cancer therapy.

  10. Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.

    PubMed

    Tristán-Clavijo, Enriqueta; Scholl, Francisco G; Macaya, Alfons; Iglesias, Gemma; Rojas, Ana M; Lucas, Miguel; Castellano, Antonio; Martinez-Mir, Amalia

    2016-11-01

    Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients. A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function. Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation. Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  11. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase

    PubMed Central

    Townsley, Fiona M.; Aristarkhov, Alexander; Beck, Sharon; Hershko, Avram; Ruderman, Joan V.

    1997-01-01

    Destruction of mitotic cyclins by ubiquitin-dependent proteolysis is required for cells to complete mitosis and enter interphase of the next cell cycle. In clam eggs, this process is catalyzed by a cyclin-selective ubiquitin carrier protein, E2-C, and the cyclosome/anaphase promoting complex (APC), a 20S particle containing cyclin-selective ubiquitin ligase activity. Here we report cloning a human homolog of E2-C, UbcH10, which shares 61% amino acid identity with clam E2-C and can substitute for clam E2-C in vitro. Dominant-negative clam E2-C and human UbcH10 proteins, created by altering the catalytic cysteine to serine, inhibit the in vitro ubiquitination and destruction of cyclin B in clam oocyte extracts. When transfected into mammalian cells, mutant UbcH10 inhibits the destruction of both cyclin A and B, arrests cells in M phase, and inhibits the onset of anaphase, presumably by blocking the ubiquitin-dependent proteolysis of proteins responsible for sister chromatid separation. Thus, E2-C/UbcH10-mediated ubiquitination is involved in both cdc2 inactivation and sister chromatid separation, processes that are normally coordinated during exit from mitosis. PMID:9122200

  12. Dominant negative RPW8.2 fusion proteins reveal the importance of haustorium-oriented protein trafficking for resistance against powdery mildew in Arabidopsis.

    PubMed

    Zhang, Qiong; Berkey, Robert; Pan, Zhiyong; Wang, Wenming; Zhang, Yi; Ma, Xianfeng; King, Harlan; Xiao, Shunyuan

    2015-01-01

    Powdery mildew fungi form feeding structures called haustoria inside epidermal cells of host plants to extract photosynthates for their epiphytic growth and reproduction. The haustorium is encased by an interfacial membrane termed the extrahaustorial membrane (EHM). The atypical resistance protein RPW8.2 from Arabidopsis is specifically targeted to the EHM where RPW8.2 activates haustorium-targeted (thus broad-spectrum) resistance against powdery mildew fungi. EHM-specific localization of RPW8.2 suggests the existence of an EHM-oriented protein/membrane trafficking pathway during EHM biogenesis. However, the importance of this specific trafficking pathway for host defense has not been evaluated via a genetic approach without affecting other trafficking pathways. Here, we report that expression of EHM-oriented, nonfunctional RPW8.2 chimeric proteins exerts dominant negative effect over functional RPW8.2 and potentially over other EHM-localized defense proteins, thereby compromising both RPW8.2-mediated and basal resistance to powdery mildew. Thus, our results highlight the importance of the EHM-oriented protein/membrane trafficking pathway for host resistance against haustorium-forming pathogens such as powdery mildew fungi.

  13. Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization.

    PubMed

    Ratisoontorn, Chootima; Fan, Gao-Feng; McEntee, Kerry; Nah, Hyun-Duck

    2003-01-01

    Various activating mutations of FgfR2 have been linked to a number of craniosynostosis syndromes, suggesting that FGFR2-mediated signaling plays significant roles in intramembranous bone formation. To define (i) the roles of FGFR2-mediated signaling in osteogenesis and (ii) bone cell functions affected by abnormal signaling induced by craniosynostosis mutations, chicken calvarial osteoblasts were infected with replication competent avian sarcoma viruses expressing FgfR2 with dominant negative (DN), P253R (Apert), or C278F (Pfeiffer and Crouzon) mutation. Analyses of the infected osteoblasts revealed that attenuated FGF/FGFR signaling by DN-FgfR2 resulted in a decrease in cell proliferation and accelerated mineralization. In contrast, the C278F mutation, which causes ligand-independent activation of the receptor, significantly stimulated cell proliferation and inhibited mineralization. Interestingly, the P253R mutation, which does not cause ligand-independent activation of the receptor, showed a weaker mitogenic effect than the C278F mutation and did not inhibit mineralization. Gene expression analysis also revealed diverse effects of C278F and P253R mutations on expression of several osteogenic genes. Based on these results, we conclude that one of the major functions of FGFR2 is to mediate mitogenic signals in osteoblasts and that distinctively different cellular mechanisms underlie the pathogenesis of craniosynostosis phenotypes resulting from P253R and C278F mutations of the FGFR2 gene.

  14. A divalent ion is crucial in the structure and dominant-negative function of ID proteins, a class of helix-loop-helix transcription regulators.

    PubMed

    Wong, Marie Vivian; Jiang, Sizun; Palasingam, Paaventhan; Kolatkar, Prasanna R

    2012-01-01

    Inhibitors of DNA binding and differentiation (ID) proteins, a dominant-negative group of helix-loop-helix (HLH) transcription regulators, are well-characterized key players in cellular fate determination during development in mammals as well as Drosophila. Although not oncogenes themselves, their upregulation by various oncogenic proteins (such as Ras, Myc) and their inhibitory effects on cell cycle proteins (such as pRb) hint at their possible roles in tumorigenesis. Furthermore, their potency as inhibitors of cellular differentiation, through their heterodimerization with subsequent inactivation of the ubiquitous E proteins, suggest possible novel roles in engineering induced pluripotent stem cells (iPSCs). We present the high-resolution 2.1Å crystal structure of ID2 (HLH domain), coupled with novel biochemical insights in the presence of a divalent ion, possibly calcium (Ca2+), in the loop of ID proteins, which appear to be crucial for the structure and activity of ID proteins. These new insights will pave the way for new rational drug designs, in addition to current synthetic peptide options, against this potent player in tumorigenesis as well as more efficient ways for stem cells reprogramming.

  15. Dominant negative RPW8.2 fusion proteins reveal the importance of haustorium-oriented protein trafficking for resistance against powdery mildew in Arabidopsis

    PubMed Central

    Zhang, Qiong; Berkey, Robert; Pan, Zhiyong; Wang, Wenming; Zhang, Yi; Ma, Xianfeng; King, Harlan; Xiao, Shunyuan

    2015-01-01

    Powdery mildew fungi form feeding structures called haustoria inside epidermal cells of host plants to extract photosynthates for their epiphytic growth and reproduction. The haustorium is encased by an interfacial membrane termed the extrahaustorial membrane (EHM). The atypical resistance protein RPW8.2 from Arabidopsis is specifically targeted to the EHM where RPW8.2 activates haustorium-targeted (thus broad-spectrum) resistance against powdery mildew fungi. EHM-specific localization of RPW8.2 suggests the existence of an EHM-oriented protein/membrane trafficking pathway during EHM biogenesis. However, the importance of this specific trafficking pathway for host defense has not been evaluated via a genetic approach without affecting other trafficking pathways. Here, we report that expression of EHM-oriented, nonfunctional RPW8.2 chimeric proteins exerts dominant negative effect over functional RPW8.2 and potentially over other EHM-localized defense proteins, thereby compromising both RPW8.2-mediated and basal resistance to powdery mildew. Thus, our results highlight the importance of the EHM-oriented protein/membrane trafficking pathway for host resistance against haustorium-forming pathogens such as powdery mildew fungi. PMID:25830634

  16. A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse.

    PubMed

    Schwieger, Maike; Löhler, Jürgen; Fischer, Meike; Herwig, Uwe; Tenen, Daniel G; Stocking, Carol

    2004-04-01

    The CCAAT/enhancer binding protein alpha (C/EBPalpha) is an essential transcription factor for granulocytic differentiation. C/EBPalpha mutations are found in approximately 8% of acute myeloid leukemia (AML) patients. Most of these mutations occur in the N-terminal coding region, resulting in a frame shift and the enhanced translation of a dominant-negative 30-kDa protein, which may be responsible for the differentiation block observed in AML. To test this hypothesis, we introduced a cDNA encoding an N-terminal mutated C/EBPalpha (mut10) into primary hematopoietic progenitors using a retroviral vector. Expression of mut10 in human CD34+ cord blood cells dramatically inhibited differentiation of both myeloid and erythroid lineages. Immunohistochemical analysis demonstrated coexpression of both myeloid and erythroid markers in the immature transformed cells. Surprisingly, mut10 did not block myelocytic differentiation in murine progenitors but did alter their differentiation kinetics and clonogenicity. Experiments were performed to confirm that the differential effect of mut10 on murine and human progenitors was not due to species-specific differences in C/EBPalpha protein sequences, expression levels, or inefficient targeting of relevant cells. Taken together, our results underline the intrinsic differences between hematopoietic controls in mouse and human and support the hypothesis that mutations in CEBPA are critical events in the disruption of myeloid differentiation in AMLs.

  17. Expression of beta 1B integrin isoform in CHO cells results in a dominant negative effect on cell adhesion and motility.

    PubMed

    Balzac, F; Retta, S F; Albini, A; Melchiorri, A; Koteliansky, V E; Geuna, M; Silengo, L; Tarone, G

    1994-10-01

    The integrin subunit beta 1B, a beta 1 isoform with a unique sequence at the cytoplasmic domain, forms heterodimers with integrin alpha chains and binds fibronectin, but it does not localize to focal adhesion sites (Balzac, F., A. Belkin, V. Koteliansky, Y. Balabanow, F. Altruda, L. Silengo, and G. Tarone. 1993. J. Cell Biol. 121:171-178). Here we analyze the functional properties of human beta 1B by expressing it in hamster CHO cells. When stimulated by specific antibodies, beta 1B does not trigger tyrosine phosphorylation of a 125-kD cytosolic protein, an intracellular signalling pathway that is activated both by the endogenous hamster or the transfected human beta 1A. Moreover, expression of beta 1B results in reduced spreading on fibronectin and laminin, but not on vitronectin. Expression of beta 1B also results in severe reduction of cell motility in the Boyden chamber assay. Reduced cell spreading and motility could not be accounted for by preferential association of beta 1B with a given integrin alpha subunit. These data, together with our previous results, indicate that beta 1B interferes with beta 1A function when expressed in CHO cells resulting in a dominant negative effect on cell adhesion and migration.

  18. An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.

    PubMed

    Bongfen, Silayuv E; Rodrigue-Gervais, Ian-Gael; Berghout, Joanne; Torre, Sabrina; Cingolani, Pablo; Wiltshire, Sean A; Leiva-Torres, Gabriel A; Letourneau, Louis; Sladek, Robert; Blanchette, Mathieu; Lathrop, Mark; Behr, Marcel A; Gruenheid, Samantha; Vidal, Silvia M; Saleh, Maya; Gros, Philippe

    2012-01-01

    Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.

  19. A dominant negative mutant of cyclin-dependent kinase A reduces endoreduplication but not cell size or gene expression in maize endosperm.

    PubMed

    Leiva-Neto, João T; Grafi, Gideon; Sabelli, Paolo A; Dante, Ricardo A; Woo, Young-min; Maddock, Sheila; Gordon-Kamm, William J; Larkins, Brian A

    2004-07-01

    Cells in maize (Zea mays) endosperm undergo multiple cycles of endoreduplication, with some attaining DNA contents as high as 96C and 192C. Genome amplification begins around 10 d after pollination, coincident with cell enlargement and the onset of starch and storage protein accumulation. Although the role of endoreduplication is unclear, it is thought to provide a mechanism that increases cell size and enhances gene expression. To investigate this process, we reduced endoreduplication in transgenic maize endosperm by ectopically expressing a gene encoding a dominant negative mutant form of cyclin-dependent kinase A. This gene was regulated by the 27-kD gamma-zein promoter, which restricted synthesis of the defective enzyme to the endoreduplication rather than the mitotic phase of endosperm development. Overexpression of a wild-type cyclin-dependent kinase A increased enzyme activity but had no effect on endoreduplication. By contrast, ectopic expression of the defective enzyme lowered kinase activity and reduced by half the mean C-value and total DNA content of endosperm nuclei. The lower level of endoreduplication did not affect cell size and only slightly reduced starch and storage protein accumulation. There was little difference in the level of endosperm gene expression with high and low levels of endoreduplication, suggesting that this process may not enhance transcription of genes associated with starch and storage protein synthesis.

  20. Expression of beta 1B integrin isoform in CHO cells results in a dominant negative effect on cell adhesion and motility

    PubMed Central

    1994-01-01

    The integrin subunit beta 1B, a beta 1 isoform with a unique sequence at the cytoplasmic domain, forms heterodimers with integrin alpha chains and binds fibronectin, but it does not localize to focal adhesion sites (Balzac, F., A. Belkin, V. Koteliansky, Y. Balabanow, F. Altruda, L. Silengo, and G. Tarone. 1993. J. Cell Biol. 121:171-178). Here we analyze the functional properties of human beta 1B by expressing it in hamster CHO cells. When stimulated by specific antibodies, beta 1B does not trigger tyrosine phosphorylation of a 125- kD cytosolic protein, an intracellular signalling pathway that is activated both by the endogenous hamster or the transfected human beta 1A. Moreover, expression of beta 1B results in reduced spreading on fibronectin and laminin, but not on vitronectin. Expression of beta 1B also results in severe reduction of cell motility in the Boyden chamber assay. Reduced cell spreading and motility could not be accounted for by preferential association of beta 1B with a given integrin alpha subunit. These data, together with our previous results, indicate that beta 1B interferes with beta 1A function when expressed in CHO cells resulting in a dominant negative effect on cell adhesion and migration. PMID:7523423

  1. Altering the GTP binding site of the DNA/RNA-binding protein, Translin/TB-RBP, decreases RNA binding and may create a dominant negative phenotype.

    PubMed

    Chennathukuzhi, V M; Kurihara, Y; Bray, J D; Yang, J; Hecht, N B

    2001-11-01

    The DNA/RNA-binding protein, Translin/Testis Brain RNA-binding protein (Translin/TB-RBP), contains a putative GTP binding site in its C-terminus which is highly conserved. To determine if guanine nucleotide binding to this site functionally alters nucleic acid binding, electrophoretic mobility shift assays were performed with RNA and DNA binding probes. GTP, but not GDP, reduces RNA binding by approximately 50% and the poorly hydrolyzed GTP analog, GTPgammaS, reduces binding by >90% in gel shift and immunoprecipitation assays. No similar reduction of DNA binding is seen. When the putative GTP binding site of TB-RBP, amino acid sequence VTAGD, is altered to VTNSD by site directed mutagenesis, GTP will no longer bind to TB-RBP(GTP) and TB-RBP(GTP) no longer binds to RNA, although DNA binding is not affected. Yeast two-hybrid assays reveal that like wild-type TB-RBP, TB-RBP(GTP) will interact with itself, with wild-type TB-RBP and with Translin associated factor X (Trax). Transfection of TB-RBP(GTP) into NIH 3T3 cells leads to a marked increase in cell death suggesting a dominant negative function for TB-RBP(GTP) in cells. These data suggest TB-RBP is an RNA-binding protein whose activity is allosterically controlled by nucleotide binding.

  2. Tumour selection advantage of non‐dominant negative P53 mutations in homozygotic MDM2‐SNP309 colorectal cancer cells

    PubMed Central

    Alazzouzi, Hafid; Suriano, Gianpaolo; Guerra, Angel; Plaja, Alberto; Espín, Eloi; Armengol, Manel; Alhopuro, Pia; Velho, Sergia; Shinomura, Yasuhisa; González‐Aguilera, Juan José; Yamamoto, Hiroyuki; Aaltonen, Lauri A; Moreno, Víctor; Capellà, Gabriel; Peinado, Miguel Angel; Seruca, Raquel; Arango, Diego

    2007-01-01

    Background Mdm2 is a natural inhibitor of p53 function and its overexpression impairs p53 transcriptional activity. T→G single‐nucleotide polymorphism at position 309 (SNP309) of mdm2 induces overexpression of mdm2, but inhibits p53. Objectives To determine whether SNP309 is a risk‐modifier polymorphism in colorectal cancer (CRC) and whether tumour selection of P53 mutations are influenced by SNP309. Methods Single‐stranded conformation polymorphism and automatic sequencing were performed. Results SNP309 is not associated with the risk of CRC or recurrence of tumours. These data do not over‐ride the tumour‐selection capabilities of P53 mutations in CRC. However, a significant association with non‐dominant‐negative P53 mutations (p = 0.02) was found. Conclusions MDM2‐SNP309 favours tumour selection of non‐dominant negative P53 mutations in CRC, which also show an earlier age of tumour onset. PMID:16825434

  3. Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury.

    PubMed

    Terzi, F; Burtin, M; Hekmati, M; Federici, P; Grimber, G; Briand, P; Friedlander, G

    2000-07-01

    The role of EGF in the evolution of renal lesions after injury is still controversial. To determine whether the EGF expression is beneficial or detrimental, we generated transgenic mice expressing a COOH-terminal-truncated EGF-R under the control of the kidney-specific type 1 gamma-glutamyl transpeptidase promoter. As expected, the transgene was expressed exclusively at the basolateral membrane of proximal tubular cells. Under basal conditions, transgenic mice showed normal renal morphology and function. Infusion of EGF to transgenic animals revealed that the mutant receptor behaved in a dominant-negative manner and prevented EGF-signaled EGF-R autophosphorylation. We next evaluated the impact of transgene expression on the development of renal lesions in two models of renal injury. After 75% reduction of renal mass, tubular dilations were less severe in transgenic mice than in wild-type animals. After prolonged renal ischemia, tubular atrophy and interstitial fibrosis were reduced in transgenic mice as compared with wild-type mice. The beneficial effect of the transgene included a reduction of tubular cell proliferation, interstitial collagen accumulation, and mononuclear cell infiltration. In conclusion, functional inactivation of the EGF-R in renal proximal tubular cells reduced tubulo-interstitial lesions after renal injury. These data suggest that blocking the EGF pathway may be a therapeutic strategy to reduce the progression of chronic renal failure.

  4. Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22

    SciTech Connect

    Pagliuca, A.; Bartoli, P.C.; Saccone, S.

    1995-05-01

    Transcription factors containing a basic helix-loop-helix (bHLH) motif regulate the expression of tissue-specific genes in a number of mammalian and insect systems. DNA-binding activity of the bHLH proteins is dependent upon formation of homo- and/or heterodimers. Dominant negative HLH proteins (Id-related genes) also contain the HLH-dimerization domain but lack the DNA-binding basic domain. Consequently, Id proteins inhibit binding to DNA and transcriptional transactivation by heterodimerization with bHLH proteins. The authors report here the cDNA sequence of a novel human HLH gene (HGMW-approved symbol ID4) that lacks the basic domain. ID4 is differentially expressed in adult organs in four mRNA molecules, which are presumably a result of differential splicing and/or alternative usage of the polyadenylation sites. Transfection experiments indicated that enforced expression of Id-4H protein inhibits the trans-activation of the muscle creatine kinase E-box enhancer by MyoD. Finally, the authors localized the ID4 gene to the chromosome 6p21-p22 region. 18 refs., 4 figs.

  5. Thyroid Nodules

    MedlinePlus

    ... by your thyroid gland. The extra thyroxine can cause symptoms of hyperthyroidism such as: Unexplained weight loss Increased perspiration Tremor ... noncancerous and isn't considered serious unless it causes bothersome symptoms from its size. Some ... Thyroid cyst. Fluid-filled cavities (cysts) in the ...

  6. Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice.

    PubMed

    Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F; Zepp, Jarod A; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L; Kalady, Matthew F; Markowitz, Sanford D; Li, Xiaoxia

    2015-12-01

    Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. We performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed

  7. Progression of Mouse Skin Carcinogenesis Is Associated with Increased Erα Levels and Is Repressed by a Dominant Negative Form of Erα

    PubMed Central

    Michalopoulos, Ioannis; Sideridou, Maria; Tsimaratou, Katerina; Christodoulou, Ioannis; Pyrillou, Katerina; Gorgoulis, Vassilis; Vlahopoulos, Spiros; Zoumpourlis, Vassilis

    2012-01-01

    Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα. PMID:22870269

  8. Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR.

    PubMed

    Nishiyama, Shoko; Slack, Olga A L; Lokugamage, Nandadeva; Hill, Terence E; Juelich, Terry L; Zhang, Lihong; Smith, Jennifer K; Perez, David; Gong, Bin; Freiberg, Alexander N; Ikegami, Tetsuro

    2016-11-16

    Rift Valley fever is a mosquito-borne zoonotic disease affecting ruminants and humans. Rift Valley fever virus (RVFV: family Bunyaviridae, genus Phlebovirus) causes abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or retinitis in humans. The live-attenuated MP-12 vaccine is conditionally licensed for veterinary use in the US. However, this vaccine lacks a marker for the differentiation of vaccinated from infected animals (DIVA). NSs gene is dispensable for RVFV replication, and thus, rMP-12 strains lacking NSs gene is applicable to monitor vaccinated animals. However, the immunogenicity of MP-12 lacking NSs was not as high as parental MP-12. Thus, chimeric MP-12 strains encoding NSs from either Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV) or Punta Toro virus Adames strain (PTA) were characterized previously. Although chimeric MP-12 strains are highly immunogenic, the attenuation through the S-segment remains unknown. Using pathogenic ZH501 strain, we aimed to demonstrate the attenuation of ZH501 strain through chimeric S-segment encoding either the NSs of TOSV, SFSV, PTA, or Punta Toro virus Balliet strain (PTB). In addition, we characterized rZH501 encoding a human dominant-negative PKR (PKRΔE7), which also enhances the immunogenicity of MP-12. Study done on mice revealed that attenuation of rZH501 occurred through the S-segment encoding either PKRΔE7 or SFSV NSs. However, rZH501 encoding either TOSV, PTA, or PTB NSs in the S-segment uniformly caused lethal encephalitis. Our results indicated that the S-segments encoding PKRΔE7 or SFSV NSs are attenuated and thus applicable toward next generation MP-12 vaccine candidates that encode a DIVA marker.

  9. A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency.

    PubMed

    Lasry, Inbal; Seo, Young Ah; Ityel, Hadas; Shalva, Nechama; Pode-Shakked, Ben; Glaser, Fabian; Berman, Bluma; Berezovsky, Igor; Goncearenco, Alexander; Klar, Aharon; Levy, Jacob; Anikster, Yair; Kelleher, Shannon L; Assaraf, Yehuda G

    2012-08-24

    Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation.

  10. Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population

    PubMed Central

    Wang, Pengyun; Yang, Qinbo; Wu, Xiaofen; Yang, Yanzong; Shi, Lisong; Wang, Chuchu; Wu, Gang; Xia, Yunlong; Yang, Bo; Zhang, Rongfeng; Xu, Chengqi; Cheng, Xiang; Li, Sisi; Zhao, Yuanyuan; Fu, Fenfen; Liao, Yuhua; Fang, Fang; Chen, Qiuyun; Tu, Xin; Wang, Qing K.

    2010-01-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinic, and accounts for more than 15% of strokes. Mutations in cardiac sodium channel α, β1 and β2 subunit genes (SCN5A, SCN1B, and SCN2B) have been identified in AF patients. We hypothesize that mutations in the sodium channel β3 subunit gene SCN3B are also associated with AF. To test this hypothesis, we carried out a large scale sequencing analysis of all coding exons and exon-intron boundaries of SCN3B in 477 AF patients (28.5% lone AF) from the GeneID Chinese Han population. A novel A130V mutation was identified in a 46 year-old patient with lone AF, and the mutation was absent in 500 controls. Mutation A130V dramatically decreased the cardiac sodium current density when expressed in HEK293/Nav1.5 stable cell line, but did not have significant effect on kinetics of activation, inactivation, and channel recovery from inactivation. When co-expressed with wild type SCN3B, the A130V mutant SCN3B negated the function of wild type SCN3B, suggesting that A130V acts by a dominant negative mechanism. Western blot analysis with biotinylated plasma membrane protein extracts revealed that A130V did not affect cell surface expression of Nav1.5 or SCN3B, suggesting that mutant A130V SCN3B may not inhibit sodium channel trafficking, instead may affect conduction of sodium ions due to its malfunction as an integral component of the channel complex. This study identifies the first AF-associated mutation in SCN3B, and suggests that mutations in SCN3B may be a new pathogenic cause of AF. PMID:20558140

  11. A spontaneous dominant-negative mutation within a 35S::AtMYB90 transgene inhibits flower pigment production in tobacco.

    PubMed

    Velten, Jeff; Cakir, Cahid; Cazzonelli, Christopher I

    2010-03-29

    In part due to the ease of visual detection of phenotypic changes, anthocyanin pigment production has long been the target of genetic and molecular research in plants. Specific members of the large family of plant myb transcription factors have been found to play critical roles in regulating expression of anthocyanin biosynthetic genes and these genes continue to serve as important tools in dissecting the molecular mechanisms of plant gene regulation. A spontaneous mutation within the coding region of an Arabidopsis 35S::AtMYB90 transgene converted the activator of plant-wide anthocyanin production to a dominant-negative allele (PG-1) that inhibits normal pigment production within tobacco petals. Sequence analysis identified a single base change that created a premature nonsense codon, truncating the encoded myb protein. The resulting mutant protein lacks 78 amino acids from the wild type C-terminus and was confirmed as the source of the white-flower phenotype. A putative tobacco homolog of AtMYB90 (NtAN2) was isolated and found to be expressed in flower petals but not leaves of all tobacco plants tested. Using transgenic tobacco constitutively expressing the NtAN2 gene confirmed the NtAN2 protein as the likely target of PG-1-based inhibition of tobacco pigment production. Messenger RNA and anthocyanin analysis of PG-1Sh transgenic lines (and PG-1Sh x purple 35S::NtAN2 seedlings) support a model in which the mutant myb transgene product acts as a competitive inhibitor of the native tobacco NtAN2 protein. This finding is important to researchers in the field of plant transcription factor analysis, representing a potential outcome for experiments analyzing in vivo protein function in test transgenic systems that over-express or mutate plant transcription factors.

  12. A Spontaneous Dominant-Negative Mutation within a 35S::AtMYB90 Transgene Inhibits Flower Pigment Production in Tobacco

    PubMed Central

    Velten, Jeff; Cakir, Cahid; Cazzonelli, Christopher I.

    2010-01-01

    Background In part due to the ease of visual detection of phenotypic changes, anthocyanin pigment production has long been the target of genetic and molecular research in plants. Specific members of the large family of plant myb transcription factors have been found to play critical roles in regulating expression of anthocyanin biosynthetic genes and these genes continue to serve as important tools in dissecting the molecular mechanisms of plant gene regulation. Findings A spontaneous mutation within the coding region of an Arabidopsis 35S::AtMYB90 transgene converted the activator of plant-wide anthocyanin production to a dominant-negative allele (PG-1) that inhibits normal pigment production within tobacco petals. Sequence analysis identified a single base change that created a premature nonsense codon, truncating the encoded myb protein. The resulting mutant protein lacks 78 amino acids from the wild type C-terminus and was confirmed as the source of the white-flower phenotype. A putative tobacco homolog of AtMYB90 (NtAN2) was isolated and found to be expressed in flower petals but not leaves of all tobacco plants tested. Using transgenic tobacco constitutively expressing the NtAN2 gene confirmed the NtAN2 protein as the likely target of PG-1-based inhibition of tobacco pigment production. Conclusions Messenger RNA and anthocyanin analysis of PG-1Sh transgenic lines (and PG-1Sh x purple 35S::NtAN2 seedlings) support a model in which the mutant myb transgene product acts as a competitive inhibitor of the native tobacco NtAN2 protein. This finding is important to researchers in the field of plant transcription factor analysis, representing a potential outcome for experiments analyzing in vivo protein function in test transgenic systems that over-express or mutate plant transcription factors. PMID:20360951

  13. Response to Multiple Radiation Doses of Human Colorectal Carcinoma Cells Infected with Recombinant Adenovirus Containing Dominant-Negative Ku70 Fragment

    PubMed Central

    Urano, Muneyasu; He, Fuqiu; Minami, Akiko; Ling, C. Clifton; Li, Gloria C.

    2010-01-01

    Purpose To investigate the effect of recombinant replication-defective adenovirus containing DN(dominant-negative)Ku70 fragment on the response of tumor cells to multiple small radiation doses. Ultimate goal is to demonstrate the feasibility of using this virus in gene-radiotherapy to enhance the radiation response of tumor cells. Materials and Methods Human colorectal HCT8 and HT29 carcinoma cells were plated in glass tubes, infected with virus (25 MOI) and irradiated with single doses or 0-5 doses of 3 Gy with 6 h intervals. Hypoxia was induced by flushing 100% N2. Cells were trypsinized 0 or 6 h after (final) irradiation, and cell survival determined by colony formation. Survival data were fitted to L-Q model or exponential line. Results Virus infection enhanced the radiation response of HCT8 and HT29 cells. Virus enhancement ratio (VER) for single dose irradiation at surviving fraction of 0.1 was ~1.3 for both oxic and hypoxic HCT8, and 1.4 and 1.1 for oxic and hypoxic HT29, respectively. Similar VER of 1.2–1.3 was observed for both oxic and hypoxic cells irradiated with multiple doses but these values were smaller than values found for DNKu70-transfected Rat-1 cells. This difference is discussed. The OERs for HCT8 and HT29 receiving fractionated doses were 1.2 and 2.0, respectively, and virus-infection slightly altered them. Conclusion Infection of recombinant replication-defective adenovirus containing DNKu70 fragment enhanced the response of human colorectal cancer cells to single and multiple doses. PMID:20510198

  14. A dominant-negative clathrin mutant differentially affects trafficking of molecules with distinct sorting motifs in the class II major histocompatibility complex (MHC) pathway.

    PubMed

    Liu, S H; Marks, M S; Brodsky, F M

    1998-03-09

    The role of clathrin in intracellular sorting was investigated by expression of a dominant-negative mutant form of clathrin, termed the hub fragment. Hub inhibition of clathrin-mediated membrane transport was established by demonstrating a block of transferrin internalization and an alteration in the intracellular distribution of the cation-independent mannose-6-phosphate receptor. Hubs had no effect on uptake of FITC-dextran, adaptor distribution, organelle integrity in the secretory pathway, or cell surface expression of constitutively secreted molecules. Hub expression blocked lysosomal delivery of chimeric molecules containing either the tyrosine-based sorting signal of H2M or the dileucine-based sorting signal of CD3gamma, confirming a role for clathrin-coated vesicles (CCVs) in recognizing these signals and sorting them to the endocytic pathway. Hub expression was then used to probe the role of CCVs in targeting native molecules bearing these sorting signals in the context of HLA-DM and the invariant chain (I chain) complexed to HLA-DR. The distribution of these molecules was differentially affected. Accumulation of hubs before expression of the DM dimer blocked DM export from the TGN, whereas hubs had no effect on direct targeting of the DR-I chain complex from the TGN to the endocytic pathway. However, concurrent expression of hubs, such that hubs were building to inhibitory concentrations during DM or DR-I chain expression, caused cell surface accumulation of both complexes. These observations suggest that both DM and DR-I chain are directly transported to the endocytic pathway from the TGN, DM in CCVs, and DR-I chain independent of CCVs. Subsequently, both complexes can appear at the cell surface from where they are both internalized by CCVs. Differential packaging in CCVs in the TGN, mediated by tyrosine- and dileucine-based sorting signals, could be a mechanism for functional segregation of DM from DR-I chain until their intended rendezvous in late

  15. Unique dominant negative mutation in the N-terminal mitochondrial targeting sequence of StAR, causing a variant form of congenital lipoid adrenal hyperplasia.

    PubMed

    Baquedano, María Sonia; Guercio, Gabriela; Marino, Roxana; Berensztein, Esperanza; Costanzo, Mariana; Bailez, Marcela; Vaiani, Elisa; Maceiras, Mercedes; Ramirez, Pablo; Chaler, Eduardo; Rivarola, Marco A; Belgorosky, Alicia

    2013-01-01

    Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency. Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism. We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization. A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.

  16. Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency: Evidence for an Allele-Specific Dominant Negative Effect and Responsiveness to Biotin Therapy

    PubMed Central

    Baumgartner, Matthias R.; Dantas, M. Fernanda; Suormala, Terttu; Almashanu, Shlomo; Giunta, Cecilia; Friebel, Dolores; Gebhardt, Boris; Fowler, Brian; Hoffmann, Georg F.; Baumgartner, E. Regula; Valle, David

    2004-01-01

    Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing α subunits and smaller β subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCCα protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA–wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo. PMID:15359379

  17. Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.

    PubMed

    Baumgartner, Matthias R; Dantas, M Fernanda; Suormala, Terttu; Almashanu, Shlomo; Giunta, Cecilia; Friebel, Dolores; Gebhardt, Boris; Fowler, Brian; Hoffmann, Georg F; Baumgartner, E Regula; Valle, David

    2004-11-01

    Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.

  18. Generation of the dominant-negative mutant of hArpNbeta: a component of human SWI/SNF chromatin remodeling complex.

    PubMed

    Choi, E Y; Park, J A; Sung, Y H; Kwon, H

    2001-11-15

    hArpNbeta, an actin-related protein located within the nucleus, is a subunit of the human SWI/SNF chromatin remodeling complex. hArpNbeta has been proposed to regulate the assembly and activity of the hSWI/SNF complex. Sequence comparisons of the potential ArpN homologs with beta-actin showed that the ArpNs have the divergent subdomains Ib and IIb in addition to the unique N-terminal short insert, MS(G/A)-(V/L)YGG. Since the proposed function of hArpNbeta requires more than two distinct but concurrently operating surfaces, we examined whether the disruption of one operating surface of hArpNbeta results in dominant-negative phenotype. When overexpressed in HeLa or 293T cells, the subdomain Ib or IIb hybrids, in which the subdomain Ib or IIb of hArpNbeta was replaced with that of beta-actin, respectively, showed no effect on cell survival. On the other hand, the overexpression of the N-terminal deletion mutant of hArpNbeta resulted in cell death probably through apoptotic process. These results indicate that the proper function of hArpNbeta is essential for cell survival in human cells. Furthermore, they suggests the possibility that the N-terminal short sequence is indispensable for the chromatin remodeling activity or the assembly of the hSWI/SNF complex after the binding of hArpNbeta with functionally essential partner proteins. Copyright 2001 Academic Press.

  19. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  20. A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

    PubMed Central

    Lasry, Inbal; Seo, Young Ah; Ityel, Hadas; Shalva, Nechama; Pode-Shakked, Ben; Glaser, Fabian; Berman, Bluma; Berezovsky, Igor; Goncearenco, Alexander; Klar, Aharon; Levy, Jacob; Anikster, Yair; Kelleher, Shannon L.; Assaraf, Yehuda G.

    2012-01-01

    Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation. PMID:22733820

  1. Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice.

    PubMed

    Yang, G-X; Sun, Y; Tsuneyama, K; Zhang, W; Leung, P S C; He, X-S; Ansari, A A; Bowlus, C; Ridgway, W M; Gershwin, M E

    2016-08-01

    During chronic inflammation, interleukin (IL)-22 expression is up-regulated in both CD4 and CD8 T cells, exerting a protective role in infections. However, in autoimmunity, IL-22 appears to have either a protective or a pathogenic role in a variety of murine models of autoimmunity and, by extrapolation, in humans. It is not clear whether IL-22 itself mediates inflammation or is a by-product of inflammation. We have taken advantage of the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice that develop both inflammatory bowel disease and autoimmune cholangitis and studied the role and the biological function of IL-22 by generating IL-22(-/-) dnTGF-βRII mice. Our data suggest that the influence of IL-22 on autoimmunity is determined in part by the local microenvironment. In particular, IL-22 deficiency exacerbates tissue injury in inflammatory bowel disease, but has no influence on either the hepatocytes or cholangiocytes in the same model. These data take on particular significance in the previously defined effects of IL-17A, IL-12p40 and IL-23p19 deficiency and emphasize that, in colitis, there is a dominant role of IL-23/T helper type 17 (Th17) signalling. Furthermore, the levels of IL-22 are IL-23-dependent. The use of cytokine therapy in patients with autoimmune disease has significant potential, but must take into account the overlapping and often promiscuous effects that can theoretically exacerbate inflammation. © 2016 British Society for Immunology.

  2. Thyroid Diseases Tests

    MedlinePlus

    ... of thyroiditis and identify autoimmune thyroid conditions Thyroid peroxidase (TPO) antibody—a marker for autoimmune thyroid disease; ... to help detect the presence of excessive calcitonin production, which can occur with C-cell hyperplasia and ...

  3. Anaplastic thyroid cancer

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000352.htm Anaplastic thyroid cancer To use the sharing features on this page, ... of cancer of the thyroid gland. Causes Anaplastic thyroid cancer is an invasive type of thyroid cancer that ...

  4. Pediatric Thyroid Cancer

    MedlinePlus

    ... Marketplace Find an ENT Doctor Near You Pediatric Thyroid Cancer Pediatric Thyroid Cancer Patient Health Information News media ... and neck issues, should be consulted. Types of thyroid cancer in children: Papillary : This form of thyroid cancer ...

  5. Thyroid cancer - medullary carcinoma

    MedlinePlus

    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC; Thyroid nodule - medullary ... in children and adults. Unlike other types of thyroid cancer, MTC is less likely to be caused by ...

  6. Thyroid gland removal - discharge

    MedlinePlus

    ... will make your scar show less. Thyroid Hormone Replacement You may need to take thyroid hormone medicine ... natural thyroid hormone. You may not need hormone replacement if only part of your thyroid was removed. ...

  7. Pregnancy and Thyroid Disease

    MedlinePlus

    ... in Some People Who Were Treated with hGH Pregnancy & Thyroid Disease What is thyroid disease? Thyroid disease ... pituitary responds by decreasing TSH production. How does pregnancy normally affect thyroid function? Two pregnancy-related hormones— ...

  8. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

    PubMed Central

    Fiesel, Fabienne C.; Caulfield, Thomas R.; Hudec, Roman; Ando, Maya; Truban, Dominika; Hou, Xu; Ogaki, Kotaro; Heckman, Michael G.; James, Elle D.; Swanberg, Maria; Jimenez-Ferrer, Itzia; Hansson, Oskar; Opala, Grzegorz; Siuda, Joanna; Boczarska-Jedynak, Magdalena; Friedman, Andrzej; Koziorowski, Dariusz; Rudzińska-Bar, Monika; Aasly, Jan O.; Lynch, Timothy; Mellick, George D.; Mohan, Megha; Silburn, Peter A.; Sanotsky, Yanosh; Vilariño-Güell, Carles; Farrer, Matthew J.; Chen, Li; Dawson, Valina L.; Dawson, Ted M.; Wszolek, Zbigniew K.; Ross, Owen A.

    2017-01-01

    size conferred by a partial dominant-negative function phenotype. PMID:27807026

  9. Cellular metabolic responses of PET radiotracers to (188)Re radiation in an MCF7 cell line containing dominant-negative mutant p53.

    PubMed

    Cheon, Gi Jeong; Chung, Hye-Kyung; Choi, Jung-A; Lee, Su-Jae; Ahn, Soon-Hyuk; Lee, Tae-Sup; Choi, Chang Woon; Lim, Sang Moo

    2007-05-01

    We investigated the relations between the cell uptakes of metabolic radiotracers and beta-radiation pretreatment using a dominant mutant p53 (p53mt) cell line to evaluate the effects of p53 genes on (18)F labeled positron emission tomography (PET) radiotracer uptakes. pCMV-Neo-Bam (control), which contains a neo-resistance marker, and p53 dominant-negative mutant expression constructs were stably transfected into MCF7 cell line. Cells were plated in 24-well plates at 1.0x10(5) cells for 18 h. Rhenium-188 ((188)Re) (a beta emitter) was added to the medium (3.7, 18.5, 37 MBq) and incubated for 24 h. We performed gamma-counting to determine the cellular uptakes of 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG), o-(2-[(18)F]fluoroethyl)-l-tyrosine (FET) and 2'-[(18)F]fluoro-2'-deoxythymidine (FLT) (370 kBq, 60 min). Cell viabilities were determined by trypan blue staining and flow cytometry. p53mt cells showed 1.5-2-fold higher FDG uptake than wild-type p53 cells in basal condition, and the difference of FDG uptake was greater after (188)Re treatment (P<.01). FET uptake increased with (188)Re dose without a significant difference between p53 statuses. p53mt cells showed lower FLT uptake than wild-type p53 cells in basal condition, and the difference of FLT uptake was greater after (188)Re treatment. By cell viability testing and FACS analysis, p53mt cells showed lower viability and a larger apoptotic fraction (sub-G1) than wild-type p53 cells after (188)Re treatment. We speculate that p53 dysfunction increases glucose and decreases thymidine metabolism in cancer cells and that this may be exaggerated by (188)Re beta-radiation. Our findings suggest that FDG could reflect tumor viability and malignant potential after (188)Re beta-radiation treatment, whereas FLT could be a more useful PET radiotracer for assessing therapeutic response to beta-radiation, especially in cancer cells with an altered function of p53.

  10. Involvement of dominant-negative spliced variants of the intermediate conductance Ca2+-activated K+ channel, K(Ca)3.1, in immune function of lymphoid cells.

    PubMed

    Ohya, Susumu; Niwa, Satomi; Yanagi, Ayano; Fukuyo, Yuka; Yamamura, Hisao; Imaizumi, Yuji

    2011-05-13

    The intermediate conductance Ca(2+)-activated K(+) channel (IK(Ca) channel) encoded by K(Ca)3.1 is responsible for the control of proliferation and differentiation in various types of cells. We identified novel spliced variants of K(Ca)3.1 (human (h) K(Ca)3.1b) from the human thymus, which were lacking the N-terminal domains of the original hK(Ca)3.1a as a result of alternative splicing events. hK(Ca)3.1b was significantly expressed in human lymphoid tissues. Western blot analysis showed that hK(Ca)3.1a proteins were mainly expressed in the plasma membrane fraction, whereas hK(Ca)3.1b was in the cytoplasmic fraction. We also identified a similar N terminus lacking K(Ca)3.1 variants from mice and rat lymphoid tissues (mK(Ca)3.1b and rK(Ca)3.1b). In the HEK293 heterologous expression system, the cellular distribution of cyan fluorescent protein-tagged hK(Ca)3.1a and/or YFP-tagged hK(Ca)3.1b isoforms showed that hK(Ca)3.1b suppressed the localization of hK(Ca)3.1a to the plasma membrane. In the Xenopus oocyte translation system, co-expression of hK(Ca)3.1b with hK(Ca)3.1a suppressed IK(Ca) channel activity of hK(Ca)3.1a in a dominant-negative manner. In addition, this study indicated that up-regulation of mK(Ca)3.1b in mouse thymocytes differentiated CD4(+)CD8(+) phenotype thymocytes into CD4(-)CD8(-) ones and suppressed concanavalin-A-stimulated thymocyte growth by down-regulation of mIL-2 transcripts. Anti-proliferative effects and down-regulation of mIL-2 transcripts were also observed in mK(Ca)3.1b-overexpressing mouse thymocytes. These suggest that the N-terminal domain of K(Ca)3.1 is critical for channel trafficking to the plasma membrane and that the fine-tuning of IK(Ca) channel activity modulated through alternative splicing events may be related to the control in physiological and pathophysiological conditions in T-lymphocytes.

  11. Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.

    PubMed

    Cortez, IbDanelo; Bulavin, Dmitry V; Wu, Ping; McGrath, Erica L; Cunningham, Kathryn A; Wakamiya, Maki; Papaconstantinou, John; Dineley, Kelly T

    2017-03-30

    A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38α(AF/+)) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38α(AF/+)) and kinase activity. As a result, aged DN-p38α(AF/+) mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38α(AF/+) and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38α(AF/+) and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38α(AF/+) exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38α(AF/+), we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38α(AF/+) mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 alpha subunit.

    PubMed

    Xu, H; Barry, D M; Li, H; Brunet, S; Guo, W; Nerbonne, J M

    1999-10-01

    An in vivo experimental strategy, involving cardiac-specific expression of a mutant Kv 2.1 subunit that functions as a dominant negative, was exploited in studies focused on exploring the role of members of the Kv2 subfamily of pore-forming (alpha) subunits in the generation of functional voltage-gated K(+) channels in the mammalian heart. A mutant Kv2.1 alpha subunit (Kv2.1N216) was designed to produce a truncated protein containing the intracellular N terminus, the S1 membrane-spanning domain, and a portion of the S1/S2 loop. The truncated Kv2.1N216 was epitope tagged at the C terminus with the 8-amino acid FLAG peptide to generate Kv2. 1N216FLAG. No ionic currents are detected on expression of Kv2. 1N216FLAG in HEK-293 cells, although coexpression of this construct with wild-type Kv2.1 markedly reduced the amplitudes of Kv2. 1-induced currents. Using the alpha-myosin heavy chain promoter to direct cardiac specific expression of the transgene, 2 lines of Kv2. 1N216FLAG-expressing transgenic mice were generated. Electrophysiological recordings from ventricular myocytes isolated from these animals revealed that I(K, slow) is selectively reduced. The attenuation of I(K, slow) is accompanied by marked action potential prolongation, and, occasionally, spontaneous triggered activity (apparently induced by early afterdepolarizations) is observed. The time constant of inactivation of I(K, slow) in Kv2. 1N216FLAG-expressing cells (mean+/-SEM=830+/-103 ms; n=17) is accelerated compared with the time constant of I(K, slow) inactivation (mean+/-SEM=1147+/-57 ms; n=25) in nontransgenic cells. In addition, unlike I(K, slow) in wild-type cells, the component of I(K, slow) remaining in the Kv2.1N216FLAG-expressing cells is insensitive to 25 mmol/L tetraethylammonium. Taken together, these observations suggest that there are 2 distinct components of I(K, slow) in mouse ventricular myocytes and that Kv2 alpha subunits underlie the more slowly inactivating, tetraethylammonium

  13. Validation of IKKβ as therapeutic target in airway inflammatory disease by adenoviral-mediated delivery of dominant-negative IKKβ to pulmonary epithelial cells

    PubMed Central

    Catley, Matthew C; Chivers, Joanna E; Holden, Neil S; Barnes, Peter J; Newton, Robert

    2005-01-01

    Asthma is an inflammatory disease of the lungs and the transcription factor NF-κB regulates the production of numerous inflammatory mediators that may have a role in the pathogenesis of asthma. Hence, the signalling pathways leading to NF-κB activation are considered prime targets for novel anti-inflammatory therapies. The prevention of NF-κB activity in mice, through the knockout of IKKβ or p65, causes fatal liver degeneration in utero making it difficult to determine the full implications of inhibiting NF-κB activity in tissues physiologically relevant to human diseases. This study used adenovirus delivery of a dominant inhibitor of NF-κB (IκBαΔN) and dominant-negative IKKα (IKKα(KM)) and IKKβ (IKKβ(KA)) to investigate the role of the individual IKKs in NF-κB activation and inflammatory gene transcription by human pulmonary A549 cells. Overexpression of IKKβ(KA) or IκBαΔN prevented NF-κB-dependent transcription and DNA binding. IKKβ(KA) also prevented IκBα kinase activity. Similarly, IKKβ(KA) and IκBαΔN overexpression also inhibited IL-1β- and TNFα-dependent increases in ICAM-1, IL-8 and GM-CSF in addition to IL-1β-mediated increases in cyclooxygenase-2 expression, whereas IKKα(KM) overexpression had little effect on these outputs. IKKβ(KA) also reduced cell viability and induced caspase-3 and PARP cleavage regardless of the stimuli, indicating the induction of apoptosis. This effect seemed to be directly related to IKKβ kinase activity since IκBαΔN only induced PARP cleavage in TNFα-treated cells. These results demonstrate that inhibition of IKKβ and NF-κB suppresses inflammatory mediator production and reduces A549 cell viability. Thus, novel therapies that target IKKβ could have potent anti-inflammatory effects and may be beneficial in the treatment of certain cancers. PMID:15723090

  14. Thyroid gland removal

    MedlinePlus

    Total thyroidectomy; Partial thyroidectomy; Thyroidectomy; Subtotal thyroidectomy; Thyroid cancer - thyroidectomy; Papillary cancer - thyroidectomy; Goiter - thyroidectomy; Thyroid nodules - thyroidectomy

  15. Can Thyroid Cancer Be Prevented?

    MedlinePlus

    ... Thyroid Cancer Causes, Risk Factors, and Prevention Can Thyroid Cancer Be Prevented? Most people with thyroid cancer ... Cancer? Can Thyroid Cancer Be Prevented? More In Thyroid Cancer About Thyroid Cancer Causes, Risk Factors, and ...

  16. Thyroid scan

    MedlinePlus

    ... rays given off by the radioactive material. A computer displays images of the thyroid gland. Other scans ... It is an even gray color on the computer image without darker or lighter areas. What Abnormal ...

  17. Thyroid Cancer

    MedlinePlus

    ... The coming of age of ultrasound-guided percutaneous ethanol ablation of selected neck nodal metastases in well-differentiated thyroid carcinoma. Journal of Clinical Endocrinology & Metabolism. 2011;96:2717. Caprelsa (prescribing information). Wilmington, Del.: ...

  18. EXPERIMENTAL THYROIDISM

    PubMed Central

    Cunningham, R. H.

    1898-01-01

    From the results of the various experiments already detailed I feel justified in drawing the following conclusions: (1) Absolutely fresh thyroid gland is not poisonous, in the usual sense of the term, when absorbed through the alimentary canal. (2) The symptoms of induced thyroidism are manifestations of an intoxication resulting from the ingestion of decomposed thyroid material, a conclusion that agrees in part with the previously related observations of Lanz. (3) The so-called experimental thyroidism is not specific for the thyroid only, for the ingestion of many substances derived from animal tissues other than the thyroid gland may produce an intoxication strikingly similar in every respect to that of experimental thyroidism. (4) Most, if not all, animal tissues yield substances which, if injected in large quantities directly into the circulation or beneath the skin, will produce an intoxication often very similar to that produced by injections of various substances derived from the fresh thyroid tissue. (5) The effects resulting from the intravascular or subcutaneous injections of aqueous extracts, decoctions and the concentrated extractives of the thyroid tissue, of the thymus, of muscle, etc., are by no means necessarily indicative of the function and the action of the hypothetical internal secretions of the same tissues during life. (6) The utilization of the fact that ingestion of decomposed thyroid material produces on certain occasions an intoxication with certain symptoms similar to some of those of G-raves' disease is not justifiable for the furtherance of the theory that the symptoms of exophthalmic goitre result from an over-production of the thyroid secretion. (7) Our results lead us to conclude with Drechsel that the fresh thyroid tissue yields at least probably two substances that are capable of palliating the symptoms of the acute cachexia in totally thyroidless dogs. (8) The thymus tissue also yields one and probably two substances that are as

  19. EXPERIMENTAL THYROIDISM.

    PubMed

    Cunningham, R H

    1898-03-01

    FROM THE RESULTS OF THE VARIOUS EXPERIMENTS ALREADY DETAILED I FEEL JUSTIFIED IN DRAWING THE FOLLOWING CONCLUSIONS: (1) Absolutely fresh thyroid gland is not poisonous, in the usual sense of the term, when absorbed through the alimentary canal. (2) The symptoms of induced thyroidism are manifestations of an intoxication resulting from the ingestion of decomposed thyroid material, a conclusion that agrees in part with the previously related observations of Lanz. (3) The so-called experimental thyroidism is not specific for the thyroid only, for the ingestion of many substances derived from animal tissues other than the thyroid gland may produce an intoxication strikingly similar in every respect to that of experimental thyroidism. (4) Most, if not all, animal tissues yield substances which, if injected in large quantities directly into the circulation or beneath the skin, will produce an intoxication often very similar to that produced by injections of various substances derived from the fresh thyroid tissue. (5) The effects resulting from the intravascular or subcutaneous injections of aqueous extracts, decoctions and the concentrated extractives of the thyroid tissue, of the thymus, of muscle, etc., are by no means necessarily indicative of the function and the action of the hypothetical internal secretions of the same tissues during life. (6) The utilization of the fact that ingestion of decomposed thyroid material produces on certain occasions an intoxication with certain symptoms similar to some of those of G-raves' disease is not justifiable for the furtherance of the theory that the symptoms of exophthalmic goitre result from an over-production of the thyroid secretion. (7) Our results lead us to conclude with Drechsel that the fresh thyroid tissue yields at least probably two substances that are capable of palliating the symptoms of the acute cachexia in totally thyroidless dogs. (8) The thymus tissue also yields one and probably two substances that are as

  20. Thyroid crises.

    PubMed

    Gavin, L A

    1991-01-01

    In the setting of characteristic features of thyrotoxicosis, the timely diagnosis and aggressive management of thyroid storm should result in a successful outcome. However, severe storm may lead to irreversible cardiovascular collapse, especially in the older patient who may have atypical features of thyrotoxicosis. The fundamental approach is prompt and optimal treatment in the emergency department once the presenting clinical features suggest its presence. Delay in the introduction of therapy while awaiting laboratory confirmation may result in further decompensation and death. The prevention of myxedema coma entails paying special attention to certain high-risk patient groups. These groups include older women with a history of Hashimoto's thyroiditis, or previous irradiation or thyroid surgery for hyperthyroidism. Inform such patients of the symptoms and signs of hypothyroidism, and perform annual thyroid function tests, such as a serum TSH, in order to provide early, adequate treatment once the test becomes positive.

  1. Thyroid inferno.

    PubMed

    Bhargava, Amit; Kaur, Manmeet

    2014-01-01

    The key to uncovering the etiology of hyperthyroidism lies in a careful history and physical examination. Autoimmune markers provide additive information, but should not solely be used to make a diagnosis. Concern has been raised that the overzealous use of thyroid ultrasound, following abnormal thyroid function tests, diverts attention from the workup of the biochemical abnormality to the workup of an incidentally found thyroid nodule. If further imaging is needed, the use ofathyroidscanhas been suggestedbythe Endocrine Society and the American Association of Clinical Endocrinologists. However, in certain scenarios, this may be contraindicated. We present the case of a 28-year-old female with hyperthyroidism, as aplatform to discuss an important clinical sign present on Doppler ultrasound of the thyroid. By recognizing the clinical information gained from a Doppler ultrasound, physicians can avoid additional invasive workup and apply the use of ultrasound where most appropriate.

  2. Anaplastic thyroid carcinoma, thyroid lymphoma, and metastasis to thyroid.

    PubMed

    Untch, Brian R; Olson, John A

    2006-07-01

    Anaplastic thyroid carcinoma, thyroid lymphoma, and secondary metastasis to the thyroid gland are uncommon thyroid malignancies. They represent significant challenges for the surgeon owing to difficulties in diagnosis, aggressive biology, and the infrequency of their presentation. An awareness and appreciation of multimodality treatment strategies is essential for their management.

  3. Association of Hashimoto's thyroiditis and thyroid cancer.

    PubMed

    Noureldine, Salem I; Tufano, Ralph P

    2015-01-01

    The association of Hashimoto's thyroiditis and thyroid cancer remains an active focus of research and controversy. Since it was first proposed in 1955, numerous studies have explored the epidemiology and etiology of these concurrent disease processes. The lymphocytic infiltration of Hashimoto's thyroiditis is frequently encountered in thyroid glands resected for a neoplasm. The most frequent association is noted with papillary thyroid cancer. Several recent studies performed on patients undergoing thyroidectomy with coexisting Hashimoto's thyroiditis report an increased prevalence of papillary thyroid cancer, with a favorable disease profile and an improved prognosis, particularly in women. Conversely, some population-based studies using fine-needle aspiration biopsy data report no linkage between serologic Hashimoto's thyroiditis and thyroid cancer, yet they are limited by the lack of definitive pathology. On the other hand, the significantly increased incidence of primary thyroid lymphomas in patients with Hashimoto's thyroiditis strongly suggests a pathogenetic link between this autoimmune disorder and malignant thyroid lymphoma. The lymphocytic infiltration of Hashimoto's thyroiditis is frequently associated with papillary thyroid cancer and may indeed be a risk factor for developing this type of cancer. Nonetheless, a pathogenesis linking these diseases remains unclear. The relationship between thyroid lymphoma and Hashimoto's thyroiditis appears to be well established.

  4. Thyroid emergencies.

    PubMed

    Burger, A G; Philippe, J

    1992-01-01

    Thyroid storm is a rapid decompensation of severe hyperthyroidism which can best be described by the three criteria of hyperthermia, tachycardia and altered mental state with severe agitation. There has to be a precipitating factor such as infection, iodine contamination, surgery or even I-131 treatment. Severe hyperthyroidism not fulfilling the criteria of thyroid storm can also be an indication for emergency treatment, particularly in the elderly with heart disease. Suppressed serum TSH and elevated free T4 levels are essential to confirm the diagnosis. When rapidly available, radioiodine uptake of the thyroid can be useful. Therapy aims at rapidly reducing the active circulating hormone pool, hypermetabolic state, tachycardia, and finally hormone synthesis. Thyroid secretion can be blocked by ioipanoic acid or ipodate while hypermetabolic state can be reduced with beta-blockers or calcium channel-blockers. Treatment of hyperthyroidism in patients with iodine contamination is a real therapeutic challenge. Myxoedema coma, a complication of severe hypothyroidism, is defined by hypothermia (rectal temperature less than 36 degrees C), bradycardia, slow mentation, precipitating factor such as infection or drug overdose, and increased serum creatine phosphokinase levels. Diagnosis of severe hypothyroidism should be confirmed by serum measurements of TSH and free T4. Treatment consists of general supporting measures including rewarming, correction of serum electrolyte disturbances, and adequate alimentation. Thyroid hormone treatment should initially be aggressive using either 300-400 micrograms of T4 or 20-40 micrograms of T3 intravenously. Cortisone therapy may be added. Patients should be under close monitoring as arrhythmias and myocardial infarction are frequent complications of myxoedema coma and/or its treatment with thyroid hormones.

  5. [Non-autoimmune thyroiditis].

    PubMed

    Rizzo, Leonardo F L; Mana, Daniela L; Bruno, Oscar D

    2014-01-01

    The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects.

  6. Key Statistics for Thyroid Cancer

    MedlinePlus

    ... and Treatment? Thyroid Cancer About Thyroid Cancer Key Statistics for Thyroid Cancer How common is thyroid cancer? ... remains very low compared with most other cancers. Statistics on survival rates for thyroid cancer are discussed ...

  7. Chronic thyroiditis (Hashimoto disease)

    MedlinePlus

    ... to determine thyroid function include: Free T4 test Serum TSH T3 Thyroid autoantibodies Imaging studies and fine needle biopsy are generally not needed to diagnose Hashimoto thyroiditis. This disease may also change the results of the following ...

  8. Thyroid Disorders Overview

    MedlinePlus

    ... are common. These nodules can be either a growth of thyroid tissue or a fluid-filled cyst, which forms a lump in the thyroid gland. Almost half of the population will have tiny thyroid nodules at some point ...

  9. Evaluation of thyroid incidentaloma.

    PubMed

    Wilhelm, Scott

    2014-06-01

    Thyroid nodules are an extremely common endocrine disorder with a generally accepted prevalence of around 4% to 7%. Incidental thyroid nodules are typically nonpalpable thyroid nodules found during radiographic evaluation for a non-thyroid-related issue (eg, computed tomographic scan, positron emission tomography scan, carotid duplex). Incidental thyroid nodules are contributing to but are not the sole reason for the rising incidence of thyroid cancer in the Unites States and other developed nations.

  10. Global expression profiling reveals gain-of-function onco-genic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis

    PubMed Central

    Lu, Changxue; Mishra, Alok; Zhu, Yuelin J; Meltzer, Paul; Cheng, Sheue-yann

    2011-01-01

    Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (Thrbpv/pv mice) was used in the present study. The Thrbpv/pv mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in Thrbpv/pv mice and Thra1-/- Thrb-/- mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of Thrbpv/pv mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in Thrbpv/pv mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote

  11. Thyroid Nodules and Thyroid Cancer: Surgical Aspects

    PubMed Central

    Clark, Orlo H.

    1980-01-01

    Patients with thyroid nodules must be treated selectively because these nodules develop far more frequently than does thyroid cancer. A thorough clinical history, family history and history of radiation, as well as an accurate physical examination, are very important in determining whether surgical treatment is indicated. Thyroid function tests, a radioactive isotope scan, a thyroid echogram and fine-needle biopsy are also useful. Although there is considerable debate concerning the amount of thyroid tissue that should be removed at operation, the minimal procedure for a “cold,” solid thyroid nodule is a total thyroid lobectomy and isthmectomy. This is the treatment of choice for patients with occult papillary thyroid carcinoma. Partial lobectomy is to be discouraged. Near total or total thyroidectomy should be considered for all other patients with differentiated thyroid cancer. Many factors influence the prognosis of patients with thyroid cancer including age, sex, type of thyroid cancer, invasion, symptoms, lymph node metastasis, metastasis to distant sites, extent of the surgical procedure, and use of radioactive iodine and thyroid hormone. With adequate treatment, the prognosis for differentiated thyroid carcinoma is excellent. PMID:7222643

  12. Hashimoto's Thyroiditis and Medullary Carcinoma of Thyroid.

    PubMed

    Dasgupta, S; Chakrabarti, S; Mandal, P K; Das, S

    2014-01-01

    Hashimoto's thyroiditis (HT) has been found to be associated with lymphoma, papillary carcinoma and Hürthle cell neoplasms of thyroid. In contrast, there are only a few reports of co-existence of HT with medullary carcinoma of thyroid. An overall prevalence of medullary carcinoma of only 0.35% has been reported in HT patients. Such a rare combination is being presented here. A 33 year old female presented with history of goiter for one year. Fine needle aspiration cytology (FNAC) of the swelling revealed cytological features suggestive of medullary carcinoma of thyroid. Histopathological examination of total thyroidectomy specimen revealed Hashimoto's thyroiditis along with medullary carcinoma of thyroid. Although Hashimoto's thyroiditis can uncommonly co-exist with thyroid neoplasm, its association with medullary carcinoma is extremely rare and hence being presented.

  13. Thyroid cancer in lingual thyroid and thyroglossal duct cyst.

    PubMed

    Sturniolo, Giacomo; Vermiglio, Francesco; Moleti, Mariacarla

    2016-11-04

    Ectopy is the most common embryogenetic defect of the thyroid gland, representing between 48 and 61% of all thyroid dysgeneses. Persistence of thyroid tissue in the context of a thyroglossal duct remnant and lingual thyroid tissue are the most common defects. Although most cases of ectopic thyroid are asymptomatic, any disease affecting the thyroid may potentially involve the ectopic tissue, including malignancies. The prevalence of differentiated thyroid carcinoma in lingual thyroid and thyroglossal duct cyst is around 1% of patients affected with the above thyroid ectopies. We here review the current literature concerning primary thyroid carcinomas originating from thyroid tissue on thyroglossal duct cysts and lingual thyroid.

  14. AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington's disease.

    PubMed

    Alto, Laura Taylor; Chen, Xi; Ruhn, Kelly A; Treviño, Isaac; Tansey, Malú G

    2014-01-01

    CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.

  15. [Thyroid dysfunctions and pregnancy].

    PubMed

    Caron, Philippe

    2011-12-01

    Advances in understanding the physiology of the thyroid function in normal pregnancy have highlighted the importance of the consequences of abnormal thyroid function on mother and fetal outcomes. Thyroid diseases are common in young women of childbearing age while management of thyroid diseases is relatively straightforward. For each thyroid dysfunction (hypothyroxinemia, hypothyroidism, hyperthyroidism, postpartum thyroiditis), the issues with the obstetric complications of the mother and the fetus are considered. Indeed, early recognition of thyroid diseases during pregnancy and appropriate management has the potential to improve outcome for the mother and the fetus.

  16. Thyroiditis: an integrated approach.

    PubMed

    Sweeney, Lori B; Stewart, Christopher; Gaitonde, David Y

    2014-09-15

    Thyroiditis is a general term that encompasses several clinical disorders characterized by inflammation of the thyroid gland. The most common is Hashimoto thyroiditis; patients typically present with a nontender goiter, hypothyroidism, and an elevated thyroid peroxidase antibody level. Treatment with levothyroxine ameliorates the hypothyroidism and may reduce goiter size. Postpartum thyroiditis is transient or persistent thyroid dysfunction that occurs within one year of childbirth, miscarriage, or medical abortion. Release of preformed thyroid hormone into the bloodstream may result in hyperthyroidism. This may be followed by transient or permanent hypothyroidism as a result of depletion of thyroid hormone stores and destruction of thyroid hormone-producing cells. Patients should be monitored for changes in thyroid function. Beta blockers can treat symptoms in the initial hyperthyroid phase; in the subsequent hypothyroid phase, levothyroxine should be considered in women with a serum thyroid-stimulating hormone level greater than 10 mIU per L, or in women with a thyroid-stimulating hormone level of 4 to 10 mIU per L who are symptomatic or desire fertility. Subacute thyroiditis is a transient thyrotoxic state characterized by anterior neck pain, suppressed thyroid-stimulating hormone, and low radioactive iodine uptake on thyroid scanning. Many cases of subacute thyroiditis follow an upper respiratory viral illness, which is thought to trigger an inflammatory destruction of thyroid follicles. In most cases, the thyroid gland spontaneously resumes normal thyroid hormone production after several months. Treatment with high-dose acetylsalicylic acid or nonsteroidal anti-inflammatory drugs is directed toward relief of thyroid pain.

  17. [Thyroid emergencies : Thyroid storm and myxedema coma].

    PubMed

    Spitzweg, C; Reincke, M; Gärtner, R

    2017-09-22

    Thyroid emergencies are rare life-threatening endocrine conditions resulting from either decompensated thyrotoxicosis (thyroid storm) or severe thyroid hormone deficiency (myxedema coma). Both conditions develop out of a long-standing undiagnosed or untreated hyper- or hypothyroidism, respectively, precipitated by an acute stress-associated event, such as infection, trauma, or surgery. Cardinal features of thyroid storm are myasthenia, cardiovascular symptoms, in particular tachycardia, as well as hyperthermia and central nervous system dysfunction. The diagnosis is made based on clinical criteria only as thyroid hormone measurements do not differentiate between thyroid storm and uncomplicated hyperthyroidism. In addition to critical care measures therapy focusses on inhibition of thyroid hormone synthesis and secretion (antithyroid drugs, perchlorate, Lugol's solution, cholestyramine, thyroidectomy) as well as inhibition of thyroid hormone effects in the periphery (β-blocker, glucocorticoids).Cardinal symptoms of myxedema coma are hypothermia, decreased mental status, and hypoventilation with risk of pneumonia and hyponatremia. The diagnosis is also purely based on clinical criteria as measurements of thyroid hormone levels do not differ between uncomplicated severe hypothyroidism and myxedema coma. In addition to substitution of thyroid hormones and glucocorticoids, therapy focusses on critical care measures to treat hypoventilation and hypercapnia, correction of hyponatremia and hypothermia.Survival of both thyroid emergencies can only be optimized by early diagnosis based on clinical criteria and prompt initiation of multimodal therapy including supportive measures and treatment of the precipitating event.

  18. Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas.

    PubMed Central

    Böttinger, E P; Jakubczak, J L; Roberts, I S; Mumy, M; Hemmati, P; Bagnall, K; Merlino, G; Wakefield, L M

    1997-01-01

    Using a dominant-negative mutant receptor (DNR) approach in transgenic mice, we have functionally inactivated transforming growth factor-beta (TGF-beta) signaling in select epithelial cells. The dominant-negative mutant type II TGF-beta receptor blocked signaling by all three TGF-beta isoforms in primary hepatocyte and pancreatic acinar cell cultures generated from transgenic mice, as demonstrated by the loss of growth inhibitory and gene induction responses. However, it had no effect on signaling by activin, the closest TGF-beta family member. DNR transgenic mice showed increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation. These results indicate that TGF-beta negatively controls growth of acinar cells and is essential for the maintenance of a differentiated acinar phenotype in the exocrine pancreas in vivo. In contrast, such abnormalities were not observed in the liver. Additional abnormalities in the pancreas included fibrosis, neoangiogenesis and mild macrophage infiltration, and these were associated with a marked up-regulation of TGF-beta expression in transgenic acinar cells. This transgenic model of targeted functional inactivation of TGF-beta signaling provides insights into mechanisms whereby loss of TGF-beta responsiveness might promote the carcinogenic process, both through direct effects on cell proliferation, and indirectly through up-regulation of TGF-betas with associated paracrine effects on stromal compartments. PMID:9184209

  19. Neurotoxicity of Thyroid Disrupting Contaminants

    EPA Science Inventory

    Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

  20. Neurotoxicity of Thyroid Disrupting Contaminants

    EPA Science Inventory

    Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

  1. Thyroid disorders in women.

    PubMed

    Li, H; Li, J

    2015-04-01

    Thyroid disorders include autoimmune thyroid diseases (AITD), thyroid goiter, nodule and cancer. AITD mainly consist of autoimmune thyroiditis and Graves disease. The common characteristic of thyroid disorders is female preponderance in their prevalence. The female-to-male rate ratio is reported at 4~6:1 for AITD and about 3~4:1 for thyroid nodule. For PTC, it is greatest during reproductive age and drops from five and more in patients aged 20-24, to 3.4 in patients aged 35-44 to one in patients over 80. The effects of female gonadal hormones and X chromosome inactivation on thyroid gland and immune system greatly contribute to the female predilection of AITD. The former mainly include prolactin and estrogen. The direct actions of estrogen on the thyroid tissue contribute to the development of thyroid goiter, nodule and cancer in women.

  2. Thyroid dysfunction and subfertility.

    PubMed

    Cho, Moon Kyoung

    2015-12-01

    The thyroid hormones act on nearly every cell in the body. Moreover, the thyroid gland continuously interacts with the ovaries, and the thyroid hormones are involved in almost all phases of reproduction. Thyroid dysfunctions are relatively common among women of reproductive age, and can affect fertility in various ways, resulting in anovulatory cycles, high prolactin levels, and sex hormone imbalances. Undiagnosed and untreated thyroid disease can be a cause of subfertility. Subclinical hypothyroidism (SCH), also known as mild thyroid failure, is diagnosed when peripheral thyroid hormone levels are within the normal reference laboratory range, but serum thyroid-stimulating hormone levels are mildly elevated. Thyroid autoimmunity (TAI) is characterized by the presence of anti-thyroid antibodies, which include anti-thyroperoxidase and anti-thyroglobulin antibodies. SCH and TAI may remain latent, asymptomatic, or even undiagnosed for an extended period. It has also been demonstrated that controlled ovarian hyperstimulation has a significant impact on thyroid function, particularly in women with TAI. In the current review, we describe the interactions between thyroid dysfunctions and subfertility, as well as the proper work-up and management of thyroid dysfunctions in subfertile women.

  3. p53-Dependent Activation of microRNA-34a in Response to Etoposide-Induced DNA Damage in Osteosarcoma Cell Lines Not Impaired by Dominant Negative p53 Expression

    PubMed Central

    Novello, Chiara; Pazzaglia, Laura; Conti, Amalia; Quattrini, Irene; Pollino, Serena; Perego, Paola; Picci, Piero; Benassi, Maria Serena

    2014-01-01

    Osteosarcoma (OS) is the most common primary malignant bone tumor and prevalently occurs in the second decade of life. Etoposide, a chemotherapeutic agent used in combined treatments of recurrent human OS, belongs to the topoisomerase inhibitor family and causes DNA breakage. In this study we evaluated the cascade of events determined by etoposide-induced DNA damage in OS cell lines with different p53 status focusing on methylation status and expression of miR-34a that modulate tumor cell growth and cell cycle progression. Wild-type p53 U2-OS cells and U2-OS cells expressing dominant-negative form of p53 (U2- OS175) were more sensitive to etoposide than p53-deficient MG63 and Saos-2 cells, showing increased levels of unmethylated miR-34a, reduced expression of CDK4 and cell cycle arrest in G1 phase. In contrast, MG63 and Saos-2 cell lines presented aberrant methylation of miR-34a promoter gene with no miR-34a induction after etoposide treatment, underlining the close connection between p53 expression and miR-34a methylation status. Consistently, in p53siRNA transfected U2-OS cells we observed loss of miR-34a induction after etoposide exposure associated with a partial gain of gene methylation and cell cycle progress towards G2/M phase. Our results suggest that the open and unmethylated conformation of the miR-34a gene may be regulated by p53 able to bind the gene promoter. In conclusion, cell response to etoposide-induced DNA damage was not compromised in cells with dominant-negative p53 expression. PMID:25490093

  4. Inhibition of intrinsic gap-junction intercellular communication and enhancement of tumorigenicity of the rat bladder carcinoma cell line BC31 by a dominant-negative connexin 43 mutant.

    PubMed

    Krutovskikh, V A; Yamasaki, H; Tsuda, H; Asamoto, M

    1998-12-01

    The tumor-suppressive property of the connexin gap-junction proteins was postulated from the fact that their function of cell coupling is impaired in most cancer cells. However, in conflict with this notion, certain cancer cells are able to communicate through gap junctions despite their malignancy. To explain this phenomenon, we studied by using a dominant-negative strategy the effect on tumorigenicity of loss of intrinsic gap-junction intercellular communication (GJIC) in the rat bladder carcinoma cell line BC31, which shows both expression of connexin 43 (Cx43) and intercellular communication. In cells transfected with a mutant Cx43 with seven residues deleted from the internal loop at positions 130-136 (Cx43delta), transport of the resulting connexin protein to the plasma membrane occurred normally, but the GJIC of the cells was effectively abolished at the level of permeability of established gap junctions. Dominant-negative inhibition of GJIC by Cx43delta accelerated growth of BC31 cells in nude mice. In contrast, when GJIC in BC31 cells was artificially enforced by transfection of wild-type Cx43, the cells lost the capacity to grow in vivo. Decreased phosphorylation of Cx43delta suggested close interaction of the internal loop of connexin with its commonly phosphorylated domains in the C-terminal tail and involvement of this interaction in gap-junction permeability. Therefore, we conclude that the intrinsic GJIC observed in cancer cells should be considered a tumor-suppressor factor and that its level may influence malignant growth capacity.

  5. Thyroid Function Tests

    MedlinePlus

    ... made in the pituitary gland located at the base of the brain, called thyroid stimulating hormone (abbreviated ... women who take control birth pills, etc). Another measurement done to assess the thyroid status of patients ...

  6. Thyroid and Weight

    MedlinePlus

    ... glands had high BMRs. Later studies linked these observations with measurements of thyroid hormone levels and showed ... the hyperthyroidism is treated. One consequence of this observation is that the use of thyroid hormone to ...

  7. Thyroid Function Tests

    MedlinePlus

    ... problem that is directly affecting the thyroid (primary hypothyroidism). The opposite situation, in which the TSH level ... making enough TSH to stimulate the thyroid (secondary hypothyroidism). In most healthy individuals, a normal TSH value ...

  8. Thyroid Disorders (For Kids)

    MedlinePlus

    ... of thyroid disorder or thyroid disease. Hyperthyroidism (say: hi-per-THYE-roy-diz-em) happens when the ... Kids with the opposite problem have hypothyroidism (say: hi-po-THYE-roy-diz-em). In this case, ...

  9. Cabozantinib (thyroid cancer)

    MedlinePlus

    ... is used to treat a certain type of thyroid cancer that is getting worse and that has spread ... only gives information about cabozantinib capsules (Cometriq) for thyroid cancer. If you are using this medication for advanced ...

  10. American Thyroid Association

    MedlinePlus

    ... 0 87th Annual Meeting of the American Thyroid Association October 18–22, 2017, Victoria, British Columbia, Canada ... the 87th annual meeting of the American Thyroid Association (ATA) is almost upon us! On... Read More ...

  11. Sarcoidosis and Thyroid Autoimmunity.

    PubMed

    Fazzi, Piera; Fallahi, Poupak; Ferrari, Silvia Martina

    2017-01-01

    Most of the studies have shown a higher risk for subclinical and clinical hypothyroidism, antithyroid autoantibodies [overall antithyroid peroxidase antibodies (TPOAb)], and in general, thyroid autoimmunity, overall in the female gender in patients with sarcoidosis (S). A significantly higher prevalence of clinical hypothyroidism and Graves' disease was also described in female S patients with respect to controls. Gallium-67 (Ga-67) scyntigraphy in S patients, in the case of thyroid uptake, suggests the presence of aggressive autoimmune thyroiditis and hypothyroidism. For this reason, ultrasonography and thyroid function should be done in the case of Ga-67 thyroid uptake. In conclusion, thyroid function, TPOAb measurement, and ultrasonography should be done to assess the clinical profile in female S patients, and the ones at high risk (female individuals, with TPOAb positivity, and hypoechoic and small thyroid) should have periodically thyroid function evaluations and suitable treatments.

  12. Thyroid Disease Definitions

    MedlinePlus

    ... A Week of Healthy Breakfasts Shyness Thyroid Disease Definitions KidsHealth > For Teens > Thyroid Disease Definitions A A ... or injury. Signs of inflammation can include redness, heat, pain, or swelling. metabolism: Metabolism refers to the ...

  13. Child thyroid anatomy (image)

    MedlinePlus

    The thyroid is a gland located in the neck. It is a part of the endocrine (hormone) system, and ... a major role in regulating the body's metabolism. Thyroid disorders are more common in older children and ...

  14. Thyroid preparation overdose

    MedlinePlus

    Thyroid preparations are medicines used to treat thyroid gland disorders. Overdose occurs when someone takes more than the normal or recommended amount of this medicine. This can be by accident or ...

  15. Thyroid Stimulating Hormone Receptor

    PubMed Central

    Tuncel, Murat

    2017-01-01

    Thyroid stimulating hormone receptor (TSHR) plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases. PMID:28117293

  16. [Thyroid and cardiovascular disorders].

    PubMed

    Zyśko, Dorota; Gajek, Jacek

    2004-05-01

    In this study three problems concerning interactions between thyroid and cardiovascular system are discussed. Cardiac arrhythmias, congestive heart failure, pleural effusion, hyperlipidaemia, arterial hypertension may be consequences of thyroid disorders leading to inappropriate hormone secretion. During such illnesses as heart failure, myocardial infarction and in patients undergoing coronary artery bypass surgery profound changes may occur in thyroid hormone metabolism known as sick euthyroid syndrome. Treatment with amiodarone may lead to changes in thyroid tests results and to development of hypothyroidism or thyrotoxicosis.

  17. Thyroid Stimulating Hormone Receptor.

    PubMed

    Tuncel, Murat

    2016-01-05

    Thyroid stimulating hormone receptor (TSHR) plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

  18. Thyroid cancer in childhood

    SciTech Connect

    Gorlin, J.B.; Sallan, S.E. )

    1990-09-01

    The incidence, clinical presentation, and types of thyroid cancers presenting in childhood are reviewed. The role of antecedent radiation in papillary and follicular thyroid cancers and genetics of medullary thyroid carcinoma are discussed. Unique aspects of therapy and prognosis for the pediatric patient with thyroid carcinoma are addressed as well as a diagnostic approach to the child who presents with a neck mass.59 references.

  19. Thyroid and menopause.

    PubMed

    del Ghianda, S; Tonacchera, M; Vitti, P

    2014-06-01

    Thyroid dysfunction is common in the general population especially in women. All thyroid diseases are in fact more common in women than in men and may interfere with the reproductive system. Thyroid function and the gonadal axes are related throughout the woman's fertile period. The relationship between the two glands is mutual. In particular, thyroid hormones affect the reproductive function both directly and indirectly through several actions. Studies on the relationship between menopause and thyroid function are few and do not allow to clarify whether menopause has an effect on the thyroid regardless of aging. With aging, the main changes regarding thyroid physiology and function are: a reduction of thyroid iodine uptake, free thyroxine and free triiodothyronine synthesis and catabolism of free thyroxine while reverse triiodothyronine increases; the level of thyroid stimulating hormone remains normal with sometimes a tendency to higher limits. These changes are present in both sexes without distinction between males and females. The complexity of the relationships can be summarized in three aspects: thyroid status does not influence significantly the climacteric syndrome; menopause may modify the clinical expression of some thyroid diseases, particularly the autoimmune ones; thyroid function is not directly involved in the pathogenesis of the complications of menopause. However, coronary atherosclerosis and osteoporosis may be aggravated in the presence of hyperthyroidism or hypothyroidism. The effects of postmenopausal estrogen replacement on thyroxine requirements in women with hypothyroidism should be considered.

  20. Stages of Thyroid Cancer

    MedlinePlus

    ... thyroid cancer and the age of the patient: Papillary and follicular thyroid cancer in patients younger than 45 years Stage I: ... the body, such as the lungs or bones. Papillary and follicular thyroid cancer in patients 45 years and older Stage I: ...

  1. Thyroid-associated paragangliomas.

    PubMed

    Phitayakorn, Roy; Faquin, William; Wei, Nancy; Barbesino, Giuseppe; Stephen, Antonia E

    2011-07-01

    Paragangliomas in the region of the thyroid gland are rare tumors that can present a diagnostic challenge by mimicking follicular and c-cell derived thyroid tumors. Thyroid-associated paragangliomas are likely a subset of laryngeal paragangliomas and, although quite rare, should be considered in the differential diagnosis of a hypervascular thyroid nodule. The preoperative diagnosis of thyroid-associated paragangliomas can be challenging since the cytologic and histologic features overlap with more common primary thyroid neoplasms, in particular medullary carcinoma. Differential expression of a panel of immunohistochemical markers, including neuro-specific enolase, chromogranin A, synaptophysin, keratin, and S100, can be used to distinguish thyroid-associated paragangliomas from primary thyroid tumors. Intraoperatively, thyroid-associated paragangliomas may be associated with significant intraoperative bleeding and are often densely adherent to surrounding tissues, including the recurrent laryngeal nerve. Interestingly, the aggressive local behavior of these tumors does not correspond to potential for malignancy, as there are no patients with malignant thyroid-associated paragangliomas reported in the medical literature. Therefore, these tumors may be treated with limited resection. Postoperatively, patients with paragangliomas should receive hormonal evaluation for functional disease, imaging evaluation for multicentric and metastatic disease, and genetic counseling. Thyroid-associated paragangliomas are an important part of the differential diagnosis of a hypervascular thyroid nodule, especially in a patient with a fine-needle aspiration biopsy suggestive of medullary thyroid carcinoma, but with unremarkable serum calcitonin levels. Consideration of a thyroid-associated paraganglioma also has important operative and postoperative implications for determining the extent of thyroid resection as well as follow-up testing.

  2. Anemia in thyroid diseases.

    PubMed

    Szczepanek-Parulska, Ewelina; Hernik, Aleksandra; Ruchała, Marek

    2017-03-28

    Anemia is a frequent, although often underestimated, clinical condition accompanying thyroid diseases. In spite of the fact that anemia and thyroid dysfunction often occur simultaneously, the causative relationship between these two disorders remains ambiguous. Thyroid hormones stimulate erythrocytes precursors proliferation directly, as well as via erythropoietin production enhancement, whereas iron-deficient anemia negatively influences thyroid hormonal status. Thus, different forms of anemia might emerge in the course of thyroid dysfunction. In fact, normocytic anemia is most common, while macrocytic or microcytic anemia occur less frequently. Anemia in hypothyroidism might result from bone marrow depression, decreased erythropoietin production, comorbid diseases, or concomitant iron, vitamin B12 or folate deficiency. Altered iron metabolism and oxidative stress may contribute to anemia in hyperthyroidism. The risk of anemia in autoimmune thyroid disease (AITD) may be posed by pernicious anemia and atrophic gastritis, celiac disease, autoimmune hemolytic syndrome, or rheumatic disorders. The simultaneous occurrence of anemia and thyroid disease, as well as their close relation, make the diseases an important clinical problem. The aim of the study is to provide a comprehensive review summarizing data on the prevalence, potential mechanisms, and therapy of anemia in the course of thyroid diseases from the clinical and pathogenetic perspective. Thyroid dysfunction and autoimmune thyroid disease should be considered in differential diagnosis of treatment-resistant or refractory anemia, as well as in case of increased red blood cell distribution width (RDW). Of note is that the presence of AITD itself, independently from thyroid hormonal status, might affect hemoglobin level.

  3. Interferon induced thyroiditis.

    PubMed

    Tomer, Yaron; Menconi, Francesca

    2009-12-01

    Interferon-alpha (IFNalpha) is used for the treatment of various disorders, most notable chronic hepatitis C virus (HCV) infection. One of the commonest side effects of IFNalpha therapy is thyroiditis, with up to 40% of HCV patients on IFNalpha developing clinical or subclinical disease. In some cases interferon induced thyroiditis (IIT) may result in severe symptomatology necessitating discontinuation of therapy. IIT can manifest as clinical autoimmune thyroiditis, presenting with symptoms of classical Hashimoto's thyroiditis or Graves' disease, or as non-autoimmune thyroiditis. Non-autoimmune thyroiditis can manifest as destructive thyroiditis, with early thyrotoxicosis and later hypothyroidism, or as non-autoimmune hypothyroidism. While the epidemiology and clinical presentation of IIT have been well characterized the mechanisms causing IIT are still poorly understood. It is likely that the hepatitis C virus (HCV) itself plays a role in the disease, as the association between HCV infection and thyroiditis is well established. It is believed that IFNalpha induces thyroiditis by both immune stimulatory effects and by direct effects on the thyroid. Early detection and therapy of this condition are important in order to avoid complications of thyroid disease such as cardiac arrhythmias.

  4. Metformin and thyroid disease.

    PubMed

    Meng, Xianghui; Xu, Shuhang; Chen, Guofang; Derwahl, Michael; Liu, Chao

    2017-04-01

    An intriguing area of research in thyroidology is the recently discovered association of insulin resistance with thyroid functional and morphological abnormalities. Individuals with hyperinsulinemia have larger thyroid gland and a higher prevalence of thyroid nodules and cancer. Accordingly, patients treated with metformin have a smaller thyroid volume and a lower risk of incident goiter, thyroid nodule and cancer. Multiple studies in vitro and in vivo have demonstrated that metformin can inhibit the growth of thyroid cells and different types of thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways. Besides, metformin treatment was associated with a decrease in the levels of serum thyroid-stimulating hormone (TSH) in diabetic patients possibly by enhancing the effects of thyroid hormones in the pituitary and activating the adenosine monophosphate-activated protein kinase (AMPK). Based on this evidence, metformin appears to be a promising therapeutic tool in patients with thyroid disease. More clinical studies are necessary to evaluate the clinical significance of metformin for the treatment of thyroid diseases. © 2017 Society for Endocrinology.

  5. Thyroid diseases in pregnancy.

    PubMed

    Gärtner, Roland

    2009-12-01

    Thyroid disorders are common in pregnancy and affect maternal and fetal outcome. The reference values for normal thyroid function during first and second trimester had been re-evaluated recently. Hypothyroxinemia affects the neuropsychological development of the child. Maternal thyroid dysfunction or only the presence of thyroid-specific antibodies is associated with increased risk for early abortion, preterm delivery and neonatal morbidity. Pregnant women under levothyroxine treatment are often undertreated or overtreated. Screening for thyroid dysfunction of pregnant women is recommended and cost-effective. Recently, the recommended dose for iodine intake during pregnancy had been increased from 200 to 250 microg/day, because recent studies revealed that even mild-to-moderate iodine intake might affect the neuropsychological development of the child. About 5-18% of all pregnant women exhibit elevated thyroid-specific antibodies, but only 0.3% develop overt hypothyroidism and 0.1-0.4% overt hyperthyroidism. However, those pregnant women with autoimmune thyroiditis and normal thyroid function may have a restricted thyroid reserve, followed by hypothyroxinemia and/or thyroid-stimulating hormone increase during pregnancy. The incidence of miscarriage, preterm delivery and small for date offspring might be increased and probably a delayed neuropsychological development. Routine thyroid function testing at least as early as possible in all pregnant women is emphasized.

  6. Thyroid and parathyroid ultrasound.

    PubMed

    Ghervan, Cristina

    2011-03-01

    Thyroid ultrasound is easy to perform due to the superficial location of the thyroid gland, but appropriate equipment is mandatory with a linear high frequency transducer (7.5 - 12) MHz. Some pathological aspects of the thyroid gland are easily diagnosed by ultrasound, like the enlargement of the thyroid volume (goiter) or the presence of nodules and cysts; while other aspects are more difficult and need more experience (diffuse changes in the structure, echogenicity and vascularization of the parenchyma, differential diagnosis of malignant nodules). Ultrasound has become the diagnostic procedure of choice in guidelines for the management of thyroid nodules; most structural abnormalities of the thyroid need evaluation and monitoring but not intervention. A good knowledge of the normal appearance of the thyroid gland is compulsory for an accurate ultrasound diagnosis.

  7. Thyroid and the heart.

    PubMed

    Grais, Ira Martin; Sowers, James R

    2014-08-01

    Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension, and cardiovascular disease all increase with advancing age, monitoring of thyroid-stimulating hormone, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions about thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases

    PubMed Central

    Fröhlich, Eleonore; Wahl, Richard

    2017-01-01

    Autoimmune diseases have a high prevalence in the population, and autoimmune thyroid disease (AITD) is one of the most common representatives. Thyroid autoantibodies are not only frequently detected in patients with AITD but also in subjects without manifest thyroid dysfunction. The high prevalence raises questions regarding a potential role in extra-thyroidal diseases. This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroid peroxidase, thyroid-stimulating hormone receptor (TSHR), and anti-thyroglobulin and their action outside the thyroid. The main issues limiting the reliability of the conclusions drawn here include problems with different specificities and sensitivities of the antibody detection assays employed, as well as potential confounding effects of altered thyroid hormone levels, and lack of prospective studies. In addition to the well-known effects of TSHR antibodies on fibroblasts in Graves’ disease (GD), studies speculate on a role of anti-thyroid antibodies in cancer. All antibodies may have a tumor-promoting role in breast cancer carcinogenesis despite anti-thyroid peroxidase antibodies having a positive prognostic effect in patients with overt disease. Cross-reactivity with lactoperoxidase leading to induction of chronic inflammation might promote breast cancer, while anti-thyroid antibodies in manifest breast cancer might be an indication for a more active immune system. A better general health condition in older women with anti-thyroid peroxidase antibodies might support this hypothesis. The different actions of the anti-thyroid antibodies correspond to differences in cellular location of the antigens, titers of the circulating antibodies, duration of antibody exposure, and immunological mechanisms in GD and Hashimoto’s thyroiditis. PMID:28536577

  9. [Riedel thyroiditis: two cases report].

    PubMed

    Zhou, Rongjin; Wang, Junguo

    2014-10-01

    Riedel thyroiditis is a benign disease, which is often self-limited. Examinations, such as CT and histologic diagnosis can distinguish it from malignant neoplasms and hashimoto's thyroiditis. Riedel thyroiditis is an uncommon form of chronic thyroiditis in which the thyroid gland is replaced by fibrous tissue. It can be cured by surgery and medicine.

  10. Thyroid hormone controls multiple independent programs required for limb development in Xenopus laevis metamorphosis.

    PubMed

    Brown, Donald D; Cai, Liquan; Das, Biswajit; Marsh-Armstrong, Nicholas; Schreiber, Alexander M; Juste, Rejeanne

    2005-08-30

    Thyroid hormone (TH) is required for limb development in Xenopus laevis. Specific cell types in the growing limb were targeted for expression of a dominant negative form of the TH receptor by sperm-mediated transgenesis. Limb muscle development, the innervation of muscle from the spinal cord, and cartilage growth can be inhibited without affecting patterning of the limb or differentiation of other cell types. Remodeling of the skin occurs late in metamorphosis after the limb has formed. The coordination of these independent programs is affected in part by the control that TH exerts over DNA replication in all cell types of the limb.

  11. What Does the Thyroid Gland Do?

    MedlinePlus

    ... where they do their work. Why are thyroid hormones important? Thyroid hormones help all your organs work ... even babies—can have thyroid problems. Having thyroid hormone levels that are too low (underactive thyroid gland) ...

  12. Signs and Symptoms of Thyroid Cancer

    MedlinePlus

    ... Detection, Diagnosis, and Staging Signs and Symptoms of Thyroid Cancer Thyroid cancer can cause any of the ... Health Care Team About Thyroid Cancer? More In Thyroid Cancer About Thyroid Cancer Causes, Risk Factors, and ...

  13. AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

    PubMed

    Kiyota, Tomomi; Yamamoto, Masaru; Schroder, Bryce; Jacobsen, Michael T; Swan, Russell J; Lambert, Mary P; Klein, William L; Gendelman, Howard E; Ransohoff, Richard M; Ikezu, Tsuneya

    2009-05-01

    Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.

  14. AAV1/2-mediated CNS Gene Delivery of Dominant-negative CCL2 Mutant Suppresses Gliosis, β-amyloidosis, and Learning Impairment of APP/PS1 Mice.

    PubMed

    Kiyota, Tomomi; Yamamoto, Masaru; Schroder, Bryce; Jacobsen, Michael T; Swan, Russell J; Lambert, Mary P; Klein, William L; Gendelman, Howard E; Ransohoff, Richard M; Ikezu, Tsuneya

    2009-05-01

    Accumulation of aggregated amyloid-β (Aβ) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, β-amyloidosis, including suppression of both fibrillar and oligomer Aβ accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.

  15. Genetic and Functional Characterization of the Escherichia coli BarA-UvrY Two-Component System: Point Mutations in the HAMP Linker of the BarA Sensor Give a Dominant-Negative Phenotype

    PubMed Central

    Tomenius, Henrik; Pernestig, Anna-Karin; Méndez-Catalá, Claudia F.; Georgellis, Dimitris; Normark, Staffan; Melefors, Öjar

    2005-01-01

    The BarA-UvrY two-component system family is strongly associated with virulence but is poorly understood at the molecular level. During our attempts to complement a barA deletion mutant, we consistently generated various mutated BarA proteins. We reasoned that characterization of the mutants would help us to better understand the signal transduction mechanism in tripartite sensors. This was aided by the demonstrated ability to activate the UvrY regulator with acetyl phosphate independently of the BarA sensor. Many of the mutated BarA proteins had poor complementation activity but could counteract the activity of the wild-type sensor in a dominant-negative fashion. These proteins carried point mutations in or near the recently identified HAMP linker, previously implicated in signal transduction between the periplasm and cytoplasm. This created sensor proteins with an impaired kinase activity and a net dephosphorylating activity. Using further site-directed mutagenesis of a HAMP linker-mutated protein, we could demonstrate that the phosphoaccepting aspartate 718 and histidine 861 are crucial for the dephosphorylating activity. Additional analysis of the HAMP linker-mutated BarA sensors demonstrated that a dephosphorylating activity can operate via phosphotransfer within a tripartite sensor dimer in vivo. This also means that a tripartite sensor can be arranged as a dimer even in the dephosphorylating mode. PMID:16237014

  16. Ikaros dominant negative isoform (Ik6) induces IL-3-independent survival of murine pro-B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels.

    PubMed

    Kano, Gen; Morimoto, Akira; Takanashi, Mami; Hibi, Shigeyoshi; Sugimoto, Tohru; Inaba, Tohru; Yagi, Tomohito; Imashuku, Shinsaku

    2008-05-01

    Ikaros is an essential regulator of lymphocyte differentiation. Mice transgenic for the Ikaros dominant negative (DN) mutation rapidly develop lymphoid malignancies. Various human leukemias have also been reported to express Ikaros DN isoforms, but its role in leukemogenesis is yet to be defined. We demonstrate that overexpressed Ikaros DN (Ik6) prolonged the survival of two different murine pro-B cell lines in cytokine deprived condition, and this was associated with increased expression of Bcl-xl. A survey of the upstream controller(s) of Bcl-xl expression revealed Ik6 overexpression enhanced the phosphorylation of JAK2 and STAT5. Interestingly, the Ik6 expressing cell lines showed reduced expression of B-cell differentiation surface marker CD45R (B220), which is also known as a JAK2 inhibitor. Although further evaluation with human clinical materials are required, these results propose a putative role of Ik6 in the development of B-lineage acute lymphoblastic leukemia, by activating the JAK2-STAT5 pathway and thus stimulating the production of Bcl-xl.

  17. GPKOW is essential for pre-mRNA splicing in vitro and suppresses splicing defect caused by dominant-negative DHX16 mutation in vivo

    PubMed Central

    Zang, Shengbing; Lin, Ting-Yu; Chen, Xinji; Gencheva, Marieta; Newo, Alain N. S.; Yang, Lixin; Rossi, Daniel; Hu, Jianda; Lin, Shwu-Bin; Huang, Aimin; Lin, Ren-Jang

    2014-01-01

    Human GPKOW [G-patch (glycine-rich) domain and KOW (Kyrpides, Ouzounis and Woese) domain] protein contains a G-patch domain and two KOW domains, and is a homologue of Arabidopsis MOS2 and Saccharomyces Spp2 protein. GPKOW is found in the human spliceosome, but its role in pre-mRNA splicing remains to be elucidated. In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. Adding back recombinant GPKOW restored splicing to the depleted extract. In vivo, overexpression of GPKOW partially suppressed the splicing defect observed in dominant-negative DHX16 mutant expressing cells. Mutations at the G-patch domain greatly diminished the GPKOW–DHX16 interaction; however, the mutant was active in splicing and was able to suppress splicing defect. Mutations at the KOW1 domain slightly altered the GPKOW–RNA interaction, but the mutant was less functional in vitro and in vivo. Our results indicated that GPKOW can functionally impact DHX16 but that interaction between the proteins is not required for this activity. PMID:25296192

  18. Interaction of MutS and Vsr: Some Dominant-Negative mutS Mutations That Disable Methyladenine-Directed Mismatch Repair Are Active in Very-Short-Patch Repair

    PubMed Central

    Lieb, Margaret; Rehmat, Shehnaz; Bhagwat, Ashok S.

    2001-01-01

    In Escherichia coli and related bacteria, the very-short-patch (VSP) repair pathway uses an endonuclease, Vsr, to correct T · G mismatches that result from the deamination of 5-methylcytosines in DNA to C · G. The products of mutS and mutL, which are required for adenine methylation-directed mismatch repair (MMR), enhance VSP repair. Multicopy plasmids carrying mutS alleles that are dominant negative for MMR were tested for their effects on VSP repair. Some mutS mutations (class I) did not lower VSP repair in a mutS+ background, and most class I mutations increased VSP repair in mutS cells more than plasmids containing mutS+. Other plasmid-borne mutS mutations (class II) and mutS+ decreased VSP repair in the mutS+ background. Thus, MutS protein lacking functions required for MMR can still participate in VSP repair, and our results are consistent with a model in which MutS binds transiently to the mispair and then translocates away from the mispair to create a specialized structure that enhances the binding of Vsr. PMID:11591694

  19. Interaction of MutS and Vsr: some dominant-negative mutS mutations that disable methyladenine-directed mismatch repair are active in very-short-patch repair.

    PubMed

    Lieb, M; Rehmat, S; Bhagwat, A S

    2001-11-01

    In Escherichia coli and related bacteria, the very-short-patch (VSP) repair pathway uses an endonuclease, Vsr, to correct T-G mismatches that result from the deamination of 5-methylcytosines in DNA to C-G. The products of mutS and mutL, which are required for adenine methylation-directed mismatch repair (MMR), enhance VSP repair. Multicopy plasmids carrying mutS alleles that are dominant negative for MMR were tested for their effects on VSP repair. Some mutS mutations (class I) did not lower VSP repair in a mutS(+) background, and most class I mutations increased VSP repair in mutS cells more than plasmids containing mutS(+). Other plasmid-borne mutS mutations (class II) and mutS(+) decreased VSP repair in the mutS(+) background. Thus, MutS protein lacking functions required for MMR can still participate in VSP repair, and our results are consistent with a model in which MutS binds transiently to the mispair and then translocates away from the mispair to create a specialized structure that enhances the binding of Vsr.

  20. Update on thyroid cancer.

    PubMed

    Benvenga, S

    2008-05-01

    With over 2 000 articles published on thyroid cancer between January 1, 2006 and September 10, 2007 it is difficult to offer an updated and complete review on this malignancy. Thus, I elected to summarize papers published in 2007 on topics frequently overlooked in other reviews or books, and papers that are likely to be followed by interesting developments. Papers include: 1) the accuracy and currency of websites on thyroid cancer; 2) the detection of the V600E BRAF mutation in very small papillary thyroid cancers that are detected histologically; 3) the relationship between thyroid cancer and Hashimoto's thyroiditis or hepatitis C virus, an association that appears to be nonrandom; 4) the not negligible frequency of coexistence of thyroid cancer with primary hyperparathyroidism; 5) the value of ultrasound elastography of thyroid nodules in distinguishing malignant form benign lesions; 6) the value of percutaneous ethanol injection in the treatment of thyroid or nodal recurrences of thyroid cancer; 7) the relatively benign course of intrathyroid metastases from renal cell carcinoma; 8) the exceedingly rare thyroid paraganglioma, though the rate of reports has increased recently; and 9) the increase in serum calcitonin caused by chronic alcoholism, an increase that cannot be reversed by three weeks of alcohol weaning.

  1. Ultrasound of the Thyroid Gland

    MedlinePlus

    ... Index A-Z Ultrasound - Thyroid Thyroid ultrasound uses sound waves to produce pictures of the thyroid gland ... pictures of the inside of the body using sound waves. Ultrasound imaging, also called ultrasound scanning or ...

  2. Submandibular ectopic thyroid with normally located thyroid gland.

    PubMed

    Yılmaz, Mahmut Sinan; Aytürk, Semra; Güven, Mehmet; Dilek, Fatma Hüsniye

    2014-01-01

    Ectopic thyroid is a rare developmental anomaly of the thyroid gland which is defined as the presence of thyroid tissue at a site other than the pretracheal area. Nearly 1 to 3% of all ectopic thyroids are located in the lateral neck. Simultaneous submandibular ectopic thyroid tissue presenting with a functional orthotopic thyroid gland is extremely rare. In this article, we report a 37-year-old female case admitted to our clinic with a complaint of swollen neck in whom ultrasonography revealed submandibular ectopic thyroid tissue presenting with an orthotopic thyroid gland.

  3. Thyroid Association Ophthalmopathy in Hashimoto's Thyroiditis: a Case Report.

    PubMed

    Jain, Deepak; Mor, Sudhir; Aggarwal, Hari Krishan; Chhabra, Pulkit; Jain, Promil

    2017-01-01

    Thyroid associated ophthalmopathy is a constellation of symptoms caused by an autoimmune process involving the orbital tissue. It is common in hyperthyroid patients due to Graves' disease and also reported in euthyroid and hypothyroid Graves' patients with positive thyroid receptor antibodies. But in Hashimoto's thyroiditis, thyroid associated ophthalmopathy is a rarely reported and poorly understood entity. Here we report thyroid associated ophthalmopathy in a patient with hypothyroidism and negative thyroid receptor antibodies who showed heterogeneously hypoechoic thyroid gland on ultrasonography, diffuse lymphocytic infiltrate on fine needle aspiration citology and reduced 99m Tc radioisotope uptake, supporting the diagnosis of Hashimoto's thyroiditis. The patient was treated with levothyroxine and artificial tear drops.

  4. Ectopic goitrous submandibular thyroid with goitrous orthotopic thyroid gland.

    PubMed

    Bhardwaj, Avinash Kumar; Mani, Vinayaga; Dixit, Rashmi; Garg, Anju

    2016-01-01

    Ectopic thyroid is a rare developmental anomaly with lingual thyroid accounting for majority of the cases. The presence of ectopic thyroid tissue lateral to the midline is very rare, and very few cases located in the submandibular region have been reported. The simultaneous finding of submandibular ectopic thyroid tissue and a functional orthotopic thyroid gland is even rarer. In the differential diagnosis of an ectopic submandibular thyroid, it is fundamental to exclude a metastasis from well-differentiated thyroid cancer, even when primary thyroid carcinoma is not demonstrable.

  5. Thyroid and the Heart

    PubMed Central

    Grais, Ira Martin; Sowers, James R.

    2015-01-01

    Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases. PMID:24662620

  6. [Thyroid involvement of sarcoidosis].

    PubMed

    Uto, Tomohiro; Inui, Naoki; Miyazaki, Hiroo; Matsushima, Sayomi; Kuroishi, Shigeki; Hashimoto, Dai; Naito, Tateaki; Nakamura, Yutaro; Sato, Jun; Suda, Takafumi; Chida, Kingo

    2008-08-01

    A 54-year-old woman was found to have abnormal shadows on her chest radiograph taken on an annual medical examination. The chest radiograph showed multiple nodules in the bilateral middle and lower lung fields accompanied with bilateral hilar lymphadenopathy. A computed tomography of the neck and chest revealed nodules in her right middle lobe and bilateral lower lobes with an enlarged thyroid. A metastatic malignant disease involving both thyroid and lungs was suspected, therefore thyroid and lung biopsies were performed. The histological examination of the thyroid and the lung specimens revealed non-caseating epithelioid cell granulomas which were compatible with sarcoidosis. Although the thyroid involvement of sarcoidosis is rare, it should be included in the differential diagnosis with patients with thyroid swelling.

  7. [Thyroid malfunction in women].

    PubMed

    Zárate, A; Basurto, L; Hernández, M

    2001-05-01

    The prevalence of thyroid dysfunctions is high in women, this female preponderance has been related with a bigger susceptibility to autoimmune abnormalities. Clinical features of thyroid disease have poor specificity and insidious onset. It is recommended to suspect thyroid pathology in the event of postpartum depression, menstrual abnormalities, amenorrhea, galactorrhea, precocious or delayed sexual development, inexplicable sterility or habitual abortus. The difficult in the clinical diagnosis is compensated by the accessibility and relative easiness of the biological diagnosis by means of the thyroid function tests, mainly the measurements of TSH and FT4 levels; thus, gynecological evaluations should be completed by obtaining thyroid function test. An opportune diagnosis of thyroid illness will solve under the best conditions the gynecological dysfunctions.

  8. [Thyroid hormone resistance syndromes].

    PubMed

    Bernal, Juan

    2011-04-01

    Thyroid hormone resistance syndromes are a group of genetic conditions characterized by decreased tissue sensitivity to thyroid hormones. Three syndromes, in which resistance to hormone action is respectively due to mutations in the gene encoding for thyroid hormone receptor TRβ, impaired T4 and T3 transport, and impaired conversion of T4 to T3 mediated by deiodinases. An updated review of each of these forms of resistance is provided, and their pathogenetic mechanisms and clinical approaches are discussed.

  9. Dual Ectopic Thyroid with Normally Located Thyroid: A Case Report

    PubMed Central

    Kumar Choudhury, Bipul; Kaimal Saikia, Uma; Sarma, Dipti; Saikia, Mihir; Dutta Choudhury, Sarojini; Barua, Santanu; Dewri, Swapna

    2011-01-01

    Dual ectopic thyroid is a rare presentation of thyroid ectopia. Only a few cases have been reported in the world literature. Dual ectopic thyroid in the presence of a normally located thyroid is even rarer. We report a case of dual ectopic thyroid in the lingual and submandibular areas in a seventeen-year-old female with hypoplastic thyroid gland in its normal location. The patient presented with a midline swelling at the base of tongue with dysphagia. Thyroid function test revealed primary hypothyroidism. Ultrasonography of the neck showed hypoplastic thyroid in its normal location. A thyroid scan with Technetium-99 m pertechnate showed two intensely hyperfunctioning foci of ectopic thyroid tissue at a higher level in the midline consistent with dual ectopic thyroid, one at the base of tongue and the other in submental region. No uptake was seen in the normal bed. PMID:21765986

  10. Thyroid cancer around Chernobyl

    SciTech Connect

    Beral, V.

    1997-03-01

    The author`s presentation on thyroid cancer around Chernobyl will focus on four different things. First will be the time trends, or the pattern of thyroid cancer occurrence before and after the accident. It is now very well known that the increase in thyroid cancer in children in several areas has been unprecedented. Second, the author discusses thyroid cancer in general and patterns of thyroid cancer around the world before the Chernobyl accident, including differences by age and pathology. Third, the author presents relatively crude analyses of risk according to dose to the thyroid gland. And last, the author attempts to contrast the findings for thyroid cancer in relation to the internal radioiodine dose in Chernobyl studies with analyses of the effects of external dose on thyroid cancer incidence. The bottom line to be developed is similar to that presented by Elaine Ron with regard to effects of external dose on thyroid cancer. The similarities between the childhood finding from Chernobyl studies and external radiation studies appear more remarkable than the differences.

  11. Human fetal thyroid function.

    PubMed

    Polak, Michel

    2014-01-01

    The early steps of thyroid development that lead to its function in the human fetus and subsequently the further maturation that allows the human fetus to secrete thyroxine (T4) in a significant amount are reviewed here. We underline the importance of the transfer of T4 from the pregnant woman to her fetus, which contributes at all stages of the pregnancy to fetal thyroid function and development. In the first trimester of pregnancy, the temporal and structural correlation of thyroid hormone synthesis with folliculogenesis supported the concept that structural and functional maturations are closely related. Human thyroid terminal differentiation follows a precisely timed gene expression program. The crucial role of the sodium/iodine symporter for the onset of thyroid function in the human fetus is shown. Fetal T4 is detected by the eleventh week of gestation and progressively increases throughout. The pattern of thyroid hormones and thyroid-stimulating hormone levels in the course of pregnancy is given from fetal blood sampling data, and the mechanisms governing this maturation in the human fetus are discussed. Finally an example of primary human fetal thyroid dysfunction, such as in Down syndrome, is given. The understanding of the physiology of the human fetal thyroid function is the basis for fetal medicine in the field of thyroidology.

  12. [Painful lymphocytic subacute thyroiditis].

    PubMed

    Cortázar, A; Ruiz de Gordejuela, J; Zabalza, I; Acinas, O; Beitia, J J

    1992-01-25

    Subacute granulomatous thyroiditis (SGT) and subacute lymphocytic thyroiditis (SLT) present a similar evolution during the first year, however, posteriorly, except on rare occasions, SGT maintains normofunction while SLT may present relapse with persistent goiter or permanent hypothyroidism requiring periodic follow up. The presence of spontaneous pain and very elevated VSG have been described accompanying SGT but not SLT histologically proven to be used for differentiating these entities. Two cases with clinical criteria and cytological diagnosis of SLT consulted for spontaneous thyroid pain are presented. VSG greater than 50 mm/1st hour was suggestive of SGT. The importance of cytology for the correct management of subacute thyroiditis is emphasized.

  13. Feline thyroid storm.

    PubMed

    Ward, Cynthia R

    2007-07-01

    Thyroid storm is a syndrome described in human medicine to define a multisystemic disorder resulting from organ exposure to excessive levels of thyroid hormone. This form of acute thyrotoxicosis, although uncommon, can be life threatening and is a significant cause of mortality in human emergency rooms. Although thyroid storm is a well-recognized clinical entity in human medicine, it has not been described in veterinary medicine. This article discusses the human syndrome and defines a similar syndrome in hyperthyroid veterinary patients. The clinical signs of and treatment modalities for feline thyroid storm are also presented.

  14. Establishment of the acute myeloid leukemia cell line Kasumi-6 from a patient with a dominant-negative mutation in the DNA-binding region of the C/EBPalpha gene.

    PubMed

    Asou, Hiroya; Gombart, Adrian F; Takeuchi, Seisho; Tanaka, Hideo; Tanioka, Maki; Matsui, Hirotaka; Kimura, Akiro; Inaba, Toshiya; Koeffler, H Phillip

    2003-02-01

    A myeloid leukemia cell line designated Kasumi-6 was established from the bone marrow cells of an individual with acute myeloid leukemia, subtype M2. Both the original leukemic cells and the Kasumi-6 cell line harbor a hemizygous point mutation in the gene encoding the CCAAT/enhancer binding protein alpha (C/EBPalpha), a critical myeloid transcriptional factor. The C to G transition at nucleotide 1063 of the C/EBPalpha gene results in amino acid transition R305P in the fork or hinge region between the DNA-binding basic region and the leucine zipper dimerization domain of the C/EBPalpha protein. The Kasumi-6 cells expressed both the p42 and p30 isoforms of the C/EBPalpha protein endogenously, but electrophoretic mobility shift assays demonstrated an absence of C/EBPalpha binding to its respective site. Exogenous expression of the mutant form of C/EBPalpha demonstrated that it was unable to bind DNA and activate transcription from a G-CSF receptor-luciferase reporter construct. Furthermore, coexpression of the wild-type and mutant forms revealed that the mutant form repressed reporter gene activation by the wild type in a dose-responsive manner. This was concomitant with a dose-responsive decrease in wild-type protein binding to the G-CSF receptor C/EBP site. The data suggest that the R305P alteration confers a dominant-negative property on the mutant C/EBPalpha protein whereby the mutant polypeptide heterodimerizes with the wild-type polypeptide and prevents it from binding to DNA, thus blocking transcriptional activation. The Kasumi-6 cell line can serve as a model to study the cellular and molecular biology of the non-t(8;21) M2 type of myeloid leukemia and can elucidate the role of mutated C/EBPalpha in leukemogenesis. Copyright 2003 Wiley-Liss, Inc.

  15. The C-terminal Domain (CTD) of Human DNA Glycosylase NEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome: DOMINANT NEGATIVE FUNCTION OF THE CTD.

    PubMed

    Hegde, Pavana M; Dutta, Arijit; Sengupta, Shiladitya; Mitra, Joy; Adhikari, Sanjay; Tomkinson, Alan E; Li, Guo-Min; Boldogh, Istvan; Hazra, Tapas K; Mitra, Sankar; Hegde, Muralidhar L

    2015-08-21

    The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA via its non-conserved C-terminal domain (CTD); replication factor C interaction results in ∼8-fold stimulation of NEIL1 activity. Disruption of NEIL1 interactions within the BERosome complex, as observed for a NEIL1 deletion mutant (N311) lacking the CTD, not only inhibits complete BER in vitro but also prevents its chromatin association and reduced recruitment at replication foci in S phase cells. This suggests that the interaction of NEIL1 with replication and other BER proteins is required for efficient repair of the replicating genome. Consistently, the CTD polypeptide acts as a dominant negative inhibitor during in vitro repair, and its ectopic expression sensitizes human cells to reactive oxygen species. We conclude that multiple interactions among BER proteins lead to large complexes, which are critical for efficient BER in mammalian cells, and the CTD interaction could be targeted for enhancing drug/radiation sensitivity of tumor cells.

  16. Manipulation of cellular GSH biosynthetic capacity via TAT-mediated protein transduction of wild-type or a dominant-negative mutant of glutamate cysteine ligase alters cell sensitivity to oxidant-induced cytotoxicity

    PubMed Central

    Backos, Donald S.; Brocker, Chad N.; Franklin, Christopher C.

    2009-01-01

    The glutathione (GSH) antioxidant defense system plays a central role in protecting mammalian cells against oxidative injury. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in GSH biosynthesis and is a heterodimeric holoenzyme composed of a catalytic (GCLC) and a modifier (GCLM) subunit. As a means of assessing the cytoprotective effects of enhanced GSH biosynthetic capacity, we have developed a protein transduction approach whereby recombinant GCL protein can be rapidly and directly transferred into cells when coupled to the HIV TAT protein transduction domain. Bacterial expression vectors encoding TAT fusion proteins of both GCL subunits were generated and recombinant fusion proteins were synthesized and purified to near homogeneity. The TAT-GCL fusion proteins were capable of heterodimerization and formation of functional GCL holoenzyme in vitro. Exposure of Hepa-1c1c7 cells to the TAT-GCL fusion proteins resulted in the time- and dose-dependent transduction of both GCL subunits and increased cellular GCL activity and GSH levels. A heterodimerization-competent, enzymatically deficient GCLC-TAT mutant was also generated in an attempt to create a dominant-negative suppressor of GCL. Transduction of cells with a catalytically inactive GCLC(E103A)-TAT mutant decreased cellular GCL activity in a dose-dependent manner. TAT-mediated manipulation of cellular GCL activity was also functionally relevant as transduction with wild-type GCLC(WT)-TAT or mutant GCLC(E103A)-TAT conferred protection or enhanced sensitivity to H2O2-induced cell death, respectively. These findings demonstrate that TAT-mediated transduction of wild-type or dominant-inhibitory mutants of the GCL subunits is a viable means of manipulating cellular GCL activity to assess the effects of altered GSH biosynthetic capacity. PMID:19914271

  17. Sequestration of muscarinic acetylcholine receptor m2 subtypes. Facilitation by G protein-coupled receptor kinase (GRK2) and attenuation by a dominant-negative mutant of GRK2.

    PubMed

    Tsuga, H; Kameyama, K; Haga, T; Kurose, H; Nagao, T

    1994-12-23

    Sequestration of m2 receptors (muscarinic acetylcholine receptor m2 subtypes), which was assessed as loss of N-[3H]methylscopolamine ([3H]NMS) binding activity from the cell surface, was examined in COS 7 and BHK-21 cells that had been transfected with expression vectors encoding the m2 receptor and, independently, vectors encoding a G protein-coupled receptor kinase (GRK2) (beta-adrenergic receptor kinase 1) or a GRK2 dominant-negative mutant (DN-GRK2). The sequestration of m2 receptors became apparent when the cells were treated with 10(-5) M or higher concentrations of carbamylcholine. In this case, approximately 40% or 20-25% of the [3H]NMS binding sites on COS 7 or BHK-21 cells, respectively, were sequestered with a half-life of 15-25 min. In cells in which GRK2 was also expressed, the sequestration became apparent in the presence of 10(-7) M carbamylcholine. Approximately 40% of the [3H]NMS binding sites on both COS 7 and BHK-21 cells were sequestered in the presence of 10(-6) M or higher concentrations of carbamylcholine. When DN-GRK2 was expressed in COS 7 cells, the proportion of [3H]NMS binding sites sequestered in the presence of 10(-5) M or higher concentrations of carbamylcholine was reduced to 20-30%. These results indicate that the phosphorylation of m2 receptors by GRK2 facilitates their sequestration. These results are in contrast with the absence of a correlation between sequestration and the phosphorylation of beta-adrenergic receptors by the GRK2 and suggests that the consequences of phosphorylation by GRK2 are different for different receptors.

  18. A herpes simplex virus 2 (HSV-2) glycoprotein D-expressing nonreplicating dominant-negative HSV-2 virus vaccine is superior to a gD2 subunit vaccine against HSV-2 genital infection in guinea pigs.

    PubMed

    Zhang, Pengwei; Xie, Lining; Balliet, John W; Casimiro, Danilo R; Yao, Feng

    2014-01-01

    We recently constructed a novel non-replicating dominant-negative HSV-2 recombinant viral vaccine (CJ2-gD2) capable of expressing various HSV-2 antigens that are dominant targets of HSV-2-specific CD8 T-cell response. Importantly, CJ2-gD2 expresses gD2, the HSV-2 major antigen glycoprotein D, as efficiently as wild-type HSV-2 infection and can lead to a nearly 500-fold reduction in wild-type HSV-2 viral replication in cells co-infected with CJ2-gD2 and wild-type HSV-2. In this report, we show that CJ2-gD2 elicits a strong antibody response to various HSV-2 antigens and is highly effective in the prevention of primary and recurrent HSV-2 genital infection and disease in the immunized guinea pigs. The direct comparison study between CJ2-gD2 and a gD2 subunit vaccine (gD2-alum/MPL) with a formulation akin to a vaccine tested in phase III clinical trials shows that CJ2-gD2 is 8 times more effective than the gD2-alum/MPL subunit vaccine in eliciting an anti-HSV-2 specific neutralizing antibody response and offers significantly superior protection against primary and recurrent HSV-2 genital infections. Importantly, no challenge wild-type HSV-2 viral DNA was detectable in dorsal root ganglia DNA isolated from CJ2-gD2-immunized guinea pigs on day 60 post-challenge. CJ2-gD2 should be an excellent HSV-2 vaccine candidate for protection against HSV-2 genital infection and disease in humans.

  19. Germline missense pathogenic variants in the BRCA1 BRCT domain, p.Gly1706Glu and p.Ala1708Glu, increase cellular sensitivity to PARP inhibitor olaparib by a dominant negative effect.

    PubMed

    Vaclová, Tereza; Woods, Nicholas T; Megías, Diego; Gomez-Lopez, Sergio; Setién, Fernando; García Bueno, José María; Macías, José Antonio; Barroso, Alicia; Urioste, Miguel; Esteller, Manel; Monteiro, Alvaro N A; Benítez, Javier; Osorio, Ana

    2016-12-15

    BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi olaparib depending on the BRCA1 mutation type. Lymphoblastoid cell lines derived from carriers of missense pathogenic variants in the BRCA1 BRCT domain (c.5117G > A, p.Gly1706Glu and c.5123C > A, p.Ala1708Glu) showed higher sensitivity to olaparib than cells with truncating variants or wild types (WT). Response to olaparib depended on a basal PARP enzymatic activity, but did not correlate with PARP1 expression. Interestingly, cellular sensitivity to the agent was associated with the level of BRCA1 recruitment into γH2AX foci, being the lowest in cells with missense variants. Since these variants lead to partially stable protein mutants, we propose a model in which the mutant protein acts in a dominant negative manner on the WT BRCA1, impairing the recruitment of BRCA1 into DNA damage sites and, consequently, increasing cellular sensitivity to PARPi. Taken together, our results indicate that carriers of different BRCA1 mutations could benefit from olaparib in a distinct way and show different toxicities to the agent, which could be especially relevant for a potential future use of PARPi as prophylactic agents in BRCA1 mutation carriers. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Binding of viral antigens to major histocompatibility complex class I H-2Db molecules is controlled by dominant negative elements at peptide non-anchor residues. Implications for peptide selection and presentation.

    PubMed

    Hudrisier, D; Mazarguil, H; Laval, F; Oldstone, M B; Gairin, J E

    1996-07-26

    Binding of viral antigens to major histocompatibility complex (MHC) class I molecules is a critical step in the activation process of CD8(+) cytotoxic T lymphocytes. In this study, we investigated the impact of structural factors at non-anchor residues in peptide-MHC interaction using the model of lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse. Altering viral genes by making reassortants, recombinants, and using synthetic peptides, CD8(+) cytotoxic T lymphocytes were shown to recognize only three H-2Db-restricted epitopes, GP amino acids 33-41/43, GP 276-286, and NP 396-404. However, LCMV NP and GP proteins contain 31 other peptides bearing the H-2Db motif. These 34 LCMV peptides and 11 other known H2-Db-restricted peptides were synthesized and examined for MHC binding properties. Despite the presence of the H-2Db binding motif, the majority of LCMV peptides showed weak or no affinity for H-2Db. We observed that dominant negative structural elements located at non-anchor positions played a crucial role in peptide-MHC interaction. By comparative sequence analysis of strong versus non-binders and using molecular modeling, we delineated these negative elements and evaluated their impact on peptide-MHC interaction. Our findings were validated by showing that a single mutation of a favorable non-anchor residue in the sequence of known viral epitopes for a negative element resulted in dramatic reduction of antigen presentation properties, while conversely, substitution of one negative for a positive element in the sequence of a non-binder conferred to the peptide an ability to now bind to MHC molecules.

  1. A dominant-negative F-box deleted mutant of E3 ubiquitin ligase, β-TrCP1/FWD1, markedly reduces myeloma cell growth and survival in mice

    PubMed Central

    Gupta, Anjana; McCluskey, Brandon; Bhaskaran, Shylesh; Muñoz, Steve; Oyajobi, Babatunde O.

    2015-01-01

    Treatment of multiple myeloma with bortezomib can result in severe adverse effects, necessitating the development of targeted inhibitors of the proteasome. We show that stable expression of a dominant-negative F-box deleted (ΔF) mutant of the E3 ubiquitin ligase, SCFβ-TrCP/FWD1, in murine 5TGM1 myeloma cells dramatically attenuated their skeletal engraftment and survival when inoculated into immunocompetent C57BL/KaLwRij mice. Similar results were obtained in immunodeficient bg-nu-xid mice, suggesting that the observed effects were independent of host recipient immune status. Bone marrow stroma offered no protection for 5TGM1-ΔF cells in cocultures treated with tumor necrosis factor (TNF), indicating a cell-autonomous anti-myeloma effect. Levels of p100, IκBα, Mcl-1, ATF4, total and cleaved caspase-3, and phospho-β-catenin were elevated in 5TGM1-ΔF cells whereas cIAP was down-regulated. TNF also activated caspase-3 and downregulated Bcl-2, correlating with the enhanced susceptibility of 5TGM1-ΔF cells to apoptosis. Treatment of 5TGM1 tumor-bearing mice with a β-TrCP1/FWD1 inhibitor, pyrrolidine dithiocarbamate (PDTC), significantly reduced tumor burden in bone. PDTC also increased levels of cleaved Mcl-1 and caspase-3 in U266 human myeloma cells, correlating with our murine data and validating the development of specific β-TrCP inhibitors as an alternative therapy to nonspecific proteasome inhibitors for myeloma patients. PMID:26009993

  2. Dominant-negative derivative of EBNA1 represses EBNA1-mediated transforming gene expression during the acute phase of Epstein-Barr virus infection independent of rapid loss of viral genome.

    PubMed

    Kariya, Yumi; Hamatake, Makiko; Urano, Emiko; Yoshiyama, Hironori; Shimizu, Norio; Komano, Jun

    2010-04-01

    The oncogenic human herpes virus, the Epstein-Barr virus (EBV), expresses EBNA1 in almost all forms of viral latency. EBNA1 plays a major role in the maintenance of the viral genome and in the transactivation of viral transforming genes, including EBNA2 and latent membrane protein (LMP-1). However, it is unknown whether inhibition of EBNA1 from the onset of EBV infection disrupts the establishment of EBV's latency and transactivation of the viral oncogenes. To address this, we measured EBV infection kinetics in the B cell lines BALL-1 and BJAB, which stably express a dominant-negative EBNA1 (dnE1) fused to green fluorescent protein (GFP). The EBV genome was surprisingly unstable 1 week post-infection: the average loss rate of EBV DNA from GFP- and GFP-dnE1-expressing cells was 53.4% and 41.0% per cell generation, respectively, which was substantially higher than that of an 'established'oriP replicon (2-4%). GFP-dnE1 did not accelerate loss of the EBV genome, suggesting that EBNA1-dependent licensing of the EBV genome occurs infrequently during the acute phase of EBV infection. In the subacute phase, establishment of EBV latency was completely blocked in GFP-dnE1-expressing cells. In contrast, C/W promoter-driven transcription was strongly restricted in GFP-dnE1-expressing cells at 2 days post-infection. These data suggest that inhibition of EBNA1 from the onset of EBV infection is effective in blocking the positive feedback loop in the transactivation of viral transforming genes, and in eradicating the EBV genome during the subacute phase. Our results suggest that gene transduction of GFP-dnE1 could be a promising therapeutic and prophylactic approach toward EBV-associated malignancies.

  3. Primary Brain Calcification Causal PiT2 Transport-Knockout Variants can Exert Dominant Negative Effects on Wild-Type PiT2 Transport Function in Mammalian Cells.

    PubMed

    Larsen, Frederik Tibert; Jensen, Nina; Autzen, Jacob Kwasi; Kongsfelt, Iben Boutrup; Pedersen, Lene

    2017-02-01

    Primary brain calcification (PBC) is a neurodegenerative disorder characterized by calcium-phosphate deposits in the basal ganglia and often also other areas of the brain. The prevalent clinical manifestations are cognitive impairment, neuropsychiatric symptoms, and movement disorders. In recent years, monoallelic variants in SLC20A2, which encodes the type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2), have been linked to the familial form of PBC in 40-50% of the families reported worldwide as well as to sporadic cases of PBC. Further insight into the disease mechanism is, however, needed. Based on co-expression studies of wild-type and variant PiT2 in Xenopus laevis oocytes, the molecular disease mechanism associated with SLC20A2 missense variants has formerly been suggested to be haploinsufficiency. We have here used mammalian cells isolated from a Slc20a2 (-/-) mouse and co-expression of human wild-type and variant PiT2. Two of the variants studied have both been reported twice in unrelated PBC cases: PiT2D28N in two sporadic cases and PiT2E575K in a familial and a sporadic case. We find that in mammalian cells, the analyzed SLC20A2 missense variants can exert their effect in a dominant negative manner resulting in decreased wild-type PiT2 Pi transport. Thus, compared to monoallelic lack of functional PiT2 protein expression, which reasonably points towards haploinsufficiency, certain SLC20A2 missense variants may be more detrimental for cellular Pi uptake and potentially contribute to an earlier disease onset and/or a more severe phenotype as observed for Slc20a2 (-/-) mice compared to Slc20a2 (+/-) mice.

  4. Manipulation of cellular GSH biosynthetic capacity via TAT-mediated protein transduction of wild-type or a dominant-negative mutant of glutamate cysteine ligase alters cell sensitivity to oxidant-induced cytotoxicity

    SciTech Connect

    Backos, Donald S.; Brocker, Chad N.; Franklin, Christopher C.

    2010-02-15

    The glutathione (GSH) antioxidant defense system plays a central role in protecting mammalian cells against oxidative injury. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in GSH biosynthesis and is a heterodimeric holoenzyme composed of catalytic (GCLC) and modifier (GCLM) subunits. As a means of assessing the cytoprotective effects of enhanced GSH biosynthetic capacity, we have developed a protein transduction approach whereby recombinant GCL protein can be rapidly and directly transferred into cells when coupled to the HIV TAT protein transduction domain. Bacterial expression vectors encoding TAT fusion proteins of both GCL subunits were generated and recombinant fusion proteins were synthesized and purified to near homogeneity. The TAT-GCL fusion proteins were capable of heterodimerization and formation of functional GCL holoenzyme in vitro. Exposure of Hepa-1c1c7 cells to the TAT-GCL fusion proteins resulted in the time- and dose-dependent transduction of both GCL subunits and increased cellular GCL activity and GSH levels. A heterodimerization-competent, enzymatically deficient GCLC-TAT mutant was also generated in an attempt to create a dominant-negative suppressor of GCL. Transduction of cells with a catalytically inactive GCLC(E103A)-TAT mutant decreased cellular GCL activity in a dose-dependent manner. TAT-mediated manipulation of cellular GCL activity was also functionally relevant as transduction with wild-type GCLC(WT)-TAT or mutant GCLC(E103A)-TAT conferred protection or enhanced sensitivity to H{sub 2}O{sub 2}-induced cell death, respectively. These findings demonstrate that TAT-mediated transduction of wild-type or dominant-inhibitory mutants of the GCL subunits is a viable means of manipulating cellular GCL activity to assess the effects of altered GSH biosynthetic capacity.

  5. Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate

    PubMed Central

    Liu, Huan; Leslie, Elizabeth J.; Jia, Zhonglin; Smith, Tiffany; Eshete, Mekonen; Butali, Azeez; Dunnwald, Martine; Murray, Jeffrey; Cornell, Robert A.

    2016-01-01

    Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome-wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead-like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here, we report that Krüppel-like factor 17 (Klf17), like Grhl3, acts downstream of Irf6 in this network in zebrafish periderm. Although Klf17 expression is absent from mammalian oral epithelium, a close homologue, Klf4, is expressed in this tissue and is required for the differentiation of epidermis. Chromosome configuration capture and reporter assays indicated that IRF6 directly regulates an oral-epithelium enhancer of KLF4. To test whether rare missense variants of KLF4 contribute risk for NSCL/P, we sequenced KLF4 in approximately 1000 NSCL/P cases and 300 controls. By one statistical test, missense variants of KLF4 as a group were enriched in cases versus controls. Moreover, two patient-derived KLF4 variants disrupted periderm differentiation upon forced expression in zebrafish embryos, suggesting that they have dominant-negative effect. These results indicate that rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation. PMID:26692521

  6. Decitabine in Treating Patients With Metastatic Papillary Thyroid Cancer or Follicular Thyroid Cancer Unresponsive to Iodine I 131

    ClinicalTrials.gov

    2014-08-20

    Recurrent Thyroid Cancer; Stage IVA Follicular Thyroid Cancer; Stage IVA Papillary Thyroid Cancer; Stage IVB Follicular Thyroid Cancer; Stage IVB Papillary Thyroid Cancer; Stage IVC Follicular Thyroid Cancer; Stage IVC Papillary Thyroid Cancer

  7. Thyroid Growth and Cancer

    PubMed Central

    Williams, Dillwyn

    2015-01-01

    It is proposed that most papillary thyroid cancers originate in infancy and childhood, based on the early rise in sporadic thyroid carcinoma incidence, the pattern of radiation-induced risk (highest in those exposed as infants), and the high prevalence of sporadic papillary thyroid cancers in children and adolescents (ultrasound screening after the Fukushima accident). The early origin can be linked to the growth pattern of follicular cells, with a high mitotic rate in infancy falling to very low replacement levels in adult life. The cell of origin of thyroid cancers, the differentiated follicular cell, has a limited growth potential. Unlike cancers originating in stem cells, loss of the usually tight link between differentiation and replicative senescence is required for immortalisation. It is suggested that this loss distinguishes larger clinically significant papillary thyroid cancers from micro-papillary thyroid cancers of little clinical significance. Papillary carcinogenesis can then be divided into 3 stages: (1) initiation, the first mutation in the carcinogenic cascade, for radiation-induced papillary thyroid cancers usually a RET rearrangement, (2) progression, acquisition of the additional mutations needed for low-grade malignancy, and (3) escape, further mutations giving immortality and a higher net growth rate. Most papillary thyroid cancers will not have achieved full immortality by adulthood, and remain as so-called micro-carcinomas with a very low growth rate. The use of the term ‘cancer’ to describe micro-papillary thyroid cancers in older patients encourages overtreatment and alarms patients. Invasive papillary thyroid tumours show a spectrum of malignancy, which at its lowest poses no threat to life. The treatment protocols and nomenclature for small papillary carcinomas need to be reconsidered in the light of the new evidence available, the continuing discovery of smaller lesions, and the model of thyroid carcinogenesis proposed. PMID

  8. Thyroid gland biopsy (image)

    MedlinePlus

    The thyroid is a gland located in the neck. It is a part of the endocrine (hormone) system, and plays a major role in regulating ... sample of cells is needed from the thyroid gland a fine needle biopsy can be performed. During ...

  9. [Ultrasound of the thyroid].

    PubMed

    Dietrich, C F; Bojunga, J

    2015-03-01

    Thyroid nodules and thyroid abnormalities are common findings in the general population. Ultrasonography is the most important imaging tool for diagnosing thyroid disease. In the majority of cases a correct diagnosis can already be made in synopsis of the sonographic together with clinical findings and basal thyroid hormone parameters and an appropriate therapy can be initiated thereafter. A differentiation of hormonally active versus inactive nodes, and in particular benign versus malignant nodules is sonographically, however, not reliably possible. In this context, radioscanning has its clinical significance predominantly in diagnosing hormonal activity of thyroid nodules. Efforts of the past years aimed to improve sonographic risk stratification to predict malignancy of thyroid nodules through standardized diagnostic assessment of evaluated risk factors in order to select patients, who need further diagnostic work up. According to the "Breast Imaging Reporting and Data System" (BI-RADS), "Thyroid Imaging Reporting and Data Systems" (TI-RADS) giving standardized categories with rates of malignancy were evaluated as a basis for further clinical management. Recent technological developments, such as elastography, also show promising data and could gain entrance into clinical practice. The ultrasound-guided fine-needle aspiration is the key element in the diagnosis of sonographically suspicious thyroid nodules and significantly contributes to the diagnosis of malignancy versus benignity.

  10. [Ultrasound of the Thyroid].

    PubMed

    Dietrich, C F; Bojunga, J

    2016-02-01

    Thyroid nodules and thyroid abnormalities are common findings in the general population. Ultrasonography is the most important imaging tool for diagnosing thyroid disease. In the majority of cases a correct diagnosis can already be made in synopsis of the sonographic together with clinical findings and basal thyroid hormone parameters and an appropriate therapy can be initiated thereafter. A differentiation of hormonally active vs. inactive nodes, and in particular benign vs. malignant nodules is sonographically, however, not reliably possible. In this context, radioscanning has its clinical significance predominantly in diagnosing hormonal activity of thyroid nodules. Efforts of the past years aimed to improve sonographic risk stratification to predict malignancy of thyroid nodules through standardized diagnostic assessment of evaluated risk factors in order to select patients, who need further diagnostic work up. According to the "Breast Imaging Reporting and Data System" (BI-RADS), "Thyroid Imaging Reporting and Data Systems" (TI-RADS) giving standardized categories with rates of malignancy were evaluated as a basis for further clinical management. Recent technological developments, such as elastography, also showpromising data and could gain entrance into clinical practice. The ultrasound-guided fineneedle aspiration is the key element in the diagnosis of sonographically suspicious thyroid nodules and significantly contributes to the diagnosis of malignancy versus benignity.

  11. Adipocytokines in Thyroid Dysfunction

    PubMed Central

    Aydogan, Berna İmge; Sahin, Mustafa

    2013-01-01

    Adipocytokines are important mediators of interorgan crosstalk in metabolic regulation. Thyroid diseases have effects on metabolism and inflammation. The mechanism of these effects is not clear. Recently, there are several reports suggesting this interrelation between adipocytokines and thyroid dysfunction. In this review, we summarize this relation according to the literature. PMID:24049662

  12. [Thyroid and radiation].

    PubMed

    Yamashita, S; Namba, H; Nagataki, S

    1993-11-20

    The topic "Thyroid and Radiation" is both an old and a new area to be solved by human beings. The thyroid is an organ that is usually susceptible to exposure to ionizing radiation, both by virtue of its ability to concentrate radioiodine (internal radiation) and by routine medical examination: Chest X-ray, Dental X-ray, X-irradiation of cervical lymphnodes etc. (external radiation). Iodine-131 is widely used for the therapy of Graves' disease and thyroid cancers, of which the disadvantage is radiation-induced hypothyroidism but not complications of thyroid tumor. The thyroid gland is comparatively radioresistant, however, the data obtained from Hiroshima, Nagasaki and Marshall islands indicates a high incidence of external radiation-induced thyroid tumors as well as hypothyroidism. The different biological effects of internal and external radiation remains to be further clarified. Interestingly, recent reports demonstrate the increased number of thyroid cancer in children around Chernobyl in Belarus. In this review, we would like to introduce the effect of radiation on the thyroid gland at the molecular, cellular and tissue levels. Furthermore the clinical usefulness of iodine-131, including the safety-control for radiation exposure will be discussed.

  13. Thyroid imaging studies

    SciTech Connect

    Drew, H.H.; LaFrance, N.D.; Chen, J.J.S.

    1987-06-01

    This is the second in a series of Continuing Education articles related to functional/quantitative imaging techniques. After reading this article, the reader should be able to: 1) discuss the clinical applications of thyroid imaging; 2) understand the relationship of related thyroid tests; and 3) recognize the pitfalls and problems associated with this procedure.

  14. Eponym : de Quervain thyroiditis.

    PubMed

    Engkakul, Pontipa; Mahachoklertwattana, Pat; Poomthavorn, Preamrudee

    2011-04-01

    de Quervain thyroiditis is a self-limited inflammatory disorder of the thyroid gland. It is an uncommon disease in adults and very rare in children. Fritz de Quervain, a Swiss surgeon, who was an authority on thyroid disease, described the unique pathology of this disease. Granulomatous changes with giant cells in thyroid tissue are the pathological findings. Viral infection in genetically predisposed individuals has been proposed as the pathogenesis of the disease. Clinical hallmarks for the diagnosis are painful thyroid enlargement, elevated erythrocyte sedimentation rate, and C-reactive protein as well as decreased uptake of the thyroid gland on thyroid scintigraphy. In addition, thyrotoxicosis is present in about 50% of cases in early phase of the disease. Serum thyroglobulin level is usually elevated. Only symptomatic treatment with analgesics is usually required for pain relief. Glucocorticoid therapy may be used in severely ill patients. de Quervain thyroiditis is generally completely resolved without complications in 6-12 months. However, permanent hypothyroidism and recurrent disease have been reported in some patients.

  15. Thyroid associated orbitopathy

    PubMed Central

    Verma, Rajesh; Gupta, Mani; Mehta, Vinod Kumar

    2013-01-01

    Thyroid-associated orbitopathy (TAO) is a self-limiting auto-immune condition usually associated with Grave's disease. It is characterised by ocular pain, eyelid swelling, chemosis, proptosis and keratopathy. As the mechanism for ophthamoplegia and optic neuropathy is the orbital swelling leading to mechanical restriction of ocular muscles and compression of optic nerve, one expects proptosis rather than ptosis in TAO. We describe a case of a young adult woman who presented with acute onset restriction of movement along with partial ptosis and severe diminution of vision in left eye. The MRI of orbit revealed significant swelling of recti along with signal alteration consistent with TAO. The radio-isotope thyroid scan revealed thyroiditis, and thyroid peroxidase (TPO) antibody was significantly high; hence, the diagnosis of Hashimoto thyroiditis was considered. A course of intravenous methylprednisolone followed by oral steroid was administered, which produced marked improvement in vision and extraocular movement. PMID:23737589

  16. Cardiovascular effects of thyroid disease.

    PubMed

    Sangster, Jodi K; Panciera, David L; Abbott, Jonathan A

    2013-07-01

    Thyroid hormones have many effects on cardiovascular function, and deficiency or excess of thyroid hormones can result in cardiac dysfunction. Abnormalities of the cardiovascular system are often identified during examination of hyperthyroid and hypothyroid patients. This article addresses the effects of thyroid hormones on the cardiovascular system and the clinical relevance of the cardiovascular response to thyroid dysfunction. In addition, treatment recommendations are presented.

  17. Cytokines and thyroid function.

    PubMed

    Ajjan, R A; Watson, P F; Weetman, A P

    1996-01-01

    Cytokines play a crucial role in autoimmune thyroid disease (ATD) through various mechanisms. They are produced in the thyroid by intrathyroidal inflammatory cells, in particular lymphocytes, as well as by the thyroid follicular cells (TFC) themselves and may thus act in a cascade to enhance the autoimmune process (Fig. 1). Cytokines upregulate the inflammatory reaction through stimulation of both T and B cells, resulting in antibody production and tissue injury. In addition, intrathyroidal cytokines induce immunological changes in TFC including enhancement of both major histocompatibility complex (MHC) class I and class II molecule expression, and upregulation of adhesion and complement regulatory molecule expression. Cytokines can also modulate both growth and function of TFC and have a role in extrathyroidal complications of ATD, most importantly thyroid-associated ophthalmopathy (TAO), where they induce fibroblast proliferation and enhance the production of glycosaminoglycans (GAG), resulting in proptosis and the other clinical features of the disease. In addition to these effects, exogenous administration of cytokines has been associated with impairment of thyroid function ranging from the appearance of autoantibodies alone to the development of frank thyroid dysfunction. Cytokines have also been implicated in subacute thyroiditis (SAT) and amiodarone-induced thyroid dysfunction, as well as in thyroid function abnormalities occurring in patients with non-thyroidal illnesses (NTI). Genetic variations in cytokine genes represent potential risk factors for ATD, and disease associations have been described for polymorphisms in IL-1ra and TNF beta genes. Recent experimental evidence suggests the possibility of novel cytokine-based therapeutic approaches for ATD and its complications, in particular TAO.

  18. [Haemorrhage after thyroid surgery].

    PubMed

    Swirta, Jarosław S; Barczyński, Marcin

    2014-01-01

    Haemorrhage after thyroid surgery is rare, but if it occurs it is a life-threatening condition necessitating emergency surgery. The aim of this study was to evaluate prevalence and risk factors of haemorrhage after thyroid surgery. A retrospective analysis was undertaken in a group of 8931 consecutive patients with various thyroid diseases treated in 2004-2013 at our institution. Potential risk factors for postoperative haemorrhage after thyroid surgery were analysed using logistic regression model. Haemorrhage after thyroid operation necessitating emergency surgery occurred in 40 (0.45%) of 8931 patients. None of the patients died within the perioperative period. Bleeding occurred within first 24 hours following surgery in 38 (95%) patients, and in the remaining 2 (5%) patients in more than 24 hours after initial surgery. The following risk factors for bleeding after thyroid operation were identified: male sex (OR 3.618; 1.762-7.430; p < 0.001), older age > or = 70 years (OR 3.052; 1.275-7.304; p = 0.012), surgery for hyperthyroidism (OR 2.873; 1.511-5.462; p = 0.001), smoking (OR 2.855; 1.502-5.428; p = 0.001), subtotal thyroidectomy in contrast to total thyroidectomy or lobectomy (OR 2.853; 1.356-6.004; p=0.006), and thyroid operation undertaken by resident in training in general surgery (OR 2.596; 1.393-4.837; p = 0.003). Haemorrhage after thyroid operation necessitating emergency surgical intervention occurs most frequently within first 24 hour following surgery. Hence, for safety reasons a minimum of 24-hour hospital stay is recommended in all patients with risk factors for postoperative bleeding after thyroid operation. Quality monitoring of thyroid surgery should include also risk factors for postoperative bleeding.

  19. Rough Endoplasmic Reticulum (rER) Trafficking Errors by Different Classes of Mutant DSPP Cause the Dominant Negative Effects in both Dentinogenesis Imperfecta and Dentin Dysplasia by Entrapping Normal DSPP

    PubMed Central

    von Marschall, Zofia; Mok, Seeun; Phillips, Matthew D.; McKnight, Dianalee A.; Fisher, Larry W.

    2012-01-01

    Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant-negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5' mutations of DSPP result in changes/loss in the first three amino acids (IPV) of mature DSPP or, for A15V, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rER of transfected HEK293 cells. Trafficking out of the rER by co-expressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3'-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5' frameshift mutations result in longer mutant hydrophobic domains but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II & III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor

  20. Pazopanib Hydrochloride in Treating Patients With Advanced Thyroid Cancer

    ClinicalTrials.gov

    2017-01-31

    Recurrent Thyroid Gland Carcinoma; Stage III Differentiated Thyroid Gland Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IVA Differentiated Thyroid Gland Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVA Thyroid Gland Undifferentiated (Anaplastic) Carcinoma; Stage IVB Differentiated Thyroid Gland Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Undifferentiated (Anaplastic) Carcinoma; Stage IVC Differentiated Thyroid Gland Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Undifferentiated (Anaplastic) Carcinoma; Thyroid Gland Undifferentiated (Anaplastic) Carcinoma

  1. Thyroid disease in pregnancy.

    PubMed

    Carney, Leo A; Quinlan, Jeff D; West, Janet M

    2014-02-15

    Thyroid disease is the second most common endocrine disorder affecting women of reproductive age, and when untreated during pregnancy is associated with an increased risk of miscarriage, placental abruption, hypertensive disorders, and growth restriction. Current guidelines recommend targeted screening of women at high risk, including those with a history of thyroid disease, type 1 diabetes mellitus, or other autoimmune disease; current or past use of thyroid therapy; or a family history of autoimmune thyroid disease. Appropriate management results in improved outcomes, demonstrating the importance of proper diagnosis and treatment. In women with hypothyroidism, levothyroxine is titrated to achieve a goal serum thyroid-stimulating hormone level less than 2.5 mIU per L. The preferred treatment for hyperthyroidism is antithyroid medications, with a goal of maintaining a serum free thyroxine level in the upper one-third of the normal range. Postpartum thyroiditis is the most common form of postpartum thyroid dysfunction and may present as hyper- or hypothyroidism. Symptomatic treatment is recommended for the former; levothyroxine is indicated for the latter in women who are symptomatic, breastfeeding, or who wish to become pregnant.

  2. Occupation and thyroid cancer.

    PubMed

    Aschebrook-Kilfoy, Briseis; Ward, Mary H; Della Valle, Curt T; Friesen, Melissa C

    2014-05-01

    Numerous occupational and environmental exposures have been shown to disrupt thyroid hormones, but much less is known about their relationships with thyroid cancer. Here we review the epidemiology studies of occupations and occupational exposures and thyroid cancer incidence to provide insight into preventable risk factors for thyroid cancer. The published literature was searched using the Web of Knowledge database for all articles through August 2013 that had in their text 'occupation' 'job' 'employment' or 'work' and 'thyroid cancer'. After excluding 10 mortality studies and 4 studies with less than 5 exposed incident cases, we summarised the findings of 30 articles that examined thyroid cancer incidence in relation to occupations or occupational exposure. The studies were grouped by exposure/occupation category, study design and exposure assessment approach. Where available, gender-stratified results are reported. The most studied (19 of 30 studies) and the most consistent associations were observed for radiation-exposed workers and healthcare occupations. Suggestive, but inconsistent, associations were observed in studies of pesticide-exposed workers and agricultural occupations. Findings for other exposures and occupation groups were largely null. The majority of studies had few exposed cases and assessed exposure based on occupation or industry category, self-report, or generic (population-based) job exposure matrices. The suggestive, but inconsistent findings for many of the occupational exposures reviewed here indicate that more studies with larger numbers of cases and better exposure assessment are necessary, particularly for exposures known to disrupt thyroid homeostasis.

  3. Thyroid Ultrasound: State of the Art Part 1 - Thyroid Ultrasound reporting and Diffuse Thyroid Diseases.

    PubMed

    Dighe, Manjiri; Barr, Richard; Bojunga, Jörg; Cantisani, Vito; Chammas, Maria Cristina; Cosgrove, David; Cui, Xin Wu; Dong, Yi; Fenner, Franziska; Radzina, Maija; Vinayak, Sudhir; Xu, Jun Mei; Dietrich, Christoph F

    2017-01-31

    Accurate differentiation of focal thyroid nodules (FTL) and thyroid abnormalities is pivotal for proper diagnostic and therapeutic work-up. In these two part articles, the role of ultrasound techniques in the characterization of FTL and evaluation of diffuse thyroid diseases is described to expand on the recently published World Federation in Ultrasound and Medicine (WFUMB) thyroid elastography guidelines and review how this guideline fits into a complete thyroid ultrasound exam.

  4. Dynamical model for thyroid

    NASA Astrophysics Data System (ADS)

    Rokni Lamooki, Gholam Reza; Shirazi, Amir H.; Mani, Ali R.

    2015-05-01

    Thyroid's main chemical reactions are employed to develop a mathematical model. The presented model is based on differential equations where their dynamics reflects many aspects of thyroid's behavior. Our main focus here is the well known, but not well understood, phenomenon so called as Wolff-Chaikoff effect. It is shown that the inhibitory effect of intake iodide on the rate of one single enzyme causes a similar effect as Wolff-Chaikoff. Besides this issue, the presented model is capable of revealing other complex phenomena of thyroid hormones homeostasis.

  5. Transoral robotic thyroid surgery

    PubMed Central

    Clark, James H.; Kim, Hoon Yub

    2015-01-01

    There is currently significant demand for minimally invasive thyroid surgery; however the majority of proposed surgical approaches necessitate a compromise between minimal tissue dissection with a visible cervical scar or extensive tissue dissection with a remote, hidden scar. The development of transoral endoscopic thyroid surgery however provides an approach which is truly minimally invasive, as it conceals the incision within the oral cavity without significantly increasing the amount of required dissection. The transoral endoscopic approach however presents multiple technical challenges, which could be overcome with the incorporation of a robotic operating system. This manuscript summarizes the literature on the feasibility and current clinical experience with transoral robotic thyroid surgery. PMID:26425456

  6. TSH (Thyroid-Stimulating Hormone) Test

    MedlinePlus

    ... symptoms of a thyroid disorder , including hyperthyroidism or hypothyroidism . TSH is produced by the pituitary gland , a ... thyroid Monitor thyroid replacement therapy in people with hypothyroidism Monitor anti-thyroid treatment in people with hyperthyroidism ...

  7. Check Your Neck for Thyroid Abnormalities

    MedlinePlus

    ... Thyroid Awareness Month. "The number of cases of thyroid cancer is rising, and while in most cases the ... the American Thyroid Association. "While in most patients thyroid cancer develops without signs or symptoms, patients who have ...

  8. Aspergillus thyroiditis in a renal transplant recipient mimicking subacute thyroiditis.

    PubMed

    Solak, Y; Atalay, H; Nar, A; Ozbek, O; Turkmen, K; Erekul, S; Turk, S

    2011-04-01

    Fungal pathogens are increasingly encountered after renal transplantation. Aspergillus causes significant morbidity and mortality in transplant patients. Fungal thyroiditis is a rare occurrence owing to unique features of the thyroid gland. Most cases are caused by Aspergillus species and have been described in immunocompromised patients. Presentation may be identical with that of subacute thyroiditis, in which hyperthyroidism features and painful thyroid are the prominent findings. Diagnosis can be ascertained by fine-needle aspiration of thyroid showing branching hyphae of Aspergillus. We describe a renal transplant patient who developed Aspergillus thyroiditis as part of a disseminated infection successfully treated with voriconazole.

  9. Thyroid gland disorder emergencies: thyroid storm and myxedema coma.

    PubMed

    Hampton, Jessica

    2013-01-01

    Although thyroid dysfunction will develop in more than 12% of the US population during their lifetimes, true thyroid emergencies are rare. Thyroid storm and myxedema coma are endocrine emergencies resulting from thyroid hormone dysregulation, usually coupled with an acute illness as a precipitant. Careful assessment of risk and rapid action, once danger is identified, are essential for limiting morbidity and mortality related to thyroid storm and myxedema coma. This article reviews which patients are at risk, explains thyroid storm and myxedema coma, and describes pharmacological treatment and supportive cares.

  10. Hashimoto's thyroiditis following Graves' disease.

    PubMed

    Umar, Husaini; Muallima, Nur; Adam, John M F; Sanusi, Harsinen

    2010-01-01

    Both Graves' disease and chronic thyroiditis (Hashimoto's thyroiditis) are autoimmune diseases of thyroid gland. Graves' disease is caused by stimulation of TSH receptor located on the thyroid gland by an antibody, which is known as TSH receptor antibody (TRAb). Furthermore, this may lead to hyperplasia and hyperfunction of the thyroid gland. On the contrary, the cause of Hashimoto's thyroiditis is thought due to a TSH stimulation-blocking antibody (TSBAb) which blocks the action of TSH hormone and subsequently brings damage and atrophy to thyroid gland. Approximately 15-20% of patients with Graves' disease had been reported to have spontaneous hypothyroidism resulting from the chronic thyroiditis (Hashimoto's disease). Pathogenesis for chronic thyroiditis following anti-thyroid drug treatment in patients with Graves' disease remains unclear. It has been estimated that chronic thyroiditis or Hashimoto's disease, which occurs following the Graves' disease episode is due to extended immune response in Graves' disease. It includes the immune response to endogenous thyroid antigens, i.e. thyroid peroxidase and thyroglobulin, which may enhance lymphocyte infiltration and finally causes Hashimoto's thyroiditis. We report four cases of chronic thyroiditis (Hashimoto's disease) in patients who have been previously diagnosed with Graves' hyperthyroidism. In three cases, Hashimoto's thyroiditis occurs in 7 to 25 years after the treatment of Grave's disease; while the other case has it only after few months of Grave's disease treatment. The diagnosis of Hashimoto's disease (chronic thyroiditis) was based on clinical manifestation, high TSHs level, positive thyroid peroxidase antibody and thyroglobulin antibody, and supported by positive results of fine needle aspiration biopsy. Moreover, the result of histopathological test has also confirmed the diagnosis in two cases. All cases have been successfully treated by levothyroxine treatment.

  11. Retrosternal thyroid surgery

    MedlinePlus

    ... ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 96. Smith PW, Salomone LJ, Hanks JB. Thyroid. In: Townsend ... commercial use must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer ...

  12. Thyroid Disease and Teens

    MedlinePlus

    ... change over just a few months. previous continue Hypothyroidism A person with mild hypothyroidism may feel just fine — in fact, the condition ... all. However, symptoms can become more obvious if hypothyroidism progresses. People with underactive thyroids might feel depressed ...

  13. Thyroid Disease (for Parents)

    MedlinePlus

    ... change over just a few months. previous continue Hypothyroidism A person with mild hypothyroidism may feel just fine — in fact, the condition ... all. However, symptoms can become more obvious if hypothyroidism progresses. People with underactive thyroids might feel depressed ...

  14. Thyroid cancer - papillary carcinoma

    MedlinePlus

    ... some noncancerous childhood conditions Radiation exposure from nuclear plant disasters Radiation given through a vein (through an IV) during medical tests and treatments does not increase the risk of developing thyroid cancer.

  15. Clinical and laboratory assessment of thyroid abnormalities

    SciTech Connect

    Kaplan, M.M.

    1985-09-01

    Clinical assessment of the patient with suspected thyroid disease remains an important part of the workup. Available laboratory tests of thyroid function include measurements of serum thyroid hormones and thyroid-stimulating hormone, titers of autoantibodies involved with Graves' disease and thyroiditis, and thyroid imaging and uptake techniques. The usefulness and limitations of each of these tests are reviewed.

  16. Thyroid and male reproduction

    PubMed Central

    Kumar, Anand; Shekhar, Skand; Dhole, Bodhana

    2014-01-01

    Male reproduction is governed by the classical hypothalamo-hypophyseal testicular axis: Hypothalamic gonadotropin releasing hormone (GnRH), pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) and the gonadal steroid, principally, testosterone. Thyroid hormones have been shown to exert a modulatory influence on this axis and consequently the sexual and spermatogenic function of man. This review will examine the modulatory influence of thyroid hormones on male reproduction. PMID:24701426

  17. Thyroid hormone transporter defects.

    PubMed

    Grüters, Annette

    2007-01-01

    In in vitro experiments, active transport of thyroid hormones had been repeatedly demonstrated. The membrane transporters for thyroid hormones which have been identified include the organic anion transporting polypeptide, heterodimeric amino acid transporters and the monocarboxylate transporters (MCT) which are the focus of this chapter. The gene encoding MCT8 which was identified as a specific thyroid hormone transporter is located on chromosome Xq13.2. The expression pattern of MCT8 indicates that MCT8 plays an important role in the development of the central nervous system by transporting thyroid hormone into neurons as its main target cells. Mutational analysis of the MCT8 gene revealed mutations or deletions in the MCT8 gene in unrelated male patients with severe psychomotor retardation and biochemical findings consistent with thyroid hormone resistance. Indeed, thyroid function tests in patients with MCT8 mutations demonstrated marked elevations of serum T3 (in the thyrotoxic range), a significant decrease in serum T4 or fT4 and normal to elevated TSH levels.

  18. [Abnormality of thyroid function].

    PubMed

    Masamune, Taishi; Matsukawa, Takashi

    2010-07-01

    The thyroid hormones are synthesized by iodine. Thyroid dysfunction can develop in patients who have received treatment with iodine-containing contrast media or treatment with amiodarone. Thyrotoxicosis is a symptom due to high levels of thyroid hormone. The entity most threatened is the cardiovascular system. beta-adrenergic receptor blockade can control the heart rate. And a decreasing heart rate may improve heart-pumping function. We should aim to avoid surgery on any patients whose thyroid function is abnormal. The avoidance of a thyroid storm is the goal in managing hyperthyroid patients. Suppression of the sympathetic tone and maintenance of a deep level of surgical anesthesia are prudent. Thyroid storm is rare nowadays but still carries a high mortality. Precipitating factors include infection, surgery, childbirth or trauma, et al. Hypothyroid patients are sensitive to the effects of anesthetic agents and many drugs, including opioids. Mild hypothyroidism may have little perioperative significance. However, overt hypothyroidism can develop in a high percentage of patients with history of subclinical hypothyroidism. An untreated patient with hypothyroidism may present as an emergency with myxedema coma. Myxedema coma is rare but carries a high mortality. Precipitating factors include hypothermia, surgery, trauma, sedative drugs, et al.

  19. The association between chronic lymphocytic thyroiditis and thyroid tumors.

    PubMed

    Tamimi, Dalal M

    2002-04-01

    An association between lymphocytic thyroiditis and thyroid papillary carcinoma is still controversial. To assess the relationship, a histopathologic analysis of surgically resected thyroid tumors together with the frequency and severity of chronic lymphocytic infiltration of the thyroid among patients with follicular adenoma, follicular carcinoma, and papillary carcinoma was performed. The prevalence of lymphocytic infiltrate, which is indicative of autoimmune thyroiditis, was significantly higher in patients with papillary carcinoma (58%) than in patients with follicular carcinoma (20%) or follicular adenoma (14%). The lymphocytic infiltration within the tumor compared with the severity of thyroiditis in the nontumorous tissue. Therefore, the association between chronic lymphocytic thyroiditis and papillary carcinoma was confirmed. The possibility that an immunologic mechanism involved in the pathogenesis of papillary carcinoma stimulates lymphocytic infiltration in the thyroid tissue through an autoimmune mechanism is suggested.

  20. Drugs Approved for Thyroid Cancer

    MedlinePlus

    ... Ask about Your Treatment Research Drugs Approved for Thyroid Cancer This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Thyroid Cancer Cabozantinib-S-Malate Caprelsa (Vandetanib) Cometriq (Cabozantinib-S-Malate) Doxorubicin ...

  1. Occupation and Thyroid Cancer

    PubMed Central

    Aschebrook-Kilfoy, Briseis; Ward, Mary H.; Valle, Curt T. Della; Friesen, Melissa C.

    2014-01-01

    Objectives Numerous occupational and environmental exposures have been shown to disrupt thyroid hormones, but much less is known about their relationships with thyroid cancer. Here we review the epidemiology studies of occupations and occupational exposures and thyroid cancer incidence to provide insight into preventable risk factors for thyroid cancer. Methods The published literature was searched using the Web of Knowledge database for all articles through August 2013 that had in their text “occupation” “job” ”employment” or “work” and “thyroid cancer”. After excluding 10 mortality studies and 4 studies with less than 5 exposed incident cases, we summarized the findings of 30 articles that examined thyroid cancer incidence in relation to occupations or occupational exposure. The studies were grouped by exposure/occupation category, study design, and exposure assessment approach. Where available, gender stratified results are reported. Results The most studied (19 of 30 studies) and the most consistent associations were observed for radiation-exposed workers and health care occupations. Suggestive, but inconsistent, associations were observed in studies of pesticide-exposed workers and agricultural occupations. Findings for other exposures and occupation groups were largely null. The majority of studies had few exposed cases and assessed exposure based on occupation or industry category, self-report, or generic (population-based) job exposure matrices. Conclusion The suggestive, but inconsistent findings for many of the occupational exposures reviewed here indicate that more studies with larger numbers of cases and better exposure assessment are necessary, particularly for exposures known to disrupt thyroid homeostasis. PMID:24604144

  2. Thyroid cancer: diagnosis and management.

    PubMed

    Cheah, W K

    2007-02-01

    Thyroid cancer is the ninth most common cancer in women in Singapore. Despite an increasing incidence of thyroid cancer in the last few decades, survival has improved due to a combination of early cytological diagnosis, low-morbidity total thyroidectomy, and postoperative radioactive iodine therapy. Thyroid cancer is one of the most curable forms of cancer. This article provides an overview of thyroid cancer and future directions in its diagnosis and treatment.

  3. [Characteristics of postpartum thyroid dysfunction].

    PubMed

    Argatska, A; Nonchev, B; Obretsova, M; Pehlivanov, B

    2015-01-01

    The risk factors and mechanisms for the development of postpartum thyroid dysfunction have been widely discussed. However data on patients suffered spontaneous or induced abortion during early pregnancy are scarce. To reveal the characteristics of thyroid dysfunction in women after an abortion in the first trimester of pregnancy. A total of 28 women (18 euthyroid, 10 with thyroid dysfunction), mean age 30.46 ± 1.01 years following abortion in the first trimester have been included in the study. Thyroid-stimulating hormone (TSH), free triiodthyronine (FT3), free thyroxine (FT4), thyreoglobulin antibodies (TgAb), thyroid peroxidase antibodies (TPOAb) were measured and ultrasound assessment of the thyroid was performed 3 and 9 months after the interruption of pregnancy. Hypothyroidism was found in 6 of the women with thyroid dysfunction and thyrotoxicosis--in 4. Clinical features of thyroid dysfunction were observed in 3 patients while in the remaining 7 cases, diagnosis was made on the basis of hormonal levels. Positive titers of thyroid autoantibodies were detected in the majority of the cases with functional disordes. In 6 patients thyroid dysfunction was transient and in 4 hormonal abnormalities persisted on by the 9th month after the abortion. The comparative analysis showed that the volume of the thyroid gland and the degree of hypoehogenicity were significantly higher in patients with thyroid dysfunction compared to euthyroid women. Thyroid dysfunction after abortion in the first trimester is mainly of autoimmune pathogenesis and its characteristics do not differ from those of postpartum thyroiditis. In the majority of patients these disorders are subclinical and may remain unrecognized. A close active follow up of patients at increased risk of functional thyroid disorders after an abortion is required in order to prevent morbidity and identify the cases developing permanent thyroid dysfunction.

  4. Thyroid disease in older people.

    PubMed

    Mitrou, Panayota; Raptis, Sotirios A; Dimitriadis, George

    2011-09-01

    Several changes in thyroid hormone secretion, metabolism, and action occur with the increase in age. Aging is often associated with a decrease in serum thyroid stimulating hormone and T3 levels, whereas serum free T4 levels usually remain unchanged. The prevalence of thyroid dysfunction is higher in the elderly as compared to the younger population. In elderly individuals the non-specific clinical manifestations of thyroid hormone excess or deprivation can cause confusion in the clinical setup; while some of the symptoms of thyroid disease are similar to those in younger patients, it is not uncommon for both hyperthyroidism and hypothyroidism to be manifested in subtle ways in older patients, often mimicking symptoms of aging or masquerading as diseases of the cardiovascular, gastrointestinal, or nervous system. In addition, diagnosis of thyroid disorders is commonly complicated, due to chronic, non-thyroidal illness or medication therapy. Early diagnosis and treatment of overt thyroid disorders is crucial, since these disorders are associated with increased morbidity and mortality in the elderly, usually due to common coexistent diseases such as diminished cardiovascular reserve. Treatment of subclinical thyroid disease should also be considered, based on a combination of age, symptoms and risk factors in the individual patients. In addition, both prevalence and aggressiveness of thyroid cancer increase with age. This review summarizes the changes of thyroid function, as well as the clinical manifestations and treatment of thyroid disorders with advancing age. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  5. Thyroid Function in Down Syndrome.

    ERIC Educational Resources Information Center

    Pueschel, Siegfried M.; And Others

    1991-01-01

    This study investigated the thyroid function of 181 patients (mean age 14 years) with Down's syndrome and found more thyroid dysfunctions than in the general population. Periodic thyroid hormone function tests are recommended for Down's syndrome individuals, especially as they get older. (Author/DB)

  6. Thyroid storm induced by strangulation.

    PubMed

    Ramírez, Jesús I; Petrone, Patrizio; Kuncir, Eric J; Asensio, Juan A

    2004-06-01

    Thyroid storm most often occurs in patients with known thyrotoxicosis. This report discusses a severe case of thyroid storm developing as a direct result of strangulation in a patient without a preexisting history of thyroid disease. Classification and treatment of this entity are discussed.

  7. General Information about Thyroid Cancer

    MedlinePlus

    ... thyroid cancer and the age of the patient: Papillary and follicular thyroid cancer in patients younger than 45 years Stage I: ... the body, such as the lungs or bones. Papillary and follicular thyroid cancer in patients 45 years and older Stage I: ...

  8. Treatment Option Overview (Thyroid Cancer)

    MedlinePlus

    ... thyroid cancer and the age of the patient: Papillary and follicular thyroid cancer in patients younger than 45 years Stage I: ... the body, such as the lungs or bones. Papillary and follicular thyroid cancer in patients 45 years and older Stage I: ...

  9. Thyroid Function in Down Syndrome.

    ERIC Educational Resources Information Center

    Pueschel, Siegfried M.; And Others

    1991-01-01

    This study investigated the thyroid function of 181 patients (mean age 14 years) with Down's syndrome and found more thyroid dysfunctions than in the general population. Periodic thyroid hormone function tests are recommended for Down's syndrome individuals, especially as they get older. (Author/DB)

  10. Sunitinib Malate in Treating Patients With Iodine-Refractory Recurrent or Metastatic Thyroid Cancer

    ClinicalTrials.gov

    2015-09-28

    Recurrent Thyroid Cancer; Stage IVA Follicular Thyroid Cancer; Stage IVA Papillary Thyroid Cancer; Stage IVB Follicular Thyroid Cancer; Stage IVB Papillary Thyroid Cancer; Stage IVC Follicular Thyroid Cancer; Stage IVC Papillary Thyroid Cancer; Thyroid Gland Medullary Carcinoma

  11. Genetics of thyroid function.

    PubMed

    Medici, Marco; Visser, Theo J; Peeters, Robin P

    2017-03-01

    Recent studies show that subtle variations in thyroid function, including subclinical thyroid dysfunction, and even variation in thyroid function within the normal range, are associated with morbidity and mortality. It is estimated that 40-65% of the inter-individual variation in serum TSH and FT4 levels is determined by genetic factors. To identify these factors, various linkage and candidate gene studies have been performed in the past, which have identified only a few genes. In the last decade, genome-wide association studies identified many new genes, while recent whole-genome sequencing efforts have also been proven to be effective. In the current review, we provide a systematic overview of these studies, including strengths and limitations. We discuss new techniques which will further clarify the genetic basis of thyroid function in the near future, as well as the potential use of these genetic markers in personalizing the management of thyroid disease patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. [Thyroid dysfunction during pregnancy].

    PubMed

    Díez, Juan J; Iglesias, Pedro; Donnay, Sergio

    2015-10-21

    Recent clinical practice guidelines on thyroid dysfunction and pregnancy have changed health care provided to pregnant women, although their recommendations are under constant revision. Trimester- and area-specific reference ranges for serum thyroid-stimulating hormone are required for proper diagnosis of hypothyroidism and hyperthyroidism. There is no doubt on the need of therapy for overt hypothyroidism, while therapy for subclinical hypothyroidism is controversial. Further research is needed to settle adverse effects of isolated hypothyroxinemia and thyroid autoimmunity. Differentiation between hyperthyroidism due to Graves' disease and the usually self-limited gestational transient thyrotoxicosis is critical. It is also important to recognize risk factors for postpartum thyroiditis. Supplementation with iodine is recommended to maintain adequate iodine nutrition during pregnancy and avoid serious consequences in offspring. Controversy remains about universal screening for thyroid disease during pregnancy or case-finding in high-risk women. Opinions of some scientific societies and recent cost-benefit studies favour universal screening. Randomized controlled studies currently under development should reduce the uncertainties that still remain in this area. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  13. Oncogenesis of Thyroid Cancer

    PubMed Central

    Younis, Enas

    2017-01-01

    Thyroid neoplasms encompass a variety of lesions that range from benign adenomas to malignancies. These latter can be well-differentiated, poorly differentiated or undifferentiated (anaplastic) carcinomas. More than 95% of thyroid cancers are derived from thyroid follicular cells, while 2-3% (medullary thyroid cancers, MTC) originate from calcitonin producing C-cells. Over the last decade, investigators have developed a clearer understanding of genetic alterations underlying thyroid carcinogenesis. A number of point mutations and translocations are involved, not only in its tumorigenesis, but also as have potential use as diagnostic and prognostic indicators and therapeutic targets. Many occur in genes for several important signaling pathways, in particular the mitogen-activated protein kinase (MAPK) pathway. Sporadic (isolated) lesions account for 75% of MTC cases, while inherited MTC, often in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, constitute the remainder. However, non-MEN familial MTC may also occur. Advances in genetic testing have revolutionized the management of MTC, with prospects of genetic screening, testing and early prophylactic thyroidectomy. Ethical concerns of these advances are addressed. PMID:28610401

  14. Obesity and thyroid cancer.

    PubMed

    Marcello, Marjory Alana; Cunha, Lucas Leite; Batista, Fernando Assis; Ward, Laura Sterian

    2014-10-01

    Many studies have provided observational data on the association of obesity and thyroid cancers, but only few of them propose mechanisms that would permit a better understanding of the causal molecular mechanisms of this association. Considering that there is an increasing incidence of both obesity and thyroid cancers, we need to summarize and link recent studies in order to characterize and understand the contribution of obesity-related factors that might affect thyroid cancer development and progression. Adipose tissue is involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of energy balance, activation of the complement system, and responses such as inflammation. Although these processes have their own molecular pathways, they involve the same molecules through which obesity and adipose tissue might exert their roles in carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also recruiting local inflammatory responses that could result in disease formation and progression. This review describes five important issues that might explain the link between excessive weight and thyroid cancer: thyroid hormones, insulin resistance, adipokines, inflammation, and sexual hormones. © 2014 Society for Endocrinology.

  15. Does normal thyroid gland by ultrasonography match with normal serum thyroid hormones and negative thyroid antibodies?

    PubMed

    Trimboli, P; Rossi, F; Condorelli, E; Laurenti, O; Ventura, C; Nigri, G; Romanelli, F; Guarino, M; Valabrega, S

    2010-10-01

    Few papers have shown that a hypoechoic appearance of the thyroid gland at ultrasonography (US) is related to a hypofunction and serum positivity of thyroid antibodies (T-Ab). However, it is not ascertained if normal thyroid appearance at US correspond to normal thyroid laboratory tests. The aim of this study was to assess the value of normal thyroid at US in predicting normal thyroid hormones and negative T-Ab in a cohort of 48 adult patients. All patients (37 females and 11 males) were referred to our hospital to undergo their first thyroid US examination, followed by a thyroid function evaluation. All subjects had normal thyroid gland at US. As a control group 65 patients with hypoechoic and inhomogeneous thyroid gland were enrolled. All 48 patients had normal free-T (3) and free-T (4) levels. While 41 patients (85.4%) showed normal TSH, in 7 subjects (14.6%) TSH was elevated and a significant (p < 0.001) difference was recorded between the two groups in mean TSH value. Positive T-Ab value was found in 5 patients (10.4%) and the remaining 43 patients (89.6%) had negative T-Ab. TSH was not significantly correlated with age, thyroid volume or BMI. The multivariate model showed that only BMI was significantly correlated to thyroid volume (p < 0.01, r(2)=0.31). These results showed that normal thyroid recorded by US matches with normal thyroid laboratory assessment to a large degree. These preliminary data need to be confirmed in a prospective study and in a larger series and should suggest the evaluation of thyrotropin and thyroid antibodies in subjects with normal thyroid gland as assessed by US.

  16. Postpartum thyroid dysfunction in women with autoimmune thyroiditis.

    PubMed

    Argatska, Antoaneta; Nonchev, Boyan; Orbetzova, Maria; Pehlivanov, Blagovest

    2016-01-01

    Autoimmune thyroiditis (AIT) is a predisposing factor for developing postpartum thyroid dysfunction (PPTD). To study the characteristics of PPTD in women with AIT. Thirty-eight women with pre-existing AIT were included in the study. Thyroid-stimulating hormone, free triiodthyronine, free thyroxine, thyroid peroxidase antibodies, thyroglobulin antibodies were measured and ultrasound evaluation of the thyroid gland was performed in the first trimester of pregnancy and during the first year following delivery. Thyroid dysfunction was recognized in 68.4% of the patients - 28.9% presented with hypothyroidism and 39.5 % with thyrotoxicosis. The immunological and morphological parameters did not differ between euthyroid women and those with thyroid dysfunction. At the end of the postpartum period restoration of euthyroid state (being on the treatment before pregnancy) was observed in 15.4% of patients with PPTD, while 84.6% required increase of the levothyroxine dose. The analysis found a significantly lower volume of the thyroid gland, shorter duration of the disease, a lower dose of levothyroxine before and during gestation in patients with impaired thyroid function at the end of the postpartum period. The risk of PPTD in women with AIT predating pregnancy is higher among women with preserved thyroid functional capacity motivating a thorough assessment of thyroid hormone levels and close follow-up of those women during the postpartum period.

  17. Thyroid nodules and thyroid cancer in Graves' disease.

    PubMed

    Tam, Abbas Ali; Kaya, Cafer; Kılıç, Fevzi Balkan Mehmet; Ersoy, Reyhan; Çakır, Bekir

    2014-12-01

    The frequency of thyroid nodules accompanying Graves' disease and the risk of thyroid cancer in presence of accompanying nodules are controversial. The aim of this study was to evaluate the frequency of thyroid nodules and the risk of thyroid cancer in patients operated because of graves' disease. Five hundred and twenty-six patients in whom thyroidectomy was performed because of Graves' disease between 2006 and 2013 were evaluated retrospectively. Patients who had received radioactive iodine treatment and external irradiation treatment in the neck region and who had had thyroid surgery previously were not included in the study. While accompanying thyroid nodule was present in 177 (33.6%) of 526 Graves' patients, thyroid nodule was absent in 349 (66.4%) patients. Forty-two (8%) patients had thyroid cancer. The rate of thyroid cancer was 5.4% (n = 19) in the Graves' patients who had no nodule, whereas it was 13% (n = 23) in the patients who had nodule. The risk of thyroid cancer increased significantly in presence of nodule (p = 0.003). Three patients had recurrence. No patient had distant metastasis. No patient died during the follow-up period. Especially Graves' patients who have been decided to be followed up should be evaluated carefully during the follow-up in terms of thyroid cancer which may accompany.

  18. Thyroid stem cells: lessons from normal development and thyroid cancer

    PubMed Central

    Thomas, Dolly; Friedman, Susan; Lin, Reigh-Yi

    2009-01-01

    Ongoing advances in stem cell research have opened new avenues for therapy for many human disorders. Until recently, however, thyroid stem cells have been relatively understudied. Here, we review what is known about thyroid stem cells and explore their utility as models of normal and malignant biological development. We also discuss the cellular origin of thyroid cancer stem cells and explore the clinical implications of cancer stem cells in the thyroid gland. Since thyroid cancer is the most common form of endocrine cancer and that thyroid hormone is needed for the growth and metabolism of each cell in the body, understanding the molecular and the cellular aspects of thyroid stem cell biology will ultimately provide insights into mechanisms underlying human disease. PMID:18310275

  19. Thyroid Langerhans cell histiocytosis and papillary thyroid carcinoma

    PubMed Central

    Algarni, Mohammed; Alhakami, Hadi; AlSubayea, Haia; Alfattani, Naif; Guler, Mohammet; Satti, Mohamed

    2016-01-01

    A 27-year-old female, married with two children, presented to our clinic with a 1-year history of thyroid swelling and pressure symptoms on lying backward and bilateral cervical lymphadenopathy. The patient was a known case of panhypopituitarism for 5 years. Comprehensive patient evaluation including FNAC with papillary thyroid cancer result then she underwent total thyroidectomy and bilateral neck dissection and final histologic examination confirmed papillary thyroid carcinoma in the background of lymphocytic thyroiditis, associated with Langerhans cell histiocytosis (LCH). The draining cervical lymph nodes were also involved by LCH and metastatic papillary thyroid carcinoma. Although the association of LCH with papillary thyroid carcinoma in the thyroid has been reported, their co-existence with LCH in the draining lymph nodes is very uncommon. PMID:27867869

  20. [Thyroid gland and fertility].

    PubMed

    Andreeva, P

    2014-01-01

    It is well-known that the thyroid hormones are associated with a number of aspects of the human reproduction. Both states, hyperthyroidism and hypothyroidism, have significant effect on the estrogen and androgen metabolism, the menstrual function and on fertility. The role of thyroid hormones (TH) during infertility has been little exploited. Interesting facts are that TH deficiency is more common in women with polycystic ovary syndrome (PCOS) and in certain cases with unexplained infertility. There are very few studies on the effect and paracrine regulation of TH and its receptors in the female reproductive tract. This report provides an overview of the most common thyroid disorders and their impact on ovarian function and reproductive performance in women as well as in cases with infertility and the implementation of assisted reproductive technologies (ART).

  1. Biochemical testing of thyroid function.

    PubMed

    Klee, G G; Hay, I D

    1997-12-01

    Various published guidelines recommending serum thyrotropin (TSH)-first thyroid testing are outlined. The entities called "subclinical hypothyroidism" and "subclinical hyperthyroidism" are defined on the basis of abnormal TSH concentrations and normal values of other biochemical thyroid tests. The controversies about follow-up and treatment of these disorders are discussed. The laboratory experience of Mayo Clinic Rochester in using TSH-first thyroid testing and the subsequent implementation of a thyroid test ordering cascade are presented. Finally, recommendations are given for further optimizing laboratory testing for thyroid disorders.

  2. [Non thyroidal illnesses (NTIS)].

    PubMed

    Luca, F; Goichot, B; Brue, T

    2010-09-01

    Abnormalities in the circulating levels of thyroid hormones, without evidence of coexisting thyroid or pituitary gland disease can be observed in all general diseases. These nonthyroidal illnesses (NTIS) are the result of complex mechanisms that combine the effect of some drugs, cytokines, nutritional and endocrine factors at all levels of the thyrotropic axis, from the hypothalamus to the cellular transporters and nuclear receptors of thyroid hormones. The patterns of NTIS depend on the underlying disease and its severity. Thirtyfive years after the initial description, the pathophysiological significance of these anomalies remains controversial. One of the dilemma of NTIS is whether the hormone responses represent an adaptive and normal, physiologic response to conserve energy and protect against hypercatabolism in case of aggression, or whether it is a maladaptive response contributing to a worsening of the disease. This debate is not just a theoretical question, because in the first case the process must be respected, in the other case a vigorous treatment to restore circulating thyroid hormone levels is justified. There have been very few clinical studies designed to address whether the substitution with thyroid hormone is advantageous, and there is at current time no permissive evidence for the use of thyroid hormone replacement in patients with NTIS. But the clinical context, the choice of the molecule or of the dose and the way of administration were not necessarily the most relevant. Theoretically, stimulation of thyreotrope axis used a continuous infusion of TRH seems to provide clinical benefit. With the expectation that randomized clinical trials will provide demonstration of NTIS treatment efficiency, the question might remain unanswered for several more years. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  3. [Post-partum thyroiditis].

    PubMed

    Neves, Celestino; Alves, Marta; Delgado, Luís; Medina, J Luís

    2009-01-01

    In the post-partum period the immune alterations are associated with the multiple autoimmune diseases relapse. After birth, immune-tolerance variation slowly disappear, and is observed a return to a normal state - after an exacerbation period - of autoimmune reactivity, during which a great increase in T cells and autoantibodies is observed. In this period - 3 to 9 months after birth - the thyroid autoimmune disease relapses or reappears. The reactivation of the immune system in the post-partum period unchains an acute phase of celular destruction which characterizes the post-partum thyroiditis.

  4. Robotic retroauricular thyroid surgery

    PubMed Central

    Alabbas, Haytham; Bu Ali, Daniah

    2016-01-01

    Surgery is the gold standard treatment for patients with thyroid cancer or nodules suspicious for cancer. Open conventional approach is the standard surgical approach. However, a visible neck incision could be a concern for most young female patients, especially for patients with a history of healing with keloid or hypertrophic scars. Robotic remote access approaches have evolved into a safe and feasible approach in selected patients, providing a hidden scar with good patient satisfaction. This review will focus on the performance and safety of robotic retroauricular thyroid surgery. PMID:28149806

  5. Robotic retroauricular thyroid surgery.

    PubMed

    Alabbas, Haytham; Bu Ali, Daniah; Kandil, Emad

    2016-12-01

    Surgery is the gold standard treatment for patients with thyroid cancer or nodules suspicious for cancer. Open conventional approach is the standard surgical approach. However, a visible neck incision could be a concern for most young female patients, especially for patients with a history of healing with keloid or hypertrophic scars. Robotic remote access approaches have evolved into a safe and feasible approach in selected patients, providing a hidden scar with good patient satisfaction. This review will focus on the performance and safety of robotic retroauricular thyroid surgery.

  6. Environmental Issues in Thyroid Diseases

    PubMed Central

    Ferrari, Silvia Martina; Fallahi, Poupak; Antonelli, Alessandro; Benvenga, Salvatore

    2017-01-01

    Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves’ disease and Graves’ ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction. PMID:28373861

  7. Environmental Issues in Thyroid Diseases.

    PubMed

    Ferrari, Silvia Martina; Fallahi, Poupak; Antonelli, Alessandro; Benvenga, Salvatore

    2017-01-01

    Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves' disease and Graves' ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction.

  8. Thyroid storm: an updated review.

    PubMed

    Chiha, Maguy; Samarasinghe, Shanika; Kabaker, Adam S

    2015-03-01

    Thyroid storm, an endocrine emergency first described in 1926, remains a diagnostic and therapeutic challenge. No laboratory abnormalities are specific to thyroid storm, and the available scoring system is based on the clinical criteria. The exact mechanisms underlying the development of thyroid storm from uncomplicated hyperthyroidism are not well understood. A heightened response to thyroid hormone is often incriminated along with increased or abrupt availability of free hormones. Patients exhibit exaggerated signs and symptoms of hyperthyroidism and varying degrees of organ decompensation. Treatment should be initiated promptly targeting all steps of thyroid hormone formation, release, and action. Patients who fail medical therapy should be treated with therapeutic plasma exchange or thyroidectomy. The mortality of thyroid storm is currently reported at 10%. Patients who have survived thyroid storm should receive definite therapy for their underlying hyperthyroidism to avoid any recurrence of this potentially fatal condition.

  9. Lingual thyroid: a clinical case.

    PubMed

    Quarracino, María; Aguas, Silvia

    2003-01-01

    Lingual thyroid is an abnormal formation appearing as the result of a deficient descent during embryological development of the thyroid gland through the thyroglossal duct to its normal pretracheal location. The lesion consists of a tumor mass of thyroid tissue located at the base of the tongue, in the region of the foramen caecum linguae. The size can vary from a few millimeters to several centimeters in diameter. More than 400 cases of lingual thyroid have been documented in the literature to date. Lingual thyroid has been identified in 10% of the tongues examined in some autopsy series. Its identification is of great significance, since it may constitute the only functional thyroid tissue in the body, and may inadvertently be destroyed as a result of histological biopsy procedures. The present study presents a clinical case of lingual thyroid in a 17-year-old female.

  10. Painless thyroiditis complicated by acromegaly.

    PubMed

    Saito, Takatoshi; Tojo, Katsuyoshi; Tajima, Naoko

    2010-01-01

    The serum thyroid stimulating hormone (TSH) level is decreased in acromegalic patients. Although this phenomenon is thought to be caused by the enhanced secretion of somatostatin which suppresses TSH production, it has not yet been proven. We describe a 60-year-old woman with acromegaly who showed a low concentration of TSH. We diagnosed her as painless thyroiditis based on an increased level of thyroglobulin, depressed radioactive iodine uptake (RAIU), normal vascularity and mild swelling of the thyroid, and normal T3, T4, free T3 and free T4 levels. To our knowledge, this is the second reported case of acromegaly complicated by painless thyroiditis. The differential diagnosis between central hypothyroidism and painless thyroiditis is so important. Since it is difficult to diagnose precisely based on only the data of a low level of TSH and normal levels of thyroid hormones, we consider that measurement of thyroglobulin and RAIU is necessary when the complication of painless thyroiditis is suspected.

  11. Thyroid cell lines in research on goitrogenesis.

    PubMed

    Gerber, H; Peter, H J; Asmis, L; Studer, H

    1991-12-01

    Thyroid cell lines have contributed a lot to the understanding of goitrogenesis. The cell lines mostly used in thyroid research are briefly discussed, namely the rat thyroid cell lines FRTL and FRTL-5, the porcine thyroid cell lines PORTHOS and ARTHOS, The sheep thyroid cell lines OVNIS 5H and 6H, the cat thyroid cell lines PETCAT 1 to 4 and ROMCAT, and the human thyroid cell lines FTC-133 and HTh 74. Chinese hamster ovary (CHO) cells and COS-7 cells, stably transfected with TSH receptor cDNA and expressing a functional TSH receptor, are discussed as examples for non-thyroidal cells, transfected with thyroid genes.

  12. Neuronal expression of a thyroid hormone receptor α mutation alters mouse behaviour.

    PubMed

    Richard, S; Aguilera, N; Thévenet, M; Dkhissi-Benyahya, O; Flamant, F

    2017-03-15

    In humans, alterations in thyroid hormone signalling are associated with mood and anxiety disorders, but the neural mechanisms underlying such association are poorly understood. The present study investigates the involvement of neuronal thyroid hormone receptor α (TRα) in anxiety, using mouse genetics and Cre/loxP technology to specifically alter TRα signalling in neurons. We evaluated the behaviour of mice expressing a dominant negative, neuron-specific mutation of TRα (TRα(AMI)/Cre3 mice), using the elevated-plus maze, light-dark box and open-field tests. In a first experiment, mice were housed individually, and the behaviour of TRα(AMI)/Cre3 mice differed significantly from that of control littermates in these 3 tests, suggesting heightened anxiety. In a second experiment, designed to evaluate the robustness of the results with the same 3 tests, mice were housed in groups. In these conditions, the behaviour of TRα(AMI)/Cre3 mice differed from that of control littermates only in the light-dark box. Thus, TRα(AMI)/Cre3 mice appear to be more likely to develop anxiety under stressful housing conditions than control mice. These results suggest that in adult mice, thyroid hormone signalling in neurons, via TRα, is involved in the control of anxiety behaviour.

  13. Thyroid-associated Ophthalmopathy

    PubMed Central

    Şahlı, Esra; Gündüz, Kaan

    2017-01-01

    Thyroid-associated ophthalmopathy is the most frequent extrathyroidal involvement of Graves’ disease but it sometimes occurs in euthyroid or hypothyroid patients. Thyroid-associated ophthalmopathy is an autoimmune disorder, but its pathogenesis is not completely understood. Autoimmunity against putative antigens shared by the thyroid and the orbit plays a role in the pathogenesis of disease. There is an increased volume of extraocular muscles, orbital connective and adipose tissues. Clinical findings of thyroid-associated ophthalmopathy are soft tissue involvement, eyelid retraction, proptosis, compressive optic neuropathy, and restrictive myopathy. To assess the activity of the ophthalmopathy and response to treatment, clinical activity score, which includes manifestations reflecting inflammatory changes, can be used. Supportive approaches can control symptoms and signs in mild cases. In severe active disease, systemic steroid and/or orbital radiotherapy are the main treatments. In inactive disease with proptosis, orbital decompression can be preferred. Miscellaneous treatments such as immunosuppressive drugs, somatostatin analogs, plasmapheresis, intravenous immunoglobulins and anticytokine therapies have been used in patients who are resistant to conventional treatments. Rehabilitative surgeries are often needed after treatment. PMID:28405484

  14. Remote access thyroid surgery

    PubMed Central

    Bhatia, Parisha; Mohamed, Hossam Eldin; Kadi, Abida; Walvekar, Rohan R.

    2015-01-01

    Robot assisted thyroid surgery has been the latest advance in the evolution of thyroid surgery after endoscopy assisted procedures. The advantage of a superior field vision and technical advancements of robotic technology have permitted novel remote access (trans-axillary and retro-auricular) surgical approaches. Interestingly, several remote access surgical ports using robot surgical system and endoscopic technique have been customized to avoid the social stigma of a visible scar. Current literature has displayed their various advantages in terms of post-operative outcomes; however, the associated financial burden and also additional training and expertise necessary hinder its widespread adoption into endocrine surgery practices. These approaches offer excellent cosmesis, with a shorter learning curve and reduce discomfort to surgeons operating ergonomically through a robotic console. This review aims to provide details of various remote access techniques that are being offered for thyroid resection. Though these have been reported to be safe and feasible approaches for thyroid surgery, further evaluation for their efficacy still remains. PMID:26425450

  15. [Postpartum thyroiditis. A review].

    PubMed

    Hurtado-Hernández, Z; Segura-Domínguez, A

    2013-01-01

    Postpartum thyroiditis (PPT) is a transient thyroid dysfunction of autoimmune origin that can occur in the first year postpartum in women who have not been previously diagnosed with thyroid disease. It may start with clinical thyrotoxicosis followed by hypothyroidism and the subsequent recovery of thyroid function, or may just appear as isolated thyrotoxicosis or hypothyroidism. PPT recurs in high percentage of patients after subsequent pregnancies. Many women develop permanent hypothyroidism sometime during the 3 to 10 year period after an episode of PPT. It is important for family physicians to be familiar with this disease, due to its high prevalence in order to make a correct diagnosis and therapeutic intervention. Family doctors also play a crucial role in the monitoring of these patients, given the negative implications of established hypothyroidism on reproduction in the female population during their reproductive years. This article reviews the principle characteristics of PPT along with its diagnosis and treatment. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  16. Immunogenetics of Hashimoto's thyroiditis

    PubMed Central

    Chistiakov, Dimitry A

    2005-01-01

    Hashimoto's thyroiditis (HT) is an organ-specific T-cell mediated disease. It is a complex disease, with a strong genetic component. To date, significant progress has been made towards the identification and functional characterization of HT susceptibility genes. In this review, we will summarize the recent advances in our understanding of the genetic input to the pathogenesis of HT. PMID:15762980

  17. What Causes Thyroid Cancer?

    MedlinePlus

    ... not yet known. Certain changes in a person’s DNA can cause thyroid cells to become cancerous. DNA is the chemical in each of our cells ... parents because they are the source of our DNA. But DNA affects more than just how we ...

  18. The thyroid gland.

    PubMed

    Hellman, D E

    1980-01-01

    Disorders of the thyroid gland are frequently unrecognized and untreated by the attending physician and present the anesthesiologist with a diagnostic and therapeutic challenge. Very large goiters distort and compress the larynx and require an experienced anesthesiologist for safe intubation. If surgery is elective and can be postponed in patients suspected of being hypo- or hyperthyroid, there is sufficient time to permit the anesthesiologist and the attending physician to obtain appropriate tests of thyroid function and institute appropriate therapeutic measures to restore the metabolic rate to normal. When there is insufficient time to confirm a clinical diagnosis of thyroid disease, the anesthesiologist is faced with important therapeutic decisions. It is the author's opinion that therapeutic intervention is, in most instances, preferable to therapeutic nihilism. In the case of a patient suspected of hypothyroidism, it is usually safe to administer a physiologic replacement dose of thyroxine to support the patient intraoperatively or postoperatively. If hypothyroidism is associated with cardiovascular disease, other debilitating illness, or advanced age, thyroxine must be given with extreme caution in order to avoid dangerous tachyarrhythmias or too rapid acceleration of the metabolic rate. The hyperthyroid patient facing nonelective surgery represents a very serious challenge to the anesthesiologist, since marked accentuation of clinical hyperthyroidism (thyroid storm) is a major risk of such surgery. In such a situation, intravenous propranolol and intravenous iodine are the optimal drugs for a safe and uncomplicated clinical course during and following surgery. In both instances, the anesthesiologist must use skillful clinical judgment in making the appropriate diagnosis and selecting appropriate therapy. Careful and continuous supervision of the patient is necessary during and following surgery and appropriate treatment and support of the patient should be

  19. Sex steroids and the thyroid.

    PubMed

    Tahboub, Rundsarah; Arafah, Baha M

    2009-12-01

    Thyroid function is modulated by genetic and environmental causes as well as other illnesses and medications such as gonadal or sex steroids. The latter class of drugs (sex steroids) modulates thyroid function. Gonadal steroids exert their influence on thyroid function primarily by altering the clearance of thyroxine-binding globulin (TBG). While oestrogen administration causes an increase in serum TBG concentration, androgen therapy results in a decrease in this binding protein. These effects of gonadal steroids on TBG clearance and concentration are modulated by the chemical structure of the steroid being used, its dose and the route of administration. Despite the gonadal steroids-induced changes in serum TBG concentrations, subjects with normal thyroid glands maintain clinical and biochemical euthyroidism without changes in their serum free thyroxine (T4) or thyroid-stimulating hormone (TSH) levels. In contrast, the administration of gonadal steroids to patients with thyroid diseases causes significant biochemical and clinical alterations requiring changes in the doses of thyroid medications. Similarly, gonadal steroid therapy might unmask thyroid illness in previously undiagnosed subjects. It would be prudent to assess thyroid function in subjects with thyroid disease 6-8 weeks after gonadal steroid administration or withdrawal.

  20. Thyroid hormone and the heart.

    PubMed

    Moolman, J A

    2002-01-01

    Thyroid hormone has important cardiovascular effects, and abnormalities of its production cause cardiovascular morbidity. The role of both excessive and insufficient thyroid hormone production in the pathogenesis of clinical cardiac diseases can be deduced from thyroid hormone-induced molecular changes. Thyroid hormone regulates the expression of myocardial genes regulating the handling of calcium, which affects both systolic and diastolic myocardial function. Thyroid hormone also has indirect and direct effects on peripheral vascular smooth muscle tone, and alters the coupling of the left ventricle and arterial system. Excessive production of thyroid hormone results in an increased cardiac output as well as increased cardiac work efficiency, but reduced cardiac reserve. Amiodarone therapy for cardiac rhythm can cause both hyper- and hypothyroidism. Amiodarone-induced thyrotoxicosis (AIT) can be due to either excessive thyroid hormone production (type I AIT) or thyroid hormone release due to an inflammatory condition (type II AIT). Classification of AIT is helpful in guiding therapy. Amiodarone causes changes in the thyroid function tests of euthyroid patients on therapy--it inhibits the conversion of T(4) and T(3), which results in decreased T(3) and slightly increased T(4) serum levels in euthyroid patients. Baseline thyroid functions should therefore be determined before starting amiodarone therapy, and at 6-monthly intervals thereafter.

  1. Thyroid hormones and cardiovascular disease.

    PubMed

    Jabbar, Avais; Pingitore, Alessandro; Pearce, Simon H S; Zaman, Azfar; Iervasi, Giorgio; Razvi, Salman

    2017-01-01

    Myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive to changes in the concentrations of circulating thyroid hormones. The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations - such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome - adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Over the past 2 decades, accumulating evidence supports the association between abnormal thyroid function at the time of an acute myocardial infarction (MI) and subsequent adverse cardiovascular outcomes. Furthermore, experimental studies showed that thyroid hormones can have an important therapeutic role in reducing infarct size and improving myocardial function after acute MI. In this Review, we summarize the literature on thyroid function in cardiovascular diseases, both as a risk factor as well as in the setting of cardiovascular diseases such as heart failure or acute MI, and outline the effect of thyroid hormone replacement therapy for reducing the risk of cardiovascular disease.

  2. Iodine deficiency and thyroid disorders.

    PubMed

    Zimmermann, Michael B; Boelaert, Kristien

    2015-04-01

    Iodine deficiency early in life impairs cognition and growth, but iodine status is also a key determinant of thyroid disorders in adults. Severe iodine deficiency causes goitre and hypothyroidism because, despite an increase in thyroid activity to maximise iodine uptake and recycling in this setting, iodine concentrations are still too low to enable production of thyroid hormone. In mild-to-moderate iodine deficiency, increased thyroid activity can compensate for low iodine intake and maintain euthyroidism in most individuals, but at a price: chronic thyroid stimulation results in an increase in the prevalence of toxic nodular goitre and hyperthyroidism in populations. This high prevalence of nodular autonomy usually results in a further increase in the prevalence of hyperthyroidism if iodine intake is subsequently increased by salt iodisation. However, this increase is transient because iodine sufficiency normalises thyroid activity which, in the long term, reduces nodular autonomy. Increased iodine intake in an iodine-deficient population is associated with a small increase in the prevalence of subclinical hypothyroidism and thyroid autoimmunity; whether these increases are also transient is unclear. Variations in population iodine intake do not affect risk for Graves' disease or thyroid cancer, but correction of iodine deficiency might shift thyroid cancer subtypes toward less malignant forms. Thus, optimisation of population iodine intake is an important component of preventive health care to reduce the prevalence of thyroid disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Etiopathogenesis of Differentiated Thyroid Carcinomas

    PubMed Central

    Makazlieva, Tanja; Vaskova, Olivija; Majstorov, Venjamin

    2016-01-01

    INTRODUCTION: Thyroid malignomas are a heterogeneous group of neoplasm consisting of most frequent differentiated encountered carcinomas, papillary and follicular thyroid carcinoma, then medullary thyroid carcinoma originating from neuroendocrine calcitonin-producing C-cells and rare forms of thyroid lymphomas arising from intrathyroidal lymphatic tissue, thyroid sarcomas and poorly differentiated anaplastic thyroid carcinoma. There are increasing numbers of epidemiological studies and publications that have suggested increased incidence rate of thyroid carcinomas. We have read, analysed and compare available reviews and original articles investigating different etiological factors in the development of thyroid carcinomas through Google Scholar and PubMed Database. DISCUSSION: Aetiology involved in the development of thyroid carcinomas is multifactorial and includes external influences, as well as constitutional predispositions and genetic etiological factors. The actual effect of environmental and constitutional factors is on promoting genetic and epigenetic alterations which result in cell proliferation and oncogenesis. Until now are identified numerous genetic alterations, assumed to have an important role in oncogenesis, with MAPK and PI3K-AKT as crucial signalling networks regulating growth, proliferation, differentiation and cell survival/apoptosis. CONCLUSION: This new molecular insight could have a crucial impact on diagnosis and also on improving and selecting an appropriate treatment to the patients with thyroid malignancies. PMID:27703585

  4. Robotic Surgery for Thyroid Disease

    PubMed Central

    Lee, Jandee; Chung, Woong Youn

    2013-01-01

    Robotic surgery is an innovation in thyroid surgery that may compensate for the drawbacks of conventional endoscopic surgery. A surgical robot provides strong advantages, including three-dimensional imaging, motion scaling, tremor elimination, and additional degrees of freedom. We review here recent adaptations, experience and applications of robotics in thyroid surgery. Robotic thyroid surgeries include thyroid lobectomy, total thyroidectomy, central compartment neck dissection, and radical neck dissection for benign and malignant thyroid diseases. Most of the current literature consists of case series of robotic thyroidectomies. Recent retrospective and prospective analyses have evaluated the safety and oncologic efficacy of robotic surgery for thyroid cancer. Although robotic thyroid surgery is often associated with longer operation times than conventional open surgery, robotic techniques have shown similar or superior levels of surgical completeness and safety compared with conventional open or endoscopic surgery. Compared to open thyroidectomy, robotic thyroidectomy has been associated with several quality-of-life benefits, including excellent cosmetic results, reduced neck pain and sensory changes, and decreased voice and swallowing discomfort after surgery. For surgeons, robotic surgery has improved ergonomics and has a shorter learning curve than open or endoscopic surgery. The advantages of robotic thyroid surgery over conventional surgery suggest that robotic thyroidectomy with or without neck dissection may become the preferred surgical option for thyroid diseases. Robotic thyroid surgery will likely continue to develop as more endocrine and head-and-neck surgeons are trained and more patients seek this newly developed surgical option. PMID:24783046

  5. Thyroid dysfunction and pregnancy outcomes

    PubMed Central

    Nazarpour, Sima; Ramezani Tehrani, Fahimeh; Simbar, Masoumeh; Azizi, Fereidoun

    2015-01-01

    Background: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. Objective: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Materials and Methods: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Results: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. Conclusion: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long

  6. Thyroid diseases and female reproduction.

    PubMed

    Mintziori, G; Anagnostis, P; Toulis, K A; Goulis, D G

    2012-02-01

    Thyroid diseases are very common in women of reproductive age. The aim of this study was to review the current evidence on physiology, pathophysiology, diagnosis and management of women with thyroid disorders that are currently seeking fertility, undergoing assisted reproduction technologies (ART) or being pregnant. Normal thyroid function is essential for normal function of the gonadal axis, thus important in maintaining normal reproductive capacity. On the contrary, any type of thyroid dysfunction may reduce the likelihood of pregnancy; the latter can be restored to normal after appropriate treatment. Over eight million children have been born as a result of assisted reproduction techniques (ART) since 1978. As these procedures are becoming more common in clinical practice, the exact impact of thyroid status on reproductive outcomes as well as that of drugs used in ART on thyroid function has to be fully elucidated. Maternal thyroid function is crucial, especially during the first weeks of gestation, for offspring's wellness and brain development. On the other hand, normal physiological mechanisms during gestation can have a major impact on maternal thyroid function. As human chorionic gonadotropin (hCG) has a thyroid stimulating hormone (TSH)-like effect, high hCG concentrations are associated with thyroid stimulation, both functionally (lower serum TSH concentrations) and anatomically (increased thyroid volume). Although the association between maternal hypothyroidism and increased perinatal morbidity has been described for over a century, more recently, even the presence of anti-thyroid antibodies has been associated with adverse pregnancy outcomes, such as recurrent abortions and placental abruption. This is of major clinical significance, as anti-thyroid antibodies are surprisingly prevalent in pregnancy, especially during the first two trimesters.

  7. Thyroid disrupting chemicals: Mechanisms and mixtures

    EPA Science Inventory

    Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

  8. What Does the Thyroid Gland Do?

    MedlinePlus

    ... where it helps other cells do their job. hypothyroidism (hi-poh-THY-royd-izm): when your thyroid ... t make enough thyroid hormone, which is called hypothyroidism. When you don’t have enough thyroid hormone, ...

  9. Thyroid disrupting chemicals: Mechanisms and mixtures

    EPA Science Inventory

    Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

  10. 2009 American Thyroid Association guidelines on thyroid nodules.

    PubMed

    Perros, P

    2010-08-01

    The American Thyroid Association guidelines on thyroid nodules and differentiated thyroid cancer, published in 2009, provide valuable recommendations based on current evidence. Inevitably, controversies and uncertainties will continue to challenge clinicians and patients. On topics where evidence is not clear-cut, judgement may be coloured by pre-existing practises and the structure of the health service in each country, so one has to be aware of the pitfalls of transferring recommendations to one's own practise.

  11. Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine

    ClinicalTrials.gov

    2016-12-02

    Recurrent Thyroid Gland Carcinoma; Stage I Thyroid Gland Papillary Carcinoma; Stage II Thyroid Gland Papillary Carcinoma; Stage III Thyroid Gland Papillary Carcinoma; Stage IV Thyroid Gland Papillary Carcinoma

  12. [Medullary thyroid carcinoma and other rare types of thyroid carcinoma].

    PubMed

    Obara, Takao

    2007-11-01

    Among 4 major traditional groups of thyroid carcinoma, papillary and follicular carcinomas are most common, and other forms, anaplastic and medullary carcinomas, are relatively rare. The 2003 WHO histological classification of thyroid tumor separated 7 other malignant thyroid tumors into distinct pathological entities, such as poorly differentiated, squamous cell, mucinous carcinomas, carcinoma showing thymus-like differentiation (CASTLE), etc. Although they are also extremely rare, recognition of their clinicopathologic features are very important. In this review, not only diagnostic and therapeutic strategies for the rare forms of thyroid carcinomas, specifically focussed on medullary carcinoma and CASTLE, but also their histogenetic abnormalities were discussed.

  13. Thyroid hormone antibodies and Hashimoto's thyroiditis in mongrel dogs

    SciTech Connect

    Rajatanavin, R.; Fang, S.L.; Pino, S.; Laurberg, P.; Braverman, L.E.; Smith, M.; Bullock, L.P.

    1989-05-01

    Abnormally elevated serum T3 concentrations measured by RIA were observed in 19 clinically euthyroid or hypothyroid mongrel dogs. The serum T4 concentrations in these sera were low, normal, or high. Measurement of the intensity of thyroid hormone binding to serum proteins was determined by equilibrium dialysis. A marked decrease in the percent free T3 was observed in these abnormal sera. Polyacrylamide gel electrophoresis, pH 7.4, of normal dog serum enriched with tracer /sup 125/I-labeled thyroid hormones demonstrated binding of (/sup 125/I)T4 to transthyretin, thyroid hormone-binding globulin, and albumin and of (/sup 125/I)T3 primarily to thyroid hormone-binding globulin. In all abnormal sera, polyacrylamide gel electrophoresis demonstrated strikingly higher binding of T3 to immunoglobulin (Ig). Eleven of 16 abnormal sera had minimal to moderate binding of T4 to Ig. The percent free T4 was lower only in dogs whose sera demonstrated markedly increased binding of T4 to Ig. All abnormal sera tested had positive antithyroglobulin antibodies, consistent with the diagnosis of autoimmune lymphocytic thyroiditis. As in humans, antibodies to thyroid hormones in dogs are more common in the presence of Hashimoto's thyroiditis and should be considered when elevated serum thyroid hormone concentrations are observed in the absence of clinical thyrotoxicosis. When an antibody to only one thyroid hormone is present, a marked discrepancy in the serum concentrations of T3 and T4 will be observed.

  14. Thyroid storm induced by blunt thyroid gland trauma.

    PubMed

    Delikoukos, Stylianos; Mantzos, Fotios

    2007-12-01

    Isolated thyroid gland injury due to blunt neck trauma is uncommon and rarely complicated by thyroid storm in patients without known hyperthyroidism. The aim of this study was to report our experience on blunt thyroid gland injury followed by massive gland hemorrhage, acute airway obstruction, and symptoms of thyroid storm. Among 231 patients with neck trauma, four patients appeared with isolated thyroid gland injury. In two of them, the diagnosis of simultaneous thyrotoxic crisis was made on the basis of clinical findings and confirmed on emergency laboratory tests. The diagnosis of thyroid gland injury was supposed by the history and physical examination and established after neck exploration. Therapy was directed at stabilizing the patients by correcting the hyperthyroid state, followed by operative treatment. Left lobectomy and total thyroidectomy were performed and, along with postoperative medical measures, led to uneventful recovery. This study demonstrates that thyroid gland injury due to blunt neck trauma, although uncommon, may result in potentially life-threatening thyroid storm due to rupture of acini and liberation of thyroid hormones into the bloodstream. This may occur in patients without known hyperthyroidism.

  15. [Diagnostic imaging of thyroid tumor].

    PubMed

    Miyakawa, Megumi

    2012-11-01

    Recently, thyroid nodules are found frequently when other imaging test was performed, and selection of diagnostic methods and its handling have become a problem clinically. Although it is possible to differentiate the malignant tumor from benign one using B-mode ultrasound, it can be obtained more detailed information in combination of other modalities such as color Doppler and tissue elasticity imaging (elastography). The malignant B-mode findings are irregular shape, indistinct border, hypoechoic and inhomogeneous internal echo, and fine calcification. CT/MRI is useful to evaluate the extention of thyroid cancer to adjacent organs beyond the thyroid capsule. It is also useful to evaluate distant metastases to lung or brain of thyroid cancer. In nuclear medicine, 125I scintigraphy is used to measure thyroid uptake rate, 131I scintigraphy is used to investigate the distant metastasis of thyroid cancer. It is necessary to be careful that some false-positive cases exist in 18FDG-PET.

  16. Perioperative Management of Thyroid Dysfunction

    PubMed Central

    Palace, Marcia Rashelle

    2017-01-01

    Due to the manifold effects of thyroid hormone across virtually all organ systems, the complications associated with thyroid dysfunction are numerous and diverse. The stresses encountered during the perioperative period may exacerbate underlying thyroid disorders, potentially precipitating decompensation and even death. Thus, it is of the utmost importance for the clinician to comprehend the mechanisms by which thyroid disease may complicate surgery and postoperative recovery and to be cognizant of the most effective means of optimizing the status of thyrotoxic and hypothyroid patients perioperatively. This article describes the adverse effects of thyroid dysfunction as they relate to the patient undergoing both thyroid and nonthyroid surgery and recommends treatment approaches aimed at decreasing perioperative risk. PMID:28469454

  17. Thyroid Tests: MedlinePlus Health Topic

    MedlinePlus

    ... Free T4 (Thyroxine) Test (American Association for Clinical Chemistry) T3 (Triiodothyronine) Test (American Association for Clinical Chemistry) Thyroid Antibodies (American Association for Clinical Chemistry) Thyroid ...

  18. Thyroid Hormones and Methylmercury Toxicity

    PubMed Central

    O’Mara, Daniel M.; Aschner, Michael

    2013-01-01

    Thyroid hormones are essential for cellular metabolism, growth, and development. In particular, an adequate supply of thyroid hormones is critical for fetal neurodevelopment. Thyroid hormone tissue activation and inactivation in brain, liver, and other tissues is controlled by the deiodinases through the removal of iodine atoms. Selenium, an essential element critical for deiodinase activity, is sensitive to mercury and, therefore, when its availability is reduced, brain development might be altered. This review addresses the possibility that high exposures to the organometal, methylmercury (MeHg), may perturb neurodevelopmental processes by selectively affecting thyroid hormone homeostasis and function. PMID:18716716

  19. Female infertility and the thyroid.

    PubMed

    Poppe, Kris; Velkeniers, Brigitte

    2004-06-01

    Difficulty to conceive or subfertility constitutes a major psychological burden. Assisted reproductive technology changed significantly the outcome of couples faced with subfertility. These techniques consequently increased tremendously our understanding of the mechanisms underlying reproductive failure and opened new perspectives for future interventions, not only to increase cumulative conception rates after ART, but also spontaneous pregnancy rates. Thyroid dysfunction adversely affects fertility. Many studies imply a role for immunology, including thyroid autoimmunity in conception failure. In this review we attempt to update the available information on the adverse effect of thyroid dysfunction and/or thyroid autoimmunity on subfertility and we propose a rationale for testing and potential treatment options.

  20. Sorafenib Tosylate in Treating Patients With Locally Advanced, Metastatic, or Locally Recurrent Thyroid Cancer

    ClinicalTrials.gov

    2014-01-15

    Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Recurrent Thyroid Cancer; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage IV Follicular Thyroid Cancer; Stage IV Papillary Thyroid Cancer

  1. Incidental thyroid nodules and thyroid cancer: considerations before determining management.

    PubMed

    Tufano, Ralph P; Noureldine, Salem I; Angelos, Peter

    2015-06-01

    The worldwide incidence of thyroid cancer is increasing substantially, almost exclusively attributable to small papillary thyroid cancers. Increased use of diagnostic imaging is considered the most likely explanation for this reported rise, but other factors may also be contributing. The increase in health care expenditures related to managing these presumably low-risk cancers, without a clear patient benefit, has resulted in a backlash against the early detection of thyroid cancer. Currently, there is no way to confidently predict which incidentally detected thyroid nodule may be the precursor to a more aggressive process. Predictions such as these would require more accurate characterization of the biology of individual thyroid cancers than is currently possible. With time, we might prove our ability to confidently differentiate low-risk from high-risk thyroid cancers, but until that happens, routine screening for thyroid cancer by imaging billed as a "health checkup" should not be performed. However, incidentally detected thyroid nodules should be reported, and a clear medical team management plan should be developed. Our ethical responsibility is to provide patients with objective, evidence-based information about their disease status, not to assume that we know what is best for them by selectively withholding information. In addition, providing patients with psychosocial assistance will help them process the information necessary to make informed decisions that will provide them with the most value when a small thyroid nodule or cancer is incidentally identified. Herein, we summarize the epidemiological data for disease incidence, discuss some controversies in disease management, and outline the key elements and ethical considerations of informed decision making as they apply to managing incidentally detected thyroid nodules and thyroid cancer.

  2. Radiofrequency ablation for postsurgical thyroid removal of differentiated thyroid carcinoma.

    PubMed

    Xu, Dong; Wang, Lipin; Long, Bin; Ye, Xuemei; Ge, Minghua; Wang, Kejing; Guo, Liang; Li, Linfa

    2016-01-01

    Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy. Surgical removal with radioactive iodine therapy is recommended for recurrent thyroid carcinoma, and the postsurgical thyroid removal is critical. This study evaluated the clinical values of radiofrequency ablation (RFA) in the postsurgical thyroid removal for DTC. 35 DTC patients who had been treated by subtotal thyroidectomy received RFA for postsurgical thyroid removal. Before and two weeks after RFA, the thyroid was examined by ultrasonography and (99m)TcO4 (-) thyroid imaging, and the serum levels of free triiodothyronine (FT3), free thyroxin (FT4), thyroid stimulating hormone (TSH) and thyroglobulin (Tg) were detected. The efficacy and complications of RFA were evaluated. Results showed that, the postsurgical thyroid removal by RFA was successfully performed in 35 patients, with no significant complication. After RFA, the average largest diameter and volume were significantly decreased in 35 patients (P > 0.05), and no obvious contrast media was observed in ablation area in the majority of patients. After RFA, the serum FT3, FT4 and Tg levels were markedly decreased (P < 0.05), and TSH level was significantly increased (P < 0.05). After RFA, radioiodine concentration in the ablation area was significantly reduced in the majority of patients. The reduction rate of thyroid update was 0.69±0.20%. DTC staging and interval between surgery and RFA had negative correlation (Pearson coefficient = -0.543; P = 0.001), with no obvious correlation among others influential factors. RFA is an effective and safe method for postsurgical thyroid removal of DTC.

  3. Sonographic appearance of thyroid cancer in patients with Hashimoto thyroiditis.

    PubMed

    Durfee, Sara M; Benson, Carol B; Arthaud, Dylan M; Alexander, Erik K; Frates, Mary C

    2015-04-01

    To determine whether the sonographic appearance of thyroid cancer differs in patients with and without Hashimoto thyroiditis. Patients with histologically proven thyroid cancer who had thyroid peroxidase (TPO) antibodies measured and sonography performed preoperatively were included. We evaluated each nodule for size, echogenicity, composition, margins, halo, and vascularity and evaluated the background heterogeneity of the gland. There were 162 thyroid cancers in 145 patients. Forty-two patients (29.0%) had Hashimoto thyroiditis with positive TPO antibodies, and 103 patients (71.0%) had negative TPO antibodies. The background echogenicity was more often heterogeneous in TPO antibody-positive patients compared to those who had negative TPO antibodies (57.1% versus 26.2%; P= .0005). Comparing cancers in TPO antibody-positive to TPO antibody-negative patients, there was no significant difference in the size, echogenicity, composition, margins, halo presence, calcification presence and type, or vascularity of the cancerous nodule (P > .05). Among TPO antibody-positive patients, comparing thyroid cancerous nodules in patients with heterogeneous glands to those with homogeneous glands, there was no significant difference in any sonographic characteristic except the margin of the nodule, which was more often irregular or poorly defined in heterogeneous glands and more often smooth in homogeneous glands (P< .05). Sonographic features of thyroid cancer are similar in patients with and without Hashimoto thyroiditis. Among patients with Hashimoto thyroiditis and thyroid cancer, the sonographic appearance of the cancerous nodule is similar, except that cancerous nodule margins are more likely to be irregular or poorly defined when the gland is heterogeneous. © 2015 by the American Institute of Ultrasound in Medicine.

  4. Radiofrequency ablation for postsurgical thyroid removal of differentiated thyroid carcinoma

    PubMed Central

    Xu, Dong; Wang, Lipin; Long, Bin; Ye, Xuemei; Ge, Minghua; Wang, Kejing; Guo, Liang; Li, Linfa

    2016-01-01

    Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy. Surgical removal with radioactive iodine therapy is recommended for recurrent thyroid carcinoma, and the postsurgical thyroid removal is critical. This study evaluated the clinical values of radiofrequency ablation (RFA) in the postsurgical thyroid removal for DTC. 35 DTC patients who had been treated by subtotal thyroidectomy received RFA for postsurgical thyroid removal. Before and two weeks after RFA, the thyroid was examined by ultrasonography and 99mTcO4 - thyroid imaging, and the serum levels of free triiodothyronine (FT3), free thyroxin (FT4), thyroid stimulating hormone (TSH) and thyroglobulin (Tg) were detected. The efficacy and complications of RFA were evaluated. Results showed that, the postsurgical thyroid removal by RFA was successfully performed in 35 patients, with no significant complication. After RFA, the average largest diameter and volume were significantly decreased in 35 patients (P > 0.05), and no obvious contrast media was observed in ablation area in the majority of patients. After RFA, the serum FT3, FT4 and Tg levels were markedly decreased (P < 0.05), and TSH level was significantly increased (P < 0.05). After RFA, radioiodine concentration in the ablation area was significantly reduced in the majority of patients. The reduction rate of thyroid update was 0.69±0.20%. DTC staging and interval between surgery and RFA had negative correlation (Pearson coefficient = -0.543; P = 0.001), with no obvious correlation among others influential factors. RFA is an effective and safe method for postsurgical thyroid removal of DTC. PMID:27186311

  5. Robotic facelift thyroid surgery

    PubMed Central

    Bomeli, Steven R.; Duke, William S.

    2015-01-01

    Techniques for thyroid surgery have advanced dramatically over the past two decades, driven by a better understanding of thyroid physiology, anatomy, and perioperative management strategies. Improvements in surgical technology have permitted surgeons to perform minimally invasive surgery associated with less dissection, decreased pain, smaller anterior cervical incisions, and most importantly a faster recovery. The advent of robotic surgical technology has allowed the development of remote access thyroidectomy for select patients who wish to avoid a visible cervical incision completely. The robotic facelift thyroidectomy (RFT) approach also offers the advantage of outpatient surgery without the need for postoperative drainage. A growing body of evidence supports the safety and efficacy of the approach, and as a result the technique is now being performed at several centers around the world. PMID:26425453

  6. Medullary thyroid carcinoma.

    PubMed

    Leboulleux, Sophie; Baudin, Eric; Travagli, Jean-Paul; Schlumberger, Martin

    2004-09-01

    Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells that produce calcitonin (CT), and accounts for 5-10% of all thyroid cancers. MTC is hereditary in about 25% of cases. The discovery of a MTC in a patient has several implications: disease extent should be evaluated, phaeochromocytoma and hyperparathyroidism should be screened for and whether the MTC is sporadic or hereditary should be determined by a direct analysis of the RET proto-oncogene. In this review, pathological characteristics, tumour markers and genetic abnormalities in MTC are discussed. The diagnostic and therapeutic modalities applied to patients with clinical MTC and those identified with preclinical disease through familial screening are also described. Progresses concerning genetics, initial treatment, follow-up, screening and treatment of pheochromocytoma have permitted an improvement in the long-term outcome. However, there is no effective treatment for distant metastases, and new therapeutic modalities are urgently needed.

  7. [Thyroid gland and sleep].

    PubMed

    Steiger, A

    1999-01-01

    A set of data suggests that the thyroid gland plays a role in the bi-directional interaction between the electrophysiological and the endocrine components of sleep, e.g. the nonREM-REM-cycle and the patterns of nocturnal hormone secretion, respectively. In detail thyroid-stimulating hormone (TSH) and thyroxin (T4) show circadian rhythms. A specific relationship was observed between TSH and REM sleep. Blunted TSH levels were found in healthy elderly subjects and, probably due to overactivity of corticotropin-releasing hormone in patients with depression in comparison to young normal controls. Pulsatile administration of thyrotropin-releasing hormone induced a decrease of sleep efficiency and an earlier occurrence of the cortisol rise in normal controls. Slow wave sleep was reduced in patients with hypothyroidism in comparison to normal controls. The sleep EEG normalised after therapy.

  8. Anticonvulsants and thyroid function.

    PubMed Central

    Yeo, P P; Bates, D; Howe, J G; Ratcliffe, W A; Schardt, C W; Heath, A; Evered, D C

    1978-01-01

    Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3. PMID:656820

  9. Thyroid dysfunction and choleduocholithiasis.

    PubMed

    Ajdarkosh, Hossein; Khansari, Mohammad Reza; Sohrabi, Masoud Reza; Hemasi, Gholam Reza; Shamspour, Najmeh; Abdolahi, Nafiseh; Zamani, Farhad

    2013-07-01

    Disturbances in lipid metabolism which occur during hypothyroidism leadto the formation of gallstones. This study aims to evaluate the thyroid functionpattern in patients with common bile duct (CBD) stones. This case-control study recruited 151 patients with preliminary diagnosesof CBD stone who underwent ERCP (cases). The control group comprisedhealthy people who met the study criteria in the same hospital. The controlgroup underwent ultrasonography to exclude any asymptomatic bile duct lithiasis.A questionnaire that included demographic and anthropometrics datawere completed by an assigned physician. Morning blood samples that followed12 hours of fasting were taken from all participants for measurements ofserum total thyroxin (T4), serum thyroid stimulating hormone (TSH), fastingblood sugar (FBS), triglycerides (TG), total cholesterol, low density lipoprotein(LDL) and high density lipoprotein (HDL). The mean TSH in patients (2.59 ± 4.86mg/dl) was higher than the controlgroup (2.53± 4.13 9mg/dl). In subclinical hypothyroidism, serum TSH levelshigher than 5 MU/L were found in 30.6% of cases compared with 22.5% ofcontrols [OR: 1.53; 95 % confidence interval (95% CI): 0.968-2.438). Hypothyroidismwas detected in 10.8% of the control group and in 11.3% of cases(OR: 1.87; 95% CI: 0.578-2.043). The mean total cholesterol levels in caseswas higher than the control group (p=0.61).The levels of TG (p=0.05), HDL(73.35 vs. 46.41; p<0.01) and LDL (64.81.88 vs. 111.04; p<0.01) was statisticallysignificant between both groups. There is an association between thyroid disorders and the presence of bileduct stones. Thyroid testing in patients with gallstone and bile duct stones isrecommended because hypothyroidism may be a predisposing factor for stonepassage from the gallbladder.

  10. Thyroid associated orbitopathy

    PubMed Central

    Maheshwari, Rajat; Weis, Ezekiel

    2012-01-01

    Thyroid associated orbitopathy, also known as Graves’ orbitopathy, is typically a self-limiting autoimmune process associated with dysthyroid states. The clinical presentation may vary from very mild disease to severe irreversible sight-threatening complications. Despite ongoing basic science and clinical research, the pathogenesis and highly effective therapeutic strategies remain elusive. The present article reviews the pathophysiology, clinical presentation, and management of this common, yet poorly understood disease, which remains a challenge to the ophthalmologist. PMID:22446901

  11. Thyroid disorders in pregnancy

    PubMed Central

    Ramprasad, Menaka; Bhattacharyya, Shaila Shamanur; Bhattacharyya, Arpandev

    2012-01-01

    Thyroid disorders are common in pregnancy and the most common disorder is subclinical hypothyroidism. Due to the complex hormonal changes during pregnancy, it is important to remember that thyroxine requirements are higher in pregnancy. According to recent American Thyroid Association (ATA) guidelines, the recommended reference ranges for TSH are 0.1 to 2.5 mIU/L in the first trimester, 0.2 to 3.0 mIU/L in the second trimester, and 0.3 to 3.0 mIU/L in the third trimester. Maternal hypothyroidism is an easily treatable condition that has been associated with increased risk of low birth weight, fetal distress, and impaired neuropsychological development. Hyperthyroidism in pregnancy is less common as conception is a problem. Majority of them are due to Graves’ disease, though gestational hyperthyroidism is to be excluded. Preferred drug is propylthiouracil (PTU) with the target to maintain free T4 in upper normal range. Doses can be reduced in third trimester due to the immune-suppressant effects of pregnancy. Early and effective treatment of thyroid disorder ensures a safe pregnancy with minimal maternal and neonatal complications. PMID:23565370

  12. The aging thyroid.

    PubMed

    Tabatabaie, Vafa; Surks, Martin I

    2013-10-01

    As life expectancy increases and population age advances, diagnosis and treatment of diseases common in the geriatric population assume an increasingly important role in modern medicine. In the last few years, the emergence of age-specific reference ranges for thyroid-stimulating hormone (TSH) has added to the complexity of diagnosis of thyroid dysfunction in this age group, especially in the 'subclinical' category. The recent studies confirm an increase in population TSH distribution with age, both in cross-sectional and longitudinal studies. Conclusive evidence about adverse cardiovascular, metabolic, and cognitive consequences of subclinical hypothyroidism in the elderly remains elusive. The transient nature of subtle degrees of thyroid dysfunction in a significant proportion of elderly patients has also been reproduced in the recent publications. A growing body of literature in the last few years, reviewed here, highlights the importance of employing additional caution before assigning diagnoses of hypothyroidism or hyperthyroidism to elderly patients and initiation of treatment modalities that can have long-lasting effects.

  13. Pediatric Medullary Thyroid Carcinoma.

    PubMed

    Starenki, Dmytro; Park, Jong-In

    Medullary thyroid carcinoma (MTC), which originates from thyroid parafollicular C cells, accounts for 3 to 5% of thyroid malignancies. MTC occurs either sporadically or in an inherited autosomal dominant manner. Hereditary MTC occurs as a familial MTC or as a part of multiple endocrine neoplasia (MEN) type 2A and B syndromes. A strong genotype-phenotype correlation has been observed between hereditary MTC and germ-line "gain of function" mutations of the RET proto-oncogene. Most cases of pediatric MTC are hereditary whereas sporadic MTC is rare in children and is usually diagnosed in adults. Therefore, MTC in children is most often diagnosed in the course of a familial genetic investigation. The standard treatment of MTC mainly requires surgery involving total thyroidectomy and central neck node dissection before extrathyroidal extension occurs. To prevent MTC development in hereditary syndromes, prophylactic thyroidectomy is performed in presymptomatic patients. An appropriate age at which the surgery should take place is determined based upon the data from genotyping, serum calcitonin measurements, and ultrasonography. For the treatment of advanced MTC cases, the broad spectrum receptor tyrosine kinase inhibitors vandetanib and cabozantinib, which also inhibit RET, are used although they are not always effective.

  14. Thyroid Gland Malignancies.

    PubMed

    Cabanillas, Maria E; Dadu, Ramona; Hu, Mimi I; Lu, Charles; Gunn, Gary Brandon; Grubbs, Elizabeth G; Lai, Stephen Y; Williams, Michelle D

    2015-12-01

    Surgery remains the most important effective treatment for differentiated (DTC) and medullary thyroid cancer (MTC). Radioactive iodine (RAI) is another important treatment but is reserved only for DTC whose disease captures RAI. Once patients fail primary therapy, observation is often recommended, as most DTC and MTC patients will have indolent disease. However, in a fraction of patients, systemic therapy must be considered. In recent decades 4 systemic therapies have been approved by the United States FDA for DTC and MTC. Sorafenib and lenvatinib are approved for DTC and vandetanib and cabozantinib for MTC. Anaplastic thyroid cancer (ATC) is a rare and rapidly progressive form of thyroid cancer with a very high mortality rate. Treatment of ATC remains a challenge. Most patients are not surgical candidates at diagnosis due to advanced disease. External beam radiation and radiosensitizing radiation are the mainstay of therapy at this time. However, exciting new drugs and approaches to therapy are on the horizon but it will take a concerted, worldwide effort to complete clinical trials in order to find effective therapies that will improve the overall survival for this devastating disease.

  15. [Thyroid nodules and differentiated thyroid cancer: Brazilian consensus].

    PubMed

    Maia, Ana Luiza; Ward, Laura S; Carvalho, Gisah A; Graf, Hans; Maciel, Rui M B; Maciel, Léa M Zanini; Rosário, Pedro W; Vaisman, Mario

    2007-07-01

    Thyroid nodules are a common manifestation of thyroid diseases. It is estimated that approximately 10% of adults have palpable thyroid nodules with the frequency increasing throughout life. The major concern on nodule evaluation is the risk of malignancy (5-10%). Differentiated thyroid carcinoma accounts for 90% of all thyroid malignant neoplasias. Although most patients with cancer have a favorable outcome, some individuals present an aggressive form of the disease and poor prognostic despite recent advances in diagnosis and treatment. Here, a set of clinical guidelines for the evaluation and management of patients with thyroid nodules or differentiated thyroid cancer was developed through consensus by 8 member of the Department of Thyroid, Sociedade Brasileira de Endocrinologia e Metabologia. The participants are from different reference medical centers within Brazil, to reflect different practice patterns. Each committee participant was initially assigned to write a section of the document and to submit it to the chairperson, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. All committee members further revised and refined the document. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information.

  16. [Hashimoto's thyroiditis(chronic thyroiditis), IgG4-related thyroiditis].

    PubMed

    Itoh, Mitsuyasu

    2012-11-01

    Hashimoto's thyroiditis emerges in patients who have genetic preponderance such as SNPs of CTLA-4 and risk factors such as excess intake of iodine, pregnancy or postpartum period, and smoking. Such risk factors also affect the entire clinical course. One of the major outcomes in Hashimoto's thyroiditis appears to be increased in cardio-vascular risks through subclinical hypothyroidism and concomitant metabolic syndrome, but in most cases, treatment with L-T4 has little effects on cardio-vascular benefit or quality of life. The pregnant women also have risks for obstetric complications and postpartum thyroid dysfunction. The women who have anti-TPO antibodies, type 1 diabetes, or previous history of post-partum thyroid dysfunction are recommended to be measured their TSH. It is noteworthy that Hashimoto's thyroiditis is sometimes complicated with encephalopathy, papillary carcinoma, or IgG4-related thyroiditis. IgG4-related thyroiditis is partly similar but partly discerned from a variant of Hashimoto's thyroiditis. The pathogenetic roles of this variant on autoimmune-based thyroiditis remain unclear.

  17. The thyroid-brain interaction in thyroid disorders and mood disorders.

    PubMed

    Bauer, M; Goetz, T; Glenn, T; Whybrow, P C

    2008-10-01

    Thyroid hormones play a critical role in the metabolic activity of the adult brain, and neuropsychiatric manifestations of thyroid disease have long been recognised. However, it is only recently that methodology such as functional neuroimaging has been available to facilitate investigation of thyroid hormone metabolism. Although the role of thyroid hormones in the adult brain is not yet specified, it is clear that without optimal thyroid function, mood disturbance, cognitive impairment and other psychiatric symptoms can emerge. Additionally, laboratory measurements of peripheral thyroid function may not adequately characterise central thyroid metabolism. Here, we review the relationship between thyroid hormone and neuropsychiatric symptoms in patients with primary thyroid disease and primary mood disorders.

  18. Homozygous Thyroid Hormone Receptor β-Gene Mutations in Resistance to Thyroid Hormone: Three New Cases and Review of the Literature

    PubMed Central

    Ferrara, Alfonso Massimiliano; Onigata, Kazumichi; Ercan, Oya; Woodhead, Helen; Weiss, Roy E.

    2012-01-01

    Context: The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor β (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event. Objective: In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRβ. Methods: We conducted clinical studies and genetic analyses. Results: The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRβ, but not in RTH due to THRB gene deletions. Conclusion: We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRβ. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRβ interferes with the function of the TRα1 in humans. PMID:22319036

  19. Breaking Tolerance to Thyroid Antigens: Changing Concepts in Thyroid Autoimmunity

    PubMed Central

    Rapoport, Basil

    2014-01-01

    Thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors. In central tolerance, intrathymic autoantigen presentation deletes immature T cells with high affinity for autoantigen-derived peptides. Regulatory T cells provide an alternative mechanism to silence autoimmune T cells in the periphery. The TSH receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (Tg) have unusual properties (“immunogenicity”) that contribute to breaking tolerance, including size, abundance, membrane association, glycosylation, and polymorphisms. Insight into loss of tolerance to thyroid proteins comes from spontaneous and induced animal models: 1) intrathymic expression controls self-tolerance to the TSHR, not TPO or Tg; 2) regulatory T cells are not involved in TSHR self-tolerance and instead control the balance between Graves' disease and thyroiditis; 3) breaking TSHR tolerance involves contributions from major histocompatibility complex molecules (humans and induced mouse models), TSHR polymorphism(s) (humans), and alternative splicing (mice); 4) loss of tolerance to Tg before TPO indicates that greater Tg immunogenicity vs TPO dominates central tolerance expectations; 5) tolerance is induced by thyroid autoantigen administration before autoimmunity is established; 6) interferon-α therapy for hepatitis C infection enhances thyroid autoimmunity in patients with intact immunity; Graves' disease developing after T-cell depletion reflects reconstitution autoimmunity; and 7) most environmental factors (including excess iodine) “reveal,” but do not induce, thyroid autoimmunity. Micro-organisms likely exert their effects via bystander stimulation. Finally, no single mechanism explains the loss of tolerance to thyroid proteins. The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen

  20. Find an Endocrinology - Thyroid Specialist

    MedlinePlus

    ... ATA Mission, Vision, Goals Work of the ATA Governance & Leadership Staff Contact the ATA ATA Headquarters 6066 Leesburg Pike Suite 550 Falls Church, VA 22041 thyroid@thyroid.org Contact Form Legal Privacy Terms of Use Is registered in the U.S. Patent ...

  1. Perchlorate, iodine and the thyroid

    PubMed Central

    Leung, Angela M.; Pearce, Elizabeth N.; Braverman, Lewis E.

    2014-01-01

    In pharmacologic doses, perchlorate inhibits thyroidal iodine uptake and subsequently decreases thyroid hormone production. Although pharmacologic doses may be used in the treatment of hyperthyroidism, recent literature has focussed on the detection of low levels of perchlorate in the environment, groundwater and foodstuffs and their potential adverse effects on human thyroid function. This is of particular concern to the developing foetus and infant, whose normal neurodevelopment depends on adequate iodine intake for the production of thyroid hormones. Further research is needed to clarify the potential health effects of low-level chronic environmental perchlorate exposure. The health impact of environmental perchlorate may be dependent upon adequate iodine intake and should be interpreted in combination with other environmental exposures that are also potential thyroidal endocrine disruptors. PMID:20172477

  2. Neonatal thyroid storm accompanied with severe anaemia.

    PubMed

    Cao, Lu-Ying; Wei, Hong; Wang, Zheng-Li

    2015-07-01

    Neonatal thyroid storm is rare; the diagnostic criteria and management of neonatal thyroid storm have not been well established. In this paper, we report a preterm infant diagnosed with neonatal hyperthyroidism secondary to maternal Graves' disease who was discharged after therapy. Unfortunately, he was rehospitalised for neonatal thyroid storm. We will discuss the diagnosis and general therapy of neonatal thyroid storm.

  3. HASHIMOTO THYROIDITIS AND VESTIBULAR DYSFUNCTION.

    PubMed

    Chiarella, Giuseppe; Russo, Diego; Monzani, Fabio; Petrolo, Claudio; Fattori, Bruno; Pasqualetti, Giuseppe; Cassandro, Ettore; Costante, Giuseppe

    2017-07-01

    The aim of this review was to analyze the existing literature concerning the relationship between Hashimoto thyroiditis (HT) and vestibular dysfunction. We used electronic databases (PubMed, EMBASE, Cochrane Library) to search and collect all published articles about the association between HT and vestibular disorders. Several observational and retrospective studies have postulated a relationship between thyroid autoimmunity and vestibular disorders. In most cases, an appropriate control group was lacking, and the impact of thyroid functional status could not precisely be established. In recent years, two well-designed prospective studies have provided convincing evidence that the association is not random. One article reported that patients with Ménière disease (MD) had a significantly higher prevalence of positive anti-thyroid autoantibody as compared to healthy controls. Moreover, more than half of MD patients had either positive anti-thyroid or non-organ-specific autoantibody titers, compared to less than 30% of both patients with unilateral vestibular paresis without cochlear involvement and healthy controls. Another study found that patients with benign paroxysmal positional vertigo (BPPV) had significantly higher serum thyroid-stimulating hormone and antithyroid autoantibody levels than healthy controls. Additionally, almost one-fifth of euthyroid patients with HT had signs of BPPV. The published results indicate that patients with MD or BPPV are potential candidates to also develop HT. Thus, in HT patients, the presence of even slight symptoms or signs potentially related to vestibular lesions should be carefully investigated. AITD = autoimmune thyroid disease; BPPV = benign paroxysmal positional vertigo; EH = endolymphatic hydrops; HT = Hashimoto thyroiditis; L-T4 = L-thyroxine; MD = Ménière disease; PS = Pendred syndrome; Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.

  4. Nivolumab-induced thyroid dysfunction.

    PubMed

    Tanaka, Ryota; Fujisawa, Yasuhiro; Maruyama, Hiroshi; Nakamura, Yasuhiro; Yoshino, Koji; Ohtsuka, Mikio; Fujimoto, Manabu

    2016-06-01

    Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

  5. Ultrasonography in the diagnosis of Hashimoto's thyroiditis.

    PubMed

    Wu, Guihua; Zou, Dazhong; Cai, Haiyun; Liu, Yajun

    2016-06-01

    Hashimoto's thyroiditis is a type of autoimmune thyroid disease with an increasing prevalence in past decades. Its diagnosisis mostly based on ultrasonography. Ultrasonography is a useful and essential tool to make this diagnosis based on the characteristics of the disease. In the differential diagnosis of thyroid nodules, ultrasound-guided fine-needle biopsy is an effective method to distinguish Hashimoto's thyroiditis from other thyroid disorders. One exciting and recent advance is that non-invasive ultrasound-based methods have supplemented fine-needle aspiration to diagnose Hashimoto's thyroiditis under more complex conditions. In this review, we discuss the recent advantages of ultrasonography in the diagnosis of Hashimoto's thyroiditis.

  6. Sonographic Elastography of the Thyroid Gland

    PubMed Central

    Menzilcioglu, Mehmet Sait; Duymus, Mahmut; Avcu, Serhat

    2016-01-01

    Summary Thyroid gland disorders include benign and malignant thyroid nodules and diffuse thyroid disorders. The incidence of malignant thyroid nodules is low and the prognosis is good. The diagnosis of thyroid cancer and diffuse parenchymal disorders is generally based on clinical manifestations and histopathological evaluation. Ultrasonography has its place in the diagnostics and follow-up of thyroid disorders. Ultrasonographic elastography is a new, developing method that shows increase in clinical practice. In this study, we aimed to review the data on thyroid ultrasound elastography. PMID:27103947

  7. Thyroid crisis in the maxillofacial trauma patient.

    PubMed

    Weinstock, Robert J; Lewis, Tashorn; Miller, Jared; Clarkson, Earl I

    2014-11-01

    Thyroid crisis, also known as thyroid storm, is a rare complication of thyrotoxicosis that results in a hypermetabolic and hyperadrenergic state. This condition requires prompt recognition and treatment because the mortality from thyroid crisis approaches 30%. Thyrotoxicosis alone will usually not progress to thyroid crisis. Thyroid crisis will typically be precipitated by some concomitant event such as infection, iodine-containing contrast agents, medications such as amiodarone, pregnancy, or surgery. Trauma is a rare precipitator of thyroid crisis. Several published studies have reported thyroid crisis resulting from blunt or penetrating neck trauma. Significant systemic trauma, such as motor vehicle accidents, has also been reported to precipitate thyroid crisis. It is very unusual for minor trauma to precipitate thyroid crisis. In the present study, we report the case of a patient who had incurred relatively minor maxillofacial trauma and developed thyroid crisis 2 weeks after the initial trauma.

  8. Etiopathogenetic factors, thyroid functions and thyroid autoimmunity in melasma patients

    PubMed Central

    Özcan, Nimet; Kılıç, Arzu; Koparal, Suha; Artüz, Ferda; Çakmak, Atıl; Köse, Kenan

    2015-01-01

    Introduction Melasma is a common chronic, acquired pigmentation disorder with a significant impact on the quality of life of patients. Aim To investigate the etiopathogenetic factors, thyroid functions and thyroid autoimmunity in patients with melasma. Material and methods Forty-five women with melasma and 45 age-matched healthy women were included in the study group. A detailed history was taken from the patients including triggering factors of melasma. Serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), anti-thyroglobulin (AbTG) and anti-thyroid peroxidase (Ab-TPO) were measured and thyroid ultrasonography was performed for each subject. Results In 26.7% of patients, pregnancy, in 17.8%, oral contraceptive use and in 13.3%, intense sunlight exposure were the triggering factors. 17.8% of patients had a family history of melasma. FT4, TSH and AbTG levels were significantly higher in the patient group. Conclusions The results suggest that a combination of factors including pregnancy, oral contraceptive use, sunlight and genetic factors often trigger melasma. Thyroid hormones and thyroid autoimmunity may also play a role in the pathogenesis which needs to be proven by further studies. PMID:26759539

  9. [Thyroid hormone treatment].

    PubMed

    Gärtner, R

    2013-07-01

    The autoimmune thyroiditis with overt or subclinical primary hypothyroidism is the most common endocrine disease. Although the diagnosis of hypothyroidism is not difficult, the question when a replacement therapy in subclinical hypothyroidism should be initiated is still under discussion. In patients with overt hypothyroidism defined as low FT4 and elevated TSH or TSH > 10 mU/L a replacement with levothyroxine is clearly indicated. In patients with subclinical hypothyroidism defined as a TSH between 4 and 10 mU/L and normal FT4, the treatment with Levothyroxine depends on the underlying disease and symptoms. Levothyroxine is a prohormone with is activated by deiodination in the organs to triiodothyronine. Therefore, levothyroxine for replacement therapy is mainly used. Some patients, however, do not feel well with this treatment and therefore studies with a combination therapy of levothyroxine and triiodothyronine had been performed and it could be shown that this might be related to a polymorphism in type 2 deiodinase in some patients, with the consequence of lower intracellular triodothyronine formation. In women on levothyroxine replacement therapy getting pregnant, the demand of levothyroxine increases up to 25-50 µg, especially in the early weeks of pregnancy. It also has to be considered that the resorption of levothyroxine depends on normal stomach acid and therefore patients on acid blockers or atrophic gastritis require higher dosages of levothyroxine. Only patients after thyroidectomy because of differentiated thyroid carcinoma with higher grad of malignancy need a TSH suppressive therapy, those with occult papillary thyroid carcinoma the TSH should be within the low normal range. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Risk assessment of thyroid follicular cell tumors.

    PubMed Central

    Hill, R N; Crisp, T M; Hurley, P M; Rosenthal, S L; Singh, D V

    1998-01-01

    Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases. Images Figure 1 Figure 2 Figure 3 PMID:9681971

  11. Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer

    ClinicalTrials.gov

    2017-01-31

    BRAF Gene Mutation; Poorly Differentiated Thyroid Gland Carcinoma; Recurrent Thyroid Gland Carcinoma; Stage IV Thyroid Gland Follicular Carcinoma; Stage IV Thyroid Gland Papillary Carcinoma; Stage IVA Thyroid Gland Follicular Carcinoma; Stage IVA Thyroid Gland Papillary Carcinoma; Stage IVB Thyroid Gland Follicular Carcinoma; Stage IVB Thyroid Gland Papillary Carcinoma; Stage IVC Thyroid Gland Follicular Carcinoma; Stage IVC Thyroid Gland Papillary Carcinoma

  12. Painful thyroid nodule, a misleading presentation of subacute thyroiditis.

    PubMed

    Jonas, Corinne; Bertrand, Claude; Michel, Luc; Donckier, Julian E

    2016-10-01

    Typical presentation of subacute thyroiditis (SAT) is an anterior neck pain radiating up to the jaw and ear, often associated with asthenia and fever. Biology shows hyperthyroidism and inflammation. The thyroid uptake is low at scintigraphy. However, the clinical presentation of SAT may be misleading. We report two cases of SAT whose initial manifestation was a painful thyroid nodule suspected of malignancy. In both cases, ultrasound feature was a heterogeneous, hypoechoic, ill-defined area with a low vascularization on colour Doppler. These areas were interpreted by radiologist as nodules. Surgery was then considered. Such a presentation should be known by clinicians to prevent unnecessary surgery.

  13. Modified Miccoli's thyroid surgery for thyroid diseases

    PubMed Central

    YU, HUI; GE, XIN; PAN, WEIKANG; WANG, HUAIJIE; HUANG, QIANG; DONG, YU; GAO, YA; YU, JIANJUN

    2015-01-01

    Minimally invasive video-assisted thyroidectomy (MIVAT), originally described by Miccoli, is considered to be the most widely practiced and easily reproducible procedure for selected patients with benign and/or malignant thyroid nodules. Modified techniques based on MIVAT, namely modified Miccoli's thyroid surgery (MMTS), were developed based on MIVAT. This study aimed to evaluate the preliminary results of MMTS compared with those of MIVAT. The enrolling criteria included a benign nodule <3.5 cm in diameter, a malignant tumor <2 cm, no previous neck surgery and no evidence of any suspected lymph node metastasis or local invasion. Unilateral lobectomy was considered for benign lesions and the additional dissection of central compartment (level VI) lymph nodes was applied for malignant disease. The modified techniques included carefully selecting the operative incision, expanding the operative space, embedding a drainage tube in situ and delicately suturing every layer inwards and crosswise, as well as measuring cervical motion. In addition to the comparison of surgical outcomes between MMTS and MIVAT, other surgical parameters, including operative time, blood loss, postoperative drainage, cosmetic satisfaction, peak angle of cervical rotation, length of hospitalization and complications, were retrospectively analyzed. A consecutive series of 70 patients, including 54 cases of benign and 16 cases of malignant disease, initially underwent MIVAT between April, 2008 and May, 2012, while 127 patients, including 98 benign and 29 malignant cases, subsequently underwent MMTS between September, 2011 and October, 2014. Patients who received MMTS exhibited significantly less blood loss (20.3±11.3 vs. 32.3±12.6 ml, P<0.01), lower volume of postoperative drainage (42.77±15.2 vs. 50.48±23.2 ml, P<0.01) and higher cosmetic satisfaction (94.6±3.5 vs. 88.9±2.7%, P<0.01), but a longer operative time (102±36 vs. 50.48±23.2 min, P<0.01) when compared with MIVAT. In addition, a

  14. Thyroid and Aging or the Aging Thyroid? An Evidence-Based Analysis of the Literature

    PubMed Central

    2013-01-01

    Thyroid hormone production, metabolism, and action change with aging. The reference ranges for serum thyrotropin and thyroid hormones are derived mainly from younger populations. Thus, the prevalence of subclinical thyroid dysfunction is increased greatly in the elderly. However, it is unclear whether mild thyroid dysfunction in the elderly is associated with adverse outcomes. In this review, we discuss current evidence-based literature on thyroid function in the elderly and whether subclinical thyroid dysfunction in the elderly should be treated. PMID:24106641

  15. Lingual thyroid: A case report

    PubMed Central

    Amr, Bassem; Monib, Sherif

    2011-01-01

    Introduction Lingual thyroid (LT) gland is a rare clinical entity which was found to occur due to the failure of the thyroid gland to descend to its normal cervical location during embryogenesis. The presence of an ectopic thyroid gland located at the base of the tongue may present with symptoms like dysphagia, dysphonia, upper airway obstruction or even hemorrhage at any time from infancy through adulthood. Presentation of case We are presenting a case of 5-year-old girl who presented with lingual thyroid, treated with Suppression treatment followed by elective surgical resection. Discussion Incidence of ectopic lingual thyroid gland is reported as 1:100,000. It is more common in females. Most of presentations due to oropharyngeal obstruction, including dysphagia, dyspnea and dysphonia. Investigations include thyroid function tests, neck US, Technetium scanning and C.T. Conclusion Lingual thyroid is a rare anomaly. Dysphagia and dysphonia are common presenting symptoms. Pathogenesis of this ectopic is unknown. Different types of surgical approaches have been described in the management. PMID:22096763

  16. Hashimoto thyroiditis: a century later.

    PubMed

    Ahmed, Rania; Al-Shaikh, Safa; Akhtar, Mohammed

    2012-05-01

    More than a century has passed since the first description of Hashimoto thyroiditis (HT) as a clinicopathologic entity. HT is an autoimmune disease in which a breakdown of immune tolerance is caused by interplay of a variety of immunologic, genetic, and environmental factors. Thyrocyte injury resulting from environmental factors results in expression of new or hidden epitopes that leads to proliferation of autoreactive T and B cells. Infiltration of thyroid by these cells results in HT. In addition to the usual type of HT, several variants such as the fibrous type and Riedal thyroiditis are also recognized. The most recently recognized variant is immunoglobulin G4(+) HT, which may occur as isolated thyroid limited disease or as part of a generalized Ig4-related sclerosing disease. The relationship between HT and Riedel thyroiditis remains unclear; however, recent evidence seems to suggest that it may also be part of the spectrum of Ig4-related sclerosing disease. HT is frequently associated with papillary thyroid carcinoma and may indeed be a risk factor for developing this type of cancer. The relationship between thyroid lymphoma and HT on the other hand appears well established.

  17. Characterization of thyroidal glutathione reductase

    SciTech Connect

    Raasch, R.J.

    1989-01-01

    Glutathione levels were determined in bovine and rat thyroid tissue by enzymatic conjugation with 1-chloro-2,4-dinitrobenzene using glutathione S-transferase. Bovine thyroid tissue contained 1.31 {+-} 0.04 mM reduced glutathione (GSH) and 0.14 {+-} 0.02 mM oxidized glutathione (GSSG). In the rat, the concentration of GSH was 2.50 {+-} 0.05 mM while GSSG was 0.21 {+-} 0.03 mM. Glutathione reductase (GR) was purified from bovine thyroid to electrophoretic homogeneity by ion exchange, affinity and molecular exclusion chromatography. A molecular weight range of 102-109 kDa and subunit size of 55 kDa were determined for GR. Thyroidal GR was shown to be a favoprotein with one FAD per subunit. The Michaelis constants of bovine thyroidal GR were determined to be 21.8 {mu}M for NADPH and 58.8 {mu}M for GSSG. The effect of thyroid stimulating hormone (TSH) and thyroxine (T{sub 4}) on in vivo levels of GR and glucose 6-phosphate dehydrogenase were determined in rat thyroid homogenates. Both enzymes were stimulated by TSH treatment and markedly reduced following T{sub 4} treatment. Lysosomal hydrolysis of ({sup 125}I)-labeled and unlabeled thyroglobulin was examined using size exclusion HPLC.

  18. Thyroid diseases and bone health.

    PubMed

    Williams, G R; Bassett, J H D

    2017-08-29

    Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

  19. Thyroid Hormone Deiodinases and Cancer

    PubMed Central

    Casula, Sabina; Bianco, Antonio C.

    2012-01-01

    Deiodinases constitute a group of thioredoxin fold-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation – in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is threefold to fourfold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a fivefold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma, and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches. PMID:22675319

  20. Coexistence of papillary thyroid cancer and Hashimoto thyroiditis in children: report of 3 cases.

    PubMed

    Koibuchi, Harumi; Omoto, Kiyoka; Fukushima, Noriyoshi; Toyotsuji, Tomonori; Taniguchi, Nobuyuki; Kawano, Mikihiko

    2014-07-01

    This report documents 3 pediatric papillary thyroid carcinoma cases with associated Hashimoto thyroiditis. In all 3 cases, hypoechoic nodules accompanied by multiple echogenic spots were noted on sonography of the thyroid. Hashimoto thyroiditis was suspected on the basis of positive thyroid autoantibody test results and pathologic examinations of thyroidectomy specimens, which revealed chronic thyroiditis with lymphocytic infiltration as the background of papillary thyroid carcinoma development. The potential for papillary carcinoma development warrants close follow-up, and meticulous sonographic examinations must be performed in children with Hashimoto thyroiditis. © 2014 by the American Institute of Ultrasound in Medicine.

  1. [Drainage in thyroid surgery].

    PubMed

    Ardito, G; Revelli, L; Guidi, M L; Murazio, M; Lucci, C; Modugno, P; Di Giovanni, V

    1999-01-01

    Bleeding represents a rare complication of thyroid surgery but when it occurs it may be life-threatening. To prevent this complication drainage is widely used. However no study has demonstrated the drains' value and recent reports have questioned its benefits. Therefore we have analyzed our experience of a 10 year-period in which 1.217 thyroidectomies were performed by the same surgical team and prophylactic routine drainage was always adopted. In 13 patients (1.06%) a benign hematoma occurred with spontaneous remission. In 6 patients the bleeding was severe and compressive hematoma occurred; it required surgical re-exploration. Such a complication is unusual in the neck surgery (0.49% in the authors' series) performed by experienced surgeons and when life-threatening hematomas do occur they depend on various uncontrolled factors and drainage is often not helpful. Otherwise a meticulous haemostatic technique is necessary and patients should be observed very closely during the few first hours following surgery on the thyroid gland. Therefore on the basis of the analysis of their series, although it is not always possible to prove the benefit of the drainage, the authors suggest its indication in the neck surgery, as in other fields with dead space, to remove blood and secretions reducing postoperative complications. They have never observed wound infections and patients were discharged within 72 hours.

  2. Ultrasound-Guided Fine Needle Aspiration Biopsy of the Thyroid

    MedlinePlus

    ... Index A-Z Ultrasound-Guided Fine Needle Aspiration Biopsy of the Thyroid An ultrasound-guided thyroid biopsy ... Thyroid? What is Ultrasound-Guided Fine Needle Aspiration Biopsy of the Thyroid? During a fine needle aspiration ...

  3. What's New in Thyroid Cancer Research and Treatment?

    MedlinePlus

    ... and Treatment? Thyroid Cancer About Thyroid Cancer What’s New in Thyroid Cancer Research and Treatment? Important research ... RAI) therapy. Doctors and researchers are looking for new ways to treat thyroid cancer that are more ...

  4. Thyroid Hormone Replacement in Patients Following Thyroidectomy for Thyroid Cancer

    PubMed Central

    Hannoush, Zeina C.; Weiss, Roy E.

    2016-01-01

    Thyroid hormone replacement therapy in patients following thyroidectomy for thyroid cancer, although a potentially straightforward clinical problem, can present the clinician and patient with a variety of challenges. Most often the problems are related to the dose and preparation of thyroid hormone (TH) to use. Some patients feel less well following thyroidectomy and/or radioiodine ablation than they did before their diagnosis. We present evidence that levothyroxine (L-T4) is the preparation of choice, and keeping the thyroid-stimulating hormone (TSH) between detectable and 0.1 mU/L should be the standard of care in most cases. In unusual circumstances, when the patient remains clinically hypothyroid despite a suppressed TSH, we acknowledge there may be as yet unidentified factors influencing the body’s response to TH, and individualized therapy may be necessary in such patients. PMID:26886951

  5. Nuclear Receptor Corepressor Recruitment by Unliganded Thyroid Hormone Receptor in Gene Repression during Xenopus laevis Development

    PubMed Central

    Sachs, Laurent M.; Jones, Peter L.; Havis, Emmanuelle; Rouse, Nicole; Demeneix, Barbara A.; Shi, Yun-Bo

    2002-01-01

    Thyroid hormone receptors (TR) act as activators of transcription in the presence of the thyroid hormone (T3) and as repressors in its absence. While many in vitro approaches have been used to study the molecular mechanisms of TR action, their physiological relevance has not been addressed. Here we investigate how TR regulates gene expression during vertebrate postembryonic development by using T3-dependent amphibian metamorphosis as a model. Earlier studies suggest that TR acts as a repressor during premetamorphosis when T3 is absent. We hypothesize that corepressor complexes containing the nuclear receptor corepressor (N-CoR) are key factors in this TR-dependent gene repression, which is important for premetamorphic tadpole growth. To test this hypothesis, we isolated Xenopus laevis N-CoR (xN-CoR) and showed that it was present in pre- and metamorphic tadpoles. Using a chromatin immunoprecipitation assay, we demonstrated that xN-CoR was recruited to the promoters of T3 response genes during premetamorphosis and released upon T3 treatment, accompanied by a local increase in histone acetylation. Furthermore, overexpression of a dominant-negative N-CoR in tadpole tail muscle led to increased transcription from a T3-dependent promoter. Our data indicate that N-CoR is recruited by unliganded TR to repress target gene expression during premetamorphic animal growth, an important process that prepares the tadpole for metamorphosis. PMID:12446772

  6. Medullary thyroid carcinoma: The third most common thyroid cancer reviewed

    PubMed Central

    STAMATAKOS, MICHAEL; PARASKEVA, PANORAIA; STEFANAKI, CHARIKLEIA; KATSARONIS, PARASKEVAS; LAZARIS, ANDREAS; SAFIOLEAS, KONSTANTINOS; KONTZOGLOU, KONSTANTINOS

    2011-01-01

    Medullary thyroid cancer is a type of thyroid cancer of neuroendocrine origin. It occurs in hereditary and sporadic forms, and its aggressive behavior is associated with the clinical presentation and type of RET mutation. Total thyroidectomy remains the ideal choice of treatment. Early diagnosis and treatment are the fundamental for a 100% cure rate. In this study, we present our experience of 3 cases, along with a complete review of the literature derived from a Pubmed Database search. PMID:22870127

  7. Hashimoto thyroiditis, anti-thyroid antibodies and systemic lupus erythematosus.

    PubMed

    Posselt, Rayana T; Coelho, Vinícius N; Skare, Thelma L

    2017-05-25

    To study the prevalence of Hashimoto thyroiditis (HT), anti-thyroid autoantibodies (anti-thyroglobulin or TgAb and thyroperoxidase or TPOAb) in systemic lupus erythematosus (SLE) patients. To analyze if associated HT, TgAb and/or TPOAb influence clinical or serological profiles, disease activity and/or its cumulative damage. Three hundred and one SLE patients and 141 controls were studied for thyroid stimulating hormone, thyroxin, TgAb and TPOAb by chemiluminescence and immunometric assays. Patients' charts were reviewed for serological and clinical profiles. Activity was measured by SLE Disease Activity Index and cumulative damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for SLE. SLE patients were divided into: (i) with HT; (ii) with anti-thyroid antibodies but without HT; and (iii) without HT and without anti-thyroid antibodies, and were then compared. Furthermore, SLE patients were compared according to the number of positive anti-thyroid antibodies. Hashimoto thyroiditis prevalence in SLE was 12.6% and 5.6% in controls (P = 0.02; odds ratio = 2.4; 95% CI = 1.09-5.2). Lupus patients with HT had less malar rash (P = 0.02) and more anti-Sm (P = 0.04). Anti-Sm was more common in those with two anti-thyroid antibodies than in those with one or negative. The presence of HT or the number of positive autoantibodies did not associate either with disease activity (P = 0.95) or with cumulative damage (P = 0.98). There is a two-fold increased risk of HT in SLE patients. Anti-Sm antibodies favor this association and also double antibody positivity. Disease activity and cumulative damage are not related to HT or with autoantibodies. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  8. [Thyroid involvement in systemic lupus erythematosus].

    PubMed

    Pedersen, L V; Herlin, T

    1995-07-24

    Systemic lupus erythematosus (SLE) is a rare disease in childhood, and is characterized by widespread inflammation of blood vessels and connective tissue. Although the disease affects a number of different organs, thyroid involvement is not included in the classification criteria set of SLE. We describe two cases of irls with SLE who developed thyroiditis with goitre, thyroid autoantibodies, elevated serum TSH and decreased thyroid function tests. One patient had thyroiditis eighteen months before SLE was diagnosed and the other developed thyroiditis six months after the onset of SLE. Recent prospective studies have shown that thyroid involvement in SLE presenting either as hyper- or hypothyroidism is more common among children than adults. We therefore recommend that thyroid function tests should regularly be performed in juvenile SLE patients and, conversely, that child patients with Hashimoto's thyroiditis should be examined for symptoms and serology of SLE.

  9. [Risk factors and pathogenesis of Hashimoto's thyroiditis].

    PubMed

    Paknys, Gintaras; Kondrotas, Anatolijus Juozas; Kevelaitis, Egidijus

    2009-01-01

    The aim of this review is to summarize the current knowledge on Hashimoto's thyroiditis and its pathogenesis and to introduce the readers to the basic concept of autoimmune thyroid disease. Hashimoto's thyroiditis and Graves' disease are different expressions of a basically similar autoimmune process, and the clinical appearance reflects the spectrum of the immune response in a particular patient. During this response, cytotoxic autoantibodies, stimulatory autoantibodies, blocking autoantibodies, or cell-mediated autoimmunity may be observed. Persons with classic Hashimoto's thyroiditis have serum antibodies reacting with thyroglobulin and thyroid peroxidase. These antibodies (particularly antibodies against thyroid peroxidase) are complement-fixing immunoglobulins and may be cytotoxic. In addition, many patients have cell-mediated immunity directed against thyroid antigens. Cell mediated-immunity is also a feature of experimental thyroiditis induced in animals by injection of thyroid antigen with adjuvants. Hashimoto's thyroiditis is predominantly the clinical expression of cell-mediated immunity leading to destruction of thyroid cells, which in its severest form causes thyroid failure. The significance of genetic component and nongenetic risk factors (pregnancy, drugs, age, sex, infection, and irradiation) in the development of Hashimoto's thyroiditis is also reviewed. Epidemiologic studies have demonstrated that the genetic component is important in the pathogenesis of Hashimoto's thyroiditis, although the pattern of inheritance is non-Mendelian and is likely to be influenced by subtle variations in the functions of multiple genes. Nongenetic risk factors (environmental factors) are also etiologically important, because the concordance rate in monozygotic twins is below 1.

  10. IL-1β a potential factor for discriminating between thyroid carcinoma and atrophic thyroiditis.

    PubMed

    Kammoun-Krichen, Maha; Bougacha-Elleuch, Noura; Mnif, Mouna; Bougacha, Fadia; Charffedine, Ilhem; Rebuffat, Sandra; Rebai, Ahmed; Glasson, Emilie; Abid, Mohamed; Ayadi, Fatma; Péraldi-Roux, Sylvie; Ayadi, Hammadi

    2012-01-01

    Interactions between cytokines and others soluble factors (hormones, antibodies...) can play an important role in the development of thyroid pathogenesis. The purpose of the present study was to examine the possible correlation between serum cytokine concentrations, thyroid hormones (FT4 and TSH) and auto-antibodies (Tg and TPO), and their usefulness in discriminating between different thyroid conditions. In this study, we investigated serum from 115 patients affected with a variety of thyroid conditions (44 Graves' disease, 17 Hashimoto's thyroiditis, 11 atrophic thyroiditis, 28 thyroid nodular goitre and 15 papillary thyroid cancer), and 30 controls. Levels of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Thyroid hormones and auto-antibodies were measured using ELISA. Our study showed that IL-1β serum concentrations allow the discrimination between atrophic thyroiditis and papillary thyroid cancer groups (p = 0.027).

  11. Painless thyroiditis associated to thyroid carcinoma: role of initial ultrasonography evaluation.

    PubMed

    Valentini, Raisa Bressan; Macedo, Bruno Mussoi de; Izquierdo, Rogério Friedrich; Meyer, Erika Laurini Souza

    2016-04-01

    Even though it is a rare event, most associations of thyroid carcinoma with subacute thyroiditis described in the literature are related to its granulomatous form (Quervain's thyroiditis). We present a patient with subacute lymphocytic thyroiditis (painless thyroiditis) and papillary thyroid cancer that was first suspected in an initial ultrasound evaluation. A 30-year old female patient who was referred to the emergency room due to hyperthyroidism symptoms was diagnosed with painless thyroiditis established by physical examination and laboratory findings. With the presence of a palpable painless thyroid nodule an ultrasound was prescribed and the images revealed a suspicious thyroid nodule, microcalcification focus in the heterogeneous thyroid parenquima and cervical lymphadenopathy. Fine needle aspiration biopsy was taken from this nodule; cytology was assessed for compatibility with papillary thyroid carcinoma. Postsurgical pathology evaluation showed a multicentric papillary carcinoma and lymphocytic infiltration. Subacute thyroiditis, regardless of type, may produce transitory ultrasound changes that obscure the coexistence of papillary carcinoma. Due to this, initial thyroid ultrasound evaluation should be delayed until clinical recovery. We recommended a thyroid ultrasound exam for initial evaluation of painless thyroiditis, particularly in patients with palpable thyroid nodule. Further cytological examination is recommended in cases presenting with suspect thyroid nodule and/or non-nodular hypoechoic (> 1 cm) or heterogeneous areas with microcalcification focus.

  12. Urticarial vasculitis reveals unsuspected thyroiditis.

    PubMed

    Ferreira, Olga; Mota, Alberto; Baudrier, Teresa; Azevedo, Filomena

    2012-01-01

    A 38-year-old woman presented with erythematous, violaceous plaques with a serpiginous and unusual appearance located on the left shoulder, left thigh, and right buttock, evolving for 5 days, which eventually became generalized. A skin biopsy revealed leukocytoclastic vasculitis and a diagnosis of urticarial vasculitis was made. The complete blood count, biochemistry, complement levels, and other immunological test results were unremarkable. However, antithyroid antibody titers were increased. Despite having normal thyroid function tests and an absence of specific symptoms, the patient underwent a thyroid ultrasound, which revealed features of thyroiditis, and was subsequently referred to an endocrinologist. Several diseases can be associated with urticarial vasculitis, namely infections and autoimmune connective-tissue disorders such as systemic lupus erythematosus and Sjögren syndrome. Thyroiditis is an uncommon association.

  13. Foetal and neonatal thyroid disorders.

    PubMed

    Radetti, G; Zavallone, A; Gentili, L; Beck-Peccoz, P; Bona, G

    2002-10-01

    Thyroid hormones have been shown to be absolutely necessary for early brain development. During pregnancy, both maternal and foetal thyroid hormones contribute to foetal brain development and maternal supply explains why most of the athyreotic newborns usually do not show any signs of hypothyroidism at birth. Foetal and/or neonatal hypothyroidism is a rare disorder. Its incidence, as indicated by neonatal screening, is about 1:4000. Abnormal thyroid development (i.e. agenesia, ectopic gland, hypoplasia) or inborn errors in thyroid hormone biosynthesis are the most common causes of permanent congenital hypothyroidism. Recent studies reported that mutations involving Thyroid Transcriptor Factors (TTF) such as TTF-1, TTF-2, PAX-8 play an important role in altered foetal thyroid development. Deficiency of transcriptor factor (Pit-1, Prop-1, LHX-3) both in mother and in the foetus represents another rare cause of foetal hypothyroidism. At birth clinical picture may be not always so obvious and typical signs appear only after several weeks but a delayed diagnosis could have severe consequences consisting of delayed physical and mental development. Even if substitutive therapy is promptly started some learning difficulties might still arise suggesting that intrauterine adequate levels of thyroid hormones are absolutely necessary for a normal neurological development. Placental transfer of maternal antithyroid antibodies inhibiting fetal thyroid function can cause transient hypothyroidism at birth. If the mother with thyroid autoimmune disease is also hypothyroid during pregnancy and she doesn't receive substitutive therapy, a worse neurological outcome may be expected for her foetus. Foetal and/or neonatal hyperthyroidism is a rare condition and its incidence has been estimated around 1:4000-40000, according to various authors. The most common causes are maternal thyroid autoimmune disorders, such as Graves' disease and Hashimoto's thyroiditis. Rarer non autoimmune causes

  14. Celiac Disease and Thyroid Conditions

    MedlinePlus

    ... whole body to slow down. This is called hypothyroidism. If your thyroid begins to over-produce hormones ... and Grave’s Disease are two common causes of hypothyroidism and hyperthyroidism (respectively). Both are autoimmune diseases: autoimmune ...

  15. Proteome analysis in thyroid pathology.

    PubMed

    Pagni, Fabio; L'Imperio, Vincenzo; Bono, Francesca; Garancini, Mattia; Roversi, Gaia; De Sio, Gabriele; Galli, Manuel; Smith, Andrew James; Chinello, Clizia; Magni, Fulvio

    2015-08-01

    The incidence of thyroid cancer has continuously increased due to its detection in the preclinical stage. Clinical research in thyroid pathology is focusing on the development of new diagnostic tools to improve the stratification of nodules that have biological, practical and economic consequences on the management of patients. Several clinical questions related to thyroid carcinoma remain open and the use of proteomic research in the hunt for new targets with potential diagnostic applications has an important role in the solutions. Many different proteomic approaches are used to investigate thyroid lesions, including mass spectrometry profiling and imaging technologies. These approaches have been applied to different human tissues (cytological specimens, frozen sections, formalin-fixed paraffin embedded tissue or Tissue Micro Arrays). Moreover, other specimens are used for biomarker discovery, such as cell lines and the secretome. Alternative approaches, such as metabolomics and lipidomics, are also used and integrated within proteomics.

  16. Thyroid hormones and heart failure.

    PubMed

    Martinez, Felipe

    2016-07-01

    Heart failure is a major health problem and its relationship to thyroid dysfunction has been increasingly investigated in recent years. Since it has been demonstrated that thyroid hormones (TH) and mainly T3 have cardioprotective effects, it is easy to understand that in the scenario of thyroid disorder, cardiac function may be damaged, and inversely in cardiac dysfunction thyroid dysregulation may be seen. The increase in plasma TH produces a clear neurohormonal activation which impacts negatively on cardiac function. In hypothyroidism, and in addition to extracardiac dysfunction, myocardial and vascular remodelling is altered and they contribute to cardiac failure. Abnormal low plasma TSH has also been shown to be a risk factor for developing HF in several recent studies, and they suggest that TSH is an independent predictor of clinical outcome including death and cardiac hospitalizations. Therefore, physicians should consider all these concepts when managing a patient with heart failure, not only for a clear diagnosis, but also for better and accurate treatment.

  17. How Is Thyroid Cancer Diagnosed?

    MedlinePlus

    ... test. This leads to low thyroid hormone levels (hypothyroidism) and causes the pituitary gland to release more ... is that it can cause the symptoms of hypothyroidism, including tiredness, depression, weight gain, sleepiness, constipation, muscle ...

  18. Thyroid hemangiomas diagnosed on sonography.

    PubMed

    Park, Sung Hee; Kim, Soo Jin; Jung, Hyun Kyung

    2014-04-01

    Primary thyroid hemangiomas are extremely rare, and only a few cases have been previously reported. Primary hemangiomas are developmental anomalies resulting from the inability of the angioblastic mesenchyme to form canals. Thyroid hemangiomas are generally considered difficult to diagnose preoperatively because of their low incidence and nonspecific imaging findings. Here we report 2 cases of thyroid hemangiomas that were diagnosed correctly on preoperative sonography. Our cases showed similar sonographic findings, such as well-circumscribed hypoechoic lesions with internal channel-like linear lines, and bloody content was aspirated during fine-needle aspirations. Our report shows that thyroid hemangiomas can be diagnosed correctly by sonography with or without confirmation of bloody content in the lesions by fine-needle aspiration.

  19. Imaging the thyroid in children.

    PubMed

    Clerc, Jérôme

    2014-03-01

    Color Doppler Ultrasounds (CDU) and Thyroid Scanning (TS) have much improved in recent years and offer a likely diagnosis of the disorder and its main subtypes. This especially applies when diagnosing permanent or transient causes of congenital hypothyroidism (CH), where dual imaging has proven to be more informative than single scanning. Though both isotopes have acceptable performances, the use of (123)I appears more advisable, since it more accurately identifies the various aetiologies of CH and probably has better dosimetric characteristics than (99m)Tc. Detailed dual imaging patterns are presented in connection with most of the underlying mechanisms explaining CH, thyroid dysgenesis (75%) and dyshormonogenesis (20%). Imaging of thyroid autoimmunity, of immunogenic thyrotoxicosis and of thyroid autonomy, is helped by CDU but most often requires a quantified (123)I-TS (molecular imaging). We finally show the interest of CDU to sort suspicious nodule and present the new TIRADS scoring system. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Thyroid storm with multiorgan failure.

    PubMed

    Chong, Hui Wen; See, Kay Choong; Phua, Jason

    2010-03-01

    Thyroid storm is a rare and potentially fatal condition. Various unusual presentations in patients with thyroid storm have been described but multiorgan dysfunction is uncommonly seen. We describe a 35-year-old patient with a history of Graves' disease who was diagnosed with thyroid storm at 2 weeks postpartum. This was complicated by acute liver failure, acute kidney injury, severe lactic acidosis, disseminated intravascular coagulation, and heart failure with acute pulmonary edema. The multiorgan dysfunction was reversed by prompt institution of antithyroid drugs and supportive management in the intensive care unit. Thyroid storm is a medical emergency. One of the challenges lies in recognizing its varied presentations. Early diagnosis and appropriate treatment is important to prevent the catastrophic outcomes associated with this condition.

  1. Rational therapy for thyroid storm.

    PubMed

    Carter, J N; Eastman, C J; Kilham, H A; Lazarus, L

    1975-10-01

    An approach to the management of patients with thyroid storm is described. The treatment regimen, which is directed against the abnormalities as they are presently understood, incorporates: (a) Propranolol to inhibit the catecholamine-mediated peripheral effects of the circulating thyronines; (b) Propylthiouracil to inhibit thyroid hormone synthesis and to inhibit peripheral conversion of thyroxine to triiodothyronine (T3), the predominant source of T3 production; (c) Iodine to block the glandular release of thyroid hormones; (d) Dexamethasone along with general supportive therapy. The regimen has been used for a 13 year old schoolgirl with thyroid storm, and the induced rapid fall in serum T3 levels is illustrated. It has also been used in patients with florid thyrotoxicosis undergoing emergency surgery and has resulted in marked clinical improvement associated with rapid decreases in serum T3 levels. It is a simple and efficient regimen, rendering cumbersome forms of therapy such as plasmapheresis and peritoneal dialysis unnecessary.

  2. Sorafenib for Metastatic Thyroid Cancer

    Cancer.gov

    A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

  3. [Genetic factors predisposing to the development of papillary thyroid cancer].

    PubMed

    Puzianowska-Kuźnicka, Monika; Pietrzak, Maciej

    2005-01-01

    protein synthesized on such hybrid template is not present in the cell membrane but in the cytoplasm, where it permanently activates transduction pathway specific for RET. NTRK1 gene encoding a member of family of neuronal growth factor receptors containing thyrosine kinase domain is also rearranged in papillary cancers. However, genes fused to its kinase domain-encoding sequence are different from the ones fused to RET. MET, a gene encoding another membrane protein with thyrosine kinase activity, which acts as a growth factor-receptor, is overexpressed in 70%-90% of papillary thyroid cancers. BRAF gene encoding another yet kinase transducing signals from RAS and RAF to the cell is mutated at position 1796 (T/A, amino acid substitution V599E) in 38-69% of papillary cancers. The presence of this activatory mutation is associated with higher degree of clinical advancement of the disease. In addition, in majority of papillary cancers tested, mutations of the genes encoding nuclear triiodothyronine receptors were found. Transgenic mice with both TRB allele replaced with dominant-negative TRB mutants develop aggressive thyroid cancers. Progression from papillary to anaplastic cancer is most possibly caused by the occurrence of additional anomalies within P53, RAS, NM23,b-catenin gene and other genes.

  4. Aflibercept in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy

    ClinicalTrials.gov

    2017-01-24

    Recurrent Thyroid Gland Carcinoma; Stage III Thyroid Gland Follicular Carcinoma; Stage III Thyroid Gland Papillary Carcinoma; Stage IV Thyroid Gland Follicular Carcinoma; Stage IV Thyroid Gland Papillary Carcinoma

  5. Thyroid hormone controls the development of connections between the spinal cord and limbs during Xenopus laevis metamorphosis.

    PubMed

    Marsh-Armstrong, Nicholas; Cai, Liquan; Brown, Donald D

    2004-01-06

    During premetamorphic stages, Xenopus laevis tadpoles expressing either a dominant-negative thyroid hormone (TH) receptor or a type-III iodothyronine deiodinase transgene in the nervous system have reduced TH-induced proliferation in the spinal cord and produce fewer hindlimb-innervating motorneurons. During prometamorphic stages, innervation of the hindlimbs is reduced, and few functional neuromuscular connections are formed. By metamorphic climax, limb movement is impaired, ranging from uncoordinated leg swimming to complete quadriplegia. This phenotype is due to transgene action in the tadpole spinal cord. The requirement of TH for neurogenesis during premetamorphosis is the earliest TH-regulated process reported to date in the sequence of metamorphic changes in anurans. The muscle formed during limb growth was previously shown to be a direct target of TH control. Here, we show that the same is true of the development of spinal cord cells that innervate the limbs.

  6. Thyroid Dysfunction from Antineoplastic Agents

    PubMed Central

    Larsen, P. Reed; Marqusee, Ellen

    2011-01-01

    Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%–50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient’s quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

  7. BRAF in Papillary Thyroid Carcinoma

    PubMed Central

    Lanzilotta, Salvatore Giovanni; Grammatica, Luciano; Paradiso, Angelo; Simone, Gianni

    2007-01-01

    Novel genetic findings about papillary thyroid carcinoma identify BRAF gene as a subject of great interest. Involvement of BRAF gene in pathogenesis of PTC, diagnostic value and the putative prognostic significance of its T1799A mutation are summarized in this article. Furthermore, a particular attention is focused to the role of pre-operative detection of BRAF mutation in the FNAB specimens of thyroid nodules and to the use of this gene as target for an effective cancer therapy. PMID:17641411

  8. Clinical Diagnosis of Thyroid Cancer

    PubMed Central

    Staunton, M. D.; Greening, W. P.

    1973-01-01

    In a survey of 293 patients with carcinoma of the thyroid, a goitre or enlarged lymph nodes in the neck were the commonest symptoms and a mass confined to one lobe the commonest sign. Hardness of the mass was an important diagnostic feature, and at least two-thirds of the tumour could be recognized before operation. It is suggested that the preoperative evaluation of thyroid swellings should be classified as benign, cancer suspected, and cancer probable. PMID:4800743

  9. Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma

    PubMed Central

    Igata, Motoyuki; Tsuruzoe, Kaku; Kawashima, Junji; Kukidome, Daisuke; Kondo, Tatsuya; Motoshima, Hiroyuki; Shimoda, Seiya; Furukawa, Noboru; Nishikawa, Takeshi; Miyamura, Nobuhiro

    2016-01-01

    Summary Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 μg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended. Learning points There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. When total thyroidectomy is performed in

  10. Thyroid hormone biosynthesis and release.

    PubMed

    Carvalho, Denise P; Dupuy, Corinne

    2017-01-31

    Thyroid hormones (TH) 3,5,3',5'- tetraiodothyronine or thyroxine (T4) and 3,5,3'- triiodothyronine (T3) contain iodine atoms as part of their structure, and their synthesis occur in the unique structures called thyroid follicles. Iodide reaches thyroid cells through the bloodstream that supplies the basolateral plasma membrane of thyrocytes, where it is avidly taken up through the sodium/iodide symporter (NIS). Thyrocytes are also specialized in the secretion of the high molecular weight protein thyroglobulin (TG) in the follicular lumen. The iodination of the tyrosyl residues of TG preceeds TH biosynthesis, which depends on the interaction of iodide, TG, hydrogen peroxide (H2O2) and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes. Thyroid hormone biosynthesis is under the tonic control of thyrotropin (TSH), while the iodide recycling ability is very important for normal thyroid function. We discuss herein the biochemical aspects of TH biosynthesis and release, highlighting the novel molecules involved in the process.

  11. Thromboembolic complications of thyroid storm.

    PubMed

    Min, T; Benjamin, S; Cozma, L

    2014-01-01

    Thyroid storm is a rare but potentially life-threatening complication of hyperthyroidism. Early recognition and prompt treatment are essential. Atrial fibrillation can occur in up to 40% of patients with thyroid storm. Studies have shown that hyperthyroidism increases the risk of thromboembolic events. There is no consensus with regard to the initiation of anticoagulation for atrial fibrillation in severe thyrotoxicosis. Anticoagulation is not routinely initiated if the risk is low on a CHADS2 score; however, this should be considered in patients with thyroid storm or severe thyrotoxicosis with impending storm irrespective of the CHADS2 risk, as it appears to increase the risk of thromboembolic episodes. Herein, we describe a case of thyroid storm complicated by massive pulmonary embolism. Diagnosis of thyroid storm is based on clinical findings. Early recognition and prompt treatment could lead to a favourable outcome.Hypercoagulable state is a recognised complication of thyrotoxicosis.Atrial fibrillation is strongly associated with hyperthyroidism and thyroid storm.Anticoagulation should be considered for patients with severe thyrotoxicosis and atrial fibrillation irrespective of the CHADS2 score.Patients with severe thyrotoxicosis and clinical evidence of thrombosis should be immediately anticoagulated until hyperthyroidism is under control.

  12. Suberoylanilide Hydroxamic Acid in Treating Patients With Metastatic and/or Locally Advanced or Locally Recurrent Thyroid Cancer

    ClinicalTrials.gov

    2014-07-23

    Insular Thyroid Cancer; Recurrent Thyroid Cancer; Stage II Follicular Thyroid Cancer; Stage II Papillary Thyroid Cancer; Stage IV Follicular Thyroid Cancer; Stage IV Papillary Thyroid Cancer; Thyroid Gland Medullary Carcinoma

  13. Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer

    ClinicalTrials.gov

    2017-08-21

    Poorly Differentiated Thyroid Gland Carcinoma; Recurrent Thyroid Gland Carcinoma; Stage I Thyroid Gland Follicular Carcinoma; Stage I Thyroid Gland Papillary Carcinoma; Stage II Thyroid Gland Follicular Carcinoma; Stage II Thyroid Gland Papillary Carcinoma; Stage III Thyroid Gland Follicular Carcinoma; Stage III Thyroid Gland Papillary Carcinoma; Stage IVA Thyroid Gland Follicular Carcinoma; Stage IVA Thyroid Gland Papillary Carcinoma; Stage IVB Thyroid Gland Follicular Carcinoma; Stage IVB Thyroid Gland Papillary Carcinoma; Stage IVC Thyroid Gland Follicular Carcinoma; Stage IVC Thyroid Gland Papillary Carcinoma; Tall Cell Variant Thyroid Gland Papillary Carcinoma; Thyroid Gland Oncocytic Follicular Carcinoma

  14. Thyroid lymphoma on a background of Hashimoto's thyroiditis: PET/CT appearances.

    PubMed

    Mane, Mayuresh; O'Neill, Ailbhe C; Tirumani, Sree Harsha; Shi, Min; Shinagare, Atul B; Fisher, David C

    2014-01-01

    Primary thyroid lymphoma is a rare thyroid tumor accounting for only 5% of all thyroid malignancies. It is more common in patients with a background history of chronic thyroiditis. PET/CT is helpful in the initial staging and for follow up to assess treatment response.

  15. Thyroid cancer in black thyroid glands: the effect of age and race.

    PubMed

    Ibrahim, Yasin; Crawford, Byron E; Murci, Mohammad; Masoodi, Hammad; Khan, Amna N; Hu, Tian; Kandil, Emad; Friedlander, Paul

    2015-01-01

    Black thyroid pigmentation is a rare entity. The risk of malignancy is higher in black thyroid compared to non-black thyroid glands. We aimed to examine the effect of age and race on the risk of malignancy in black thyroid glands. We identified a series of consecutive patients who underwent thyroidectomy at an academic institution between January 1998 and May 2013. Patient demographics, clinical characteristics, and histopathology data were reviewed. Among 925 patients who underwent thyroidectomy, 112 (12.1%) patients with black thyroid glands were identified. The incidence of thyroid cancer was 55.4% in black thyroid glands compared to 32.8% in non-black thyroid glands (p < 0.0001). The incidence of papillary thyroid cancer among the black and non-black thyroid glands was 34.8 and 20%, respectively (p < 0.001). The mean age (± SD) for patients with black thyroid glands and those with non-black thyroid was 54.3 ± 12.8 and 51.2 ± 15.7 years, respectively (p = 0.05). Black thyroid glands were also associated with a higher incidence of microcarcinomas (76 vs. 59%, p = 0.02). Among patients with black thyroid glands, Caucasians had a higher malignancy rate (63.4%) than African-Americans (37%; p = 0.03). The incidence of malignancy is higher in black thyroid compared to non-black thyroid glands, specifically in Caucasians. © 2015 S. Karger AG, Basel.

  16. Thyroid Cancer Statistics | Did You Know?

    Cancer.gov

    Thyroid cancer represents the 8th most common cancer in the United States. Did you know that this cancer, located at the base of the throat in the thyroid gland, is highly treatable and usually curable?

  17. IODIDE DEFICIENCY, THYROID HORMONES, AND NEURODEVELOPMENT

    EPA Science Inventory

    ABSTRACT BODY: Iodide is an essential nutrient for thyroid hormone synthesis. Severe iodide insufficiency during early development is associated with cognitive deficits. Environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under conditio...

  18. IODIDE DEFICIENCY, THYROID HORMONES, AND NEURODEVELOPMENT

    EPA Science Inventory

    ABSTRACT BODY: Iodide is an essential nutrient for thyroid hormone synthesis. Severe iodide insufficiency during early development is associated with cognitive deficits. Environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under conditio...

  19. Riedel's thyroiditis associated with hypothyroidism and hypoparathyroidism.

    PubMed Central

    Marín, F.; Araujo, R.; Páramo, C.; Lucas, T.; Salto, L.

    1989-01-01

    Hypoparathyroidism secondary to Riedel's thyroiditis is rare, only 2 previous cases having been reported. We present the case of a 36 year old woman with Riedel's thyroiditis which developed into hypothyroidism and hypoparathyroidism. Images Figure 1 PMID:2608578

  20. Thyroid storm following suicide attempt by hanging

    PubMed Central

    Shrum, J M; Byers, B; Parhar, K

    2014-01-01

    Summary A 19-year-old woman with asphyxiation complicated by cardiac arrest, following an unsuccessful suicide attempt by hanging, developed an uncommon complication of trauma-induced thyroid storm. She was initially admitted to the intensive care unit intubated and mechanically ventilated for postcardiac arrest management. Investigation of thyroid storm was pursued after the patient was noted to be persistently hypertensive, tachycardic and agitated despite high levels of sedation. Thyroid function tests confirmed the clinical suspicion of progressive thyrotoxicosis, with associated imaging consistent with thyroid inflammation secondary to band-like traumatic pressure to the lower half of the thyroid gland. Treatment with β-blockers and a thionamide resulted in the eventual resolution of her thyroid storm state and normalisation of her thyroid function. We conclude that traumatically induced thyroid storm should be considered in all hypermetabolic patients following blunt neck injuries including hanging, and that traditional treatment of hyperthyroidism can be successfully applied. PMID:25008337

  1. Thyroid storm following suicide attempt by hanging.

    PubMed

    Shrum, J M; Byers, B; Parhar, K

    2014-07-09

    Summary A 19-year-old woman with asphyxiation complicated by cardiac arrest, following an unsuccessful suicide attempt by hanging, developed an uncommon complication of trauma-induced thyroid storm. She was initially admitted to the intensive care unit intubated and mechanically ventilated for postcardiac arrest management. Investigation of thyroid storm was pursued after the patient was noted to be persistently hypertensive, tachycardic and agitated despite high levels of sedation. Thyroid function tests confirmed the clinical suspicion of progressive thyrotoxicosis, with associated imaging consistent with thyroid inflammation secondary to band-like traumatic pressure to the lower half of the thyroid gland. Treatment with β-blockers and a thionamide resulted in the eventual resolution of her thyroid storm state and normalisation of her thyroid function. We conclude that traumatically induced thyroid storm should be considered in all hypermetabolic patients following blunt neck injuries including hanging, and that traditional treatment of hyperthyroidism can be successfully applied. 2014 BMJ Publishing Group Ltd.

  2. Triple ectopic thyroid: A rare entity

    PubMed Central

    Nilegaonkar, Sujit; Naik, Chetna; Sonar, Sameer; Hirawe, Deepti

    2011-01-01

    Ectopic thyroid tissue is an uncommon congenital aberration. It is extremely rare to have three ectopic foci at three different sites. The thyroid scan has been used successfully to diagnose ectopic thyroid tissue. We report a case of ectopic thyroid tissue at base of tongue, another at the level of hyoid and third one as aberrant tissue at suprahyoid location in a 16 year old female who presented with swelling in front of neck. This patient was clinically diagnosed as thyroglossal cyst and was being planned for surgery. Preoperative thyroid scan helped in establishing diagnosis of ectopic thyroid which was the only functioning thyroid tissue. Thus, it prevented unnecessary surgery. Therefore it is suggested that thyroid scan and USG/CT scan must be done as routine work up in neck swellings pre operatively to avoid unnecessary surgeries. PMID:23559716

  3. Lenvatinib approved for certain thyroid cancers.

    PubMed

    2015-04-01

    The FDA approved lenvatinib to treat progressive, differentiated thyroid cancer, potentially offering the most effective treatment to date for a subset of thyroid cancer patients who do not respond to standard therapy.

  4. Thyroid nodules and cancers in children.

    PubMed

    Josefson, Jami; Zimmerman, Donald

    2008-09-01

    The incidence of thyroid nodules in children is estimated to be 1 to 1.5% based on clinical examination. Children with thyroid nodules, compared to adults with thyroid nodules, have a fourfold greater risk of developing malignant thyroid disease. Differentiated thyroid carcinoma is the most common pediatric endocrine tumor, constituting 0.5-3% of all childhood malignancies. The thyroid is one of the most frequent sites of secondary neoplasm in children who receive radiation therapy for other malignancies. Thyroid carcinoma has been studied extensively in adults. However, the pediatric literature on this subject is much less complete, owing to the rarity of its diagnosis. This article reviews the predisposing factors, genetics, pathology, pathogenesis , clinical presentation, detailed treatment and follow-up management of children with thyroid carcinoma. Additionally, a discussion regarding the controversial aspects of radioiodine therapy in children is included.

  5. Sarcoma of the thyroid region mimicking Riedel's thyroiditis

    PubMed Central

    Torres-Montaner, A; Beltran, M; d Romero; Oliva, H

    2001-01-01

    Because sarcomas of the anterior lower neck region occur so infrequently, they are not usually considered in the differential diagnosis of Riedel's thyroiditis. Riedel's thyroiditis itself may be confused on clinical grounds alone with malignant neoplasms because of its invasive features. Sarcomatoid carcinoma is the main entity to be discarded in this regard. This is accomplished through histological examination by the finding of carcinomatous areas and/or reactivity with epithelial markers. These features also set apart sarcomatoid carcinoma from true sarcomas. This report concerns a patient with a sarcoma of the anterior lower neck region which was initially suspected to be Riedel's thyroiditis or sarcomatoid carcinoma on clinical and radiological grounds. A peroperative biopsy was interpreted by two independent pathologists as consistent with Riedel's thyroiditis. The subsequent clinical course and postmortem examination demonstrated a high grade sarcoma with metastasis to both lungs and the pleura, and invasion of adjacent neck structures. Nevertheless, some areas of the postmortem material showed a microscopic pattern similar to mediastinal fibrosis, raising the possibility of the malignant transformation of a fibrosclerotic lesion. Key Words: Riedel's thyroiditis • sarcomatoid carcinoma • fibrous histiocytoma • differential diagnosis PMID:11429435

  6. Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer—A Review

    PubMed Central

    Gonçalves, Carlos F. L.; de Freitas, Mariana L.; Ferreira, Andrea C. F.

    2017-01-01

    Thyroid cancer is the most common malignant tumor of the endocrine system and the incidence has been increasing in recent years. In a great part of the differentiated carcinomas, thyrocytes are capable of uptaking iodide. In these cases, the main therapeutic approach includes thyroidectomy followed by ablative therapy with radioiodine. However, in part of the patients, the capacity to concentrate iodide is lost due to down-regulation of the sodium-iodide symporter (NIS), the protein responsible for transporting iodide into the thyrocytes. Thus, therapy with radioiodide becomes ineffective, limiting therapeutic options and reducing the life expectancy of the patient. Excessive ingestion of some flavonoids has been associated with thyroid dysfunction and goiter. Nevertheless, studies have shown that some flavonoids can be beneficial for thyroid cancer, by reducing cell proliferation and increasing cell death, besides increasing NIS mRNA levels and iodide uptake. Recent data show that the flavonoids apingenin and rutin are capable of increasing NIS function and expression in vivo. Herein we review literature data regarding the effect of flavonoids on thyroid cancer, besides the effect of these compounds on the expression and function of the sodium-iodide symporter. We will also discuss the possibility of using flavonoids as adjuvants for therapy of thyroid cancer. PMID:28604619

  7. Clinical concepts on thyroid emergencies.

    PubMed

    Papi, Giampaolo; Corsello, Salvatore Maria; Pontecorvi, Alfredo

    2014-01-01

    Thyroid-related emergencies are caused by overt dysfunction of the gland which are so severe that require admission to intensive care units (ICU) frequently. Nonetheless, in the ICU setting, it is crucial to differentiate patients with non-thyroidal illness and alterations in thyroid function tests from those with intrinsic thyroid disease. This review presents and discusses the main etiopathogenetical and clinical aspects of hypothyroid coma (HC) and thyrotoxic storm (TS), including therapeutic strategy flow-charts. Furthermore, a special chapter is dedicated to the approach to massive goiter, which represents a surgical thyroid emergency. We searched the electronic MEDLINE database on September 2013. Data Selection and Data Extraction: Reviews, original articles, and case reports on "myxedematous coma," "HC," "thyroid storm," "TS," "massive goiter," "huge goiter," "prevalence," "etiology," "diagnosis," "therapy," and "prognosis" were selected. Severe excess or defect of thyroid hormone is rare conditions, which jeopardize the life of patients in most cases. Both HC and TS are triggered by precipitating factors, which occur in patients with severe hypothyroidism or thyrotoxicosis, respectively. The pillars of HC therapy are high-dose l-thyroxine and/or tri-iodothyroinine; i.v. glucocorticoids; treatment of hydro-electrolyte imbalance (mainly, hyponatraemia); treatment of hypothermia; often, endotracheal intubation and assisted mechanic ventilation are needed. Therapy of TS is based on beta-blockers, thyrostatics, and i.v. glucocorticoids; eventually, high-dose of iodide compounds or lithium carbonate may be of benefit. Surgery represents the gold standard treatment in patients with euthyroid massive nodular goiter, although new techniques - e.g., percutaneous laser ablation - are helpful in subjects at high surgical risk or refusing operation.

  8. Clinical Concepts on Thyroid Emergencies

    PubMed Central

    Papi, Giampaolo; Corsello, Salvatore Maria; Pontecorvi, Alfredo

    2014-01-01

    Objective: Thyroid-related emergencies are caused by overt dysfunction of the gland which are so severe that require admission to intensive care units (ICU) frequently. Nonetheless, in the ICU setting, it is crucial to differentiate patients with non-thyroidal illness and alterations in thyroid function tests from those with intrinsic thyroid disease. This review presents and discusses the main etiopathogenetical and clinical aspects of hypothyroid coma (HC) and thyrotoxic storm (TS), including therapeutic strategy flow-charts. Furthermore, a special chapter is dedicated to the approach to massive goiter, which represents a surgical thyroid emergency. Data Source: We searched the electronic MEDLINE database on September 2013. Data Selection and Data Extraction: Reviews, original articles, and case reports on “myxedematous coma,” “HC,” “thyroid storm,” “TS,” “massive goiter,” “huge goiter,” “prevalence,” “etiology,” “diagnosis,” “therapy,” and “prognosis” were selected. Data Synthesis and Conclusion: Severe excess or defect of thyroid hormone is rare conditions, which jeopardize the life of patients in most cases. Both HC and TS are triggered by precipitating factors, which occur in patients with severe hypothyroidism or thyrotoxicosis, respectively. The pillars of HC therapy are high-dose l-thyroxine and/or tri-iodothyroinine; i.v. glucocorticoids; treatment of hydro-electrolyte imbalance (mainly, hyponatraemia); treatment of hypothermia; often, endotracheal intubation and assisted mechanic ventilation are needed. Therapy of TS is based on beta-blockers, thyrostatics, and i.v. glucocorticoids; eventually, high-dose of iodide compounds or lithium carbonate may be of benefit. Surgery represents the gold standard treatment in patients with euthyroid massive nodular goiter, although new techniques – e.g., percutaneous laser ablation – are helpful in subjects at high surgical risk or refusing operation. PMID:25071718

  9. The thyroid and metabolism: the action continues.

    PubMed

    Hollenberg, Anthony N; Forrest, Douglas

    2008-07-01

    On March 27, 2008, the American Thyroid Association sponsored a research summit on the Thyroid and Metabolism. The goals of the summit were to explore emerging new concepts and potential therapies arising from recent insights into the action of thyroid hormone signaling. New advances have identified functions previously thought to be distinct from thyroid hormone signaling pathways and suggest new avenues of therapy for metabolic disease.

  10. Parasitic thyroid nodules: cancer or not?

    PubMed

    Baker, Lauren J; Gill, Anthony J; Chan, Charles; Lin, Betty P C; Crawford, Bronwyn A

    2014-01-01

    In 2006, a 58-year-old woman presented with thyrotoxicosis. She had undergone left hemithyroidectomy 14 years before for a benign follicular adenoma. Ultrasound imaging demonstrated bilateral cervical lymphadenopathy with enhanced tracer uptake in the left lateral neck on a Technetium-99m uptake scan. Fine-needle aspiration biopsy of a left lateral neck node was insufficient for a cytological diagnosis; however, thyroglobulin (Tg) washings were strongly positive. The clinical suspicion was of functionally active metastatic thyroid cancer in cervical lymph nodes. A completion thyroidectomy and bilateral cervical lymph node dissection were performed. Histology demonstrated benign multinodularity in the right hemithyroid, with bilateral reactive lymphadenopathy and 24 benign hyperplastic thyroid nodules in the left lateral neck that were classified as parasitic thyroid nodules. As there had been a clinical suspicion of thyroid cancer, and the hyperplastic/parasitic thyroid tissue in the neck was extensive, the patient was given ablative radioactive iodine (3.7 GBq). After 2 years, a diagnostic radioactive iodine scan was clear and the serum Tg was undetectable. The patient has now been followed for 7 years with no evidence of recurrence. Archived tissue from a left lateral neck thyroid nodule has recently been analysed for BRAF V600E mutation, which was negative. Thyrotoxicosis due to functional thyroid tissue in the lateral neck is very rare and may be due to metastatic thyroid cancer or benign parasitic thyroid tissue.Parasitic thyroid nodules should be considered as a differential diagnosis of lateral neck thyroid deposits, particularly where there is a history of prior thyroid surgery.Parasitic thyroid nodules may occur as a result of traumatic rupture or implantation from a follicular adenoma at the time of surgery.The use of ablative radioactive iodine may be appropriate, as resection of all parasitic thyroid tissue can prove difficult.BRAF mutational analysis

  11. Concurrent medullary and papillary carcinoma of thyroid.

    PubMed

    Ateşpare, Altay; Çalış, Aslı Batur; Çelik, Öner; Yener, Neşe; Vural, Çetin

    2015-01-01

    Simultaneous occurrence of papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) in the same thyroid gland is a rare condition. These tumors derive from different cells; PTC originates from follicular cells whereas MTC originates from parafollicular cells. Because of this, the treatment of these tumors also differs. This article describes two rare cases of the simultaneous occurrence of MTC and PTC in the thyroid gland.

  12. Thyroid Hormones as Renal Cell Cancer Regulators

    PubMed Central

    Matak, Damian; Bartnik, Ewa; Szczylik, Cezary; Czarnecka, Anna M.

    2016-01-01

    It is known that thyroid hormone is an important regulator of cancer development and metastasis. What is more, changes across the genome, as well as alternative splicing, may affect the activity of the thyroid hormone receptors. Mechanism of action of the thyroid hormone is different in every cancer; therefore in this review thyroid hormone and its receptor are presented as a regulator of renal cell carcinoma. PMID:27034829

  13. Dual ectopic thyroid gland: sonography and scintigraphy of lingual and sublingual thyroid.

    PubMed

    Marković, Vinko; Glavina, Gordana; Eterović, Davor; Punda, Ante; Brdar, Dubravka

    2014-06-01

    Dual ectopic lingual and sublingual thyroid gland is an extraordinarily rare condition. We present 1 patient with subclinical hypothyroidism. The clinical examination revealed that the thyroid gland was not palpable in its usual cervical location, whereas ultrasonography confirmed an empty thyroid bed without any ectopic thyroid tissue in the rest of the neck. The final diagnosis of dual ectopic lingual and sublingual thyroid was established by ultrasound examination through the mouth floor and confirmed by scintigraphy and CT thereafter.

  14. THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

    EPA Science Inventory

    A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

  15. Thyroid hormone dysfunction during pregnancy: A review

    PubMed Central

    Alemu, Aynadis; Terefe, Betelihem; Abebe, Molla; Biadgo, Belete

    2016-01-01

    Thyroid dysfunctions such as hypothyroidism, thyrotoxicosis and thyroid nodules may develop during pregnancy leading to abortion, placental abruptions, preeclampsia, preterm delivery and reduced intellectual function in the offspring. Epidemiological data have shown the significant role of maternal thyroid hormone in fetal neurologic development and maternal health. It has been suggested that the deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neuro-intellectual development in the early life of the child. Pregnancy poses an important challenge to the maternal thyroid gland as hormone requirements are increased during gestation as a result of an increase in thyroid- binding globulin, the stimulatory effect of HCG on TSH receptors, and increased peripheral thyroid hormone requirements. Maternal thyroid dysfunction is associated with increased risk for early abortion, preterm delivery, neonatal morbidity and other obstetrical complications. Early diagnosis for thyroid dysfunction of pregnant women and treatment of thyroid dysfunction during pregnancy is important and cost effective to avoid both fetal and maternal complications secondary to thyroid dysfunction. Therefore the aim of this review was to assess the thyroid function changes occurring during pregnancy, the different disorders with their maternal and fetal implications, the laboratory diagnosis and the best ways of management of these conditions. PMID:27981252

  16. THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

    EPA Science Inventory

    A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

  17. Treatment Options by Stage (Thyroid Cancer)

    MedlinePlus

    ... thyroid cancer and the age of the patient: Papillary and follicular thyroid cancer in patients younger than 45 years Stage I: ... the body, such as the lungs or bones. Papillary and follicular thyroid cancer in patients 45 years and older Stage I: ...

  18. Thyroid disorders during pregnancy and postpartum.

    PubMed

    Pearce, Elizabeth N

    2015-07-01

    An awareness of the gestational changes to thyroid physiology and the impact of uncontrolled thyroid disease on pregnancy and infant outcome is essential for the successful management of hypothyroidism and hyperthyroidism. This review summarizes strategies for the management of thyroid disease in pregnancy and post partum, and it highlights areas where there is still a lack of consensus.

  19. Hashimoto's thyroiditis and papillary thyroid cancer: are they immunologically linked?

    PubMed

    Ehlers, Margret; Schott, Matthias

    2014-12-01

    Hashimoto's thyroiditis (HT) is the most common autoimmune disease in humans frequently leading to hypothyroidism. HT is characterized by a cellular immune response with lymphatic infiltration of the thyroid gland by T and B cells, as well as by a humoral immune response leading to specific antibody production. The synchronous appearance of HT and papillary thyroid cancer (PTC) indicates an immunological link between the two entities. Three different pathomechanisms may be postulated, including preexisting autoimmunity leading to malignancy due to inflammation, immunity towards preexisiting tumor cells leading to specific autoimmunity, and immune tolerance leading to malignancy despite (auto)immunity. In this article we review data describing these potential mechanisms that might lead to the synchronous appearance of HT and PTC. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. [Intraoperative neuromonitoring in thyroid surgery].

    PubMed

    Motos-Micó, José Jacob; Felices-Montes, Manuel; Abad-Aguilar, Teresa

    Intraoperative neuromonitoring of the recurrent laryngeal nerve in thyroid surgery facilitates the identification of anatomical structures in cervical endocrine surgery reducing the frequency of vocal cord paralysis. To study the normal electrophysiological values of the vague and recurrent laryngeal nerves before and after thyroid surgery. To compare rates of injury of recurrent nerve before and after the introduction of the intraoperative neuromonitoring in thyroid surgery. An observational, descriptive and prospective study in which a total of 490 patients were included. Between 2003-2010, surgery was performed on 411 patients (703 nerves at risk) with systematic identification of recurrent laryngeal nerves. Between 2010-2011 neuromonitorization was also systematically performed on 79 patients. Before the introduction of intraoperative neuromonitoring of 704 nerves at risk, there were 14 recurrent laryngeal nerve injuries. Since 2010, after the introduction of the intraoperative neuromonitoring in thyroid surgery, there has been no nerve injury in 135 nerves at risk. We consider the systematic identification of the recurrent laryngeal nerve is the 'gold standard' in thyroid surgery and the intraoperative neuromonitoring of nerves can never replace surgery but can complement it. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.