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  • 1
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    Online Resource
    A novel FoxD3 Variant Is Associated With Vitiligo and Elevated Thyroid Auto-Antibodies
    The Endocrine Society ; 2015
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 100, No. 10 ( 2015-10-01), p. E1335-E1342
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 100, No. 10 ( 2015-10-01), p. E1335-E1342
    Abstract: Vitiligo frequently coincides with autoimmune endocrinopathies, particularly Hashimoto's thyroiditis (HT). Genetic susceptibility may underlie this coincident occurrence. One candidate region is the autoimmunity susceptibility locus on chromosome 1, which encompasses forkhead transcription factor D3 (FoxD3), a gene involved in embryonal melanogenesis. We identified a promotor variant (rs78645479) in an index case of vitiligo + HT + candidiasis and evaluated its clinical and functional relevance. Design: We genotyped 281 patients with variable autoimmune endocrinopathies: HT, Graves' disease (GD), type 1 diabetes (T1D), Addison's disease (AD), autoimmune polyglandular syndrome (APS), and/or vitiligo and 1858 controls. Furthermore, we experimentally assessed the effect of the variant on promotor activity and assessed the expression of FoxD3 in human thyroid tissue samples. Results: Patients with vitiligo had a higher frequency of the risk allele (30%) compared with healthy controls (18.2%). In addition, the variant was associated with the incidence of elevated anti-TPO antibodies and anti-Tg antibodies, but not with TSH, FT3, or FT4 levels and also not with GD, T1D, AD, or APS. Functionally, the variant increased transcriptional activity in Jurkat and in Hek293 cells. We confirmed gene expression of FoxD3 in human thyroid tissue, which seemed elevated in thyroid tissue samples of some patients with GD and nonautoimmune goiter but not in patients with HT. Conclusion: In addition to a possible association of rs78645479 in FoxD3 with vitiligo, our data on the association of this FoxD3 variant with thyroid autoantibodies suggest a potential involvement of FoxD3 in thyroid immunoregulation.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2015-2126
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2015
    detail.hit.zdb_id: 2026217-6
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  • 2
    Online Resource
    Online Resource
    Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome
    The Endocrine Society ; 2018
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 103, No. 10 ( 2018-10-01), p. 3845-3855
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 103, No. 10 ( 2018-10-01), p. 3845-3855
    Abstract: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting Observational study in the UK Severe Insulin Resistance Service. Patients Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti–insulin antibody (IA). Main Outcome Measures Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2018-00972
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2018
    detail.hit.zdb_id: 2026217-6
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  • 3
    Online Resource
    Online Resource
    Successful Treatment of Type B Insulin Resistance With Rituximab
    The Endocrine Society ; 2015
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 100, No. 5 ( 2015-05-01), p. 1719-1722
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 100, No. 5 ( 2015-05-01), p. 1719-1722
    Abstract: Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high ( & gt;50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone. Case Description: A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels & gt; 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patient's condition was deteriorating, we started rituximab (750 mg/m2 in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings. Conclusion: In this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2014-3552
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2015
    detail.hit.zdb_id: 2026217-6
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  • 4
    Online Resource
    Online Resource
    TSH Compensates Thyroid-Specific IGF-I Receptor Knockout and Causes Papillary Thyroid Hyperplasia
    The Endocrine Society ; 2011
    In:  Molecular Endocrinology Vol. 25, No. 11 ( 2011-11-01), p. 1867-1879
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 25, No. 11 ( 2011-11-01), p. 1867-1879
    Abstract: Although TSH stimulates all aspects of thyroid physiology IGF-I signaling through a tyrosine kinase-containing transmembrane receptor exhibits a permissive impact on TSH action. To better understand the importance of the IGF-I receptor in the thyroid in vivo, we inactivated the Igf1r with a Tg promoter-driven Cre-lox system in mice. We studied male and female mice with thyroidal wild-type, Igf1r+/−, and Igf1r−/− genotypes. Targeted Igf1r inactivation did transiently reduce thyroid hormone levels and significantly increased TSH levels in both heterozygous and homozygous mice without affecting thyroid weight. Histological analysis of thyroid tissue with Igf1r inactivation revealed hyperplasia and heterogeneous follicle structure. From 4 months of age, we detected papillary thyroid architecture in heterozygous and homozygous mice. We also noted increased body weight of male mice with a homozygous thyroidal null mutation in the Igf1r locus, compared with wild-type mice, respectively. A decrease of mRNA and protein for thyroid peroxidase and increased mRNA and protein for IGF-II receptor but no significant mRNA changes for the insulin receptor, the TSH receptor, and the sodium-iodide-symporter in both Igf1r+/− and Igf1r−/− mice were detected. Our results suggest that the strong increase of TSH benefits papillary thyroid hyperplasia and completely compensates the loss of IGF-I receptor signaling at the level of thyroid hormones without significant increase in thyroid weight. This could indicate that the IGF-I receptor signaling is less essential for thyroid hormone synthesis but maintains homeostasis and normal thyroid morphogenesis.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2011-0065
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2011
    detail.hit.zdb_id: 1492112-1
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  • 5
    Online Resource
    Online Resource
    Aging Alters Phenotypic Traits of Thyroid Dysfunction in Male Mice With Divergent Effects on Complex Systems but Preserved Thyroid Hormone Action in Target Organs
    Oxford University Press (OUP) ; 2019
    In:  The Journals of Gerontology: Series A Vol. 74, No. 8 ( 2019-07-12), p. 1162-1169
    Details
    In: The Journals of Gerontology: Series A, Oxford University Press (OUP), Vol. 74, No. 8 ( 2019-07-12), p. 1162-1169
    Abstract: Clinical manifestation of hyperthyroidism and hypothyroidism vary with age, with an attenuated, oligosymptomatic presentation of thyroid dysfunction (TD) in older patients. We asked, whether in rodents TD phenotypes are influenced by age and whether this involves changes in systemic and/or organ thyroid hormone (TH) signaling. Chronic hyper- or hypothyroidism was induced in male mice at different life stages (5, 12, and 20 months). TH excess resulted in pronounced age-specific body weight changes (increase in youngest and decrease in old mice), neither explained by changes in food intake (similar increase at all ages), nor by thermogenic gene expression in brown adipose tissue (BAT) or TH serum concentrations. Relative increase in body temperature and activity were more pronounced in old compared to young hyperthyroid mice. An attenuated hypothyroid state was found in old mice for locomotor activity and in heart and BAT on functional (less bradycardia) and gene expression level (heart and BAT). In contrast, decrease in body weight was pronounced in old hypothyroid mice. Thus, age has divergent impact on features of TD in mice, whereby effects on highly complex systems, such as energy homeostasis are not proportional to serum TH state, in contrast to organ-specific responses in heart and BAT.
    Type of Medium: Online Resource
    ISSN: 1079-5006 , 1758-535X
    URL: Article
    DOI: 10.1093/gerona/glz040
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2043927-1
    SSG: 12
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  • 6
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    Online Resource
    A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A
    The Endocrine Society ; 2016
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 101, No. 3 ( 2016-03-01), p. 1016-1022
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 101, No. 3 ( 2016-03-01), p. 1016-1022
    Abstract: Multiple endocrine neoplasia type 2 (MEN2) is usually caused by missense mutations in the proto-oncogene, RET. Objective: This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later. Methods: Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay. Results: Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET. Conclusion: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6-base-pair deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways, and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We therefore recommend screening the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2015-2948
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2016
    detail.hit.zdb_id: 2026217-6
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  • 7
    Online Resource
    Online Resource
    Proteomic Profiling of Cold Thyroid Nodules
    The Endocrine Society ; 2007
    In:  Endocrinology Vol. 148, No. 4 ( 2007-04-01), p. 1754-1763
    Details
    In: Endocrinology, The Endocrine Society, Vol. 148, No. 4 ( 2007-04-01), p. 1754-1763
    Abstract: Cold thyroid nodules (CTNs) represent a frequent endocrine disorder accounting for up to 85% of thyroid nodules in a population living in an iodine-deficient area. Benign CTNs need to be distinguished from thyroid cancer, which is relatively rare. The molecular etiology of benign CTNs is unresolved. To obtain novel insights into their pathogenesis, protein expression profiling was performed in a series of 27 solitary CTNs (10 follicular adenoma and 20 adenomatous nodules) and surrounding normal thyroid tissues using two-dimensional gel electrophoresis combined with mass spectrometry analysis, Western blotting, and immunohistochemistry. The proteome analysis revealed a specific fingerprint of CTNs with up-regulation of three functional systems: 1) thyroid cell proliferation, 2) turnover of thyroglobulin, and 3) H2O2 detoxification. Western blot analysis and immunohistochemistry confirmed the proteome data and showed that CTNs exhibit significant up-regulation of proteins involved in thyroid hormone synthesis yet are deficient in T4-containing thyroglobulin. This is consequential to intranodular iodide deficiency, mainly due to cytoplasmic sodium iodide symporter localization, and portrays the CTN as an activated proliferating lesion with an intranodular hypothyroid milieu. Furthermore, we provide preliminary evidence that up-regulation of H2O2 generation in CTNs could override the antioxidative system resulting in oxidative stress, which is suggested by the finding of raised 8-oxo-guanidine DNA adduct formation in CTNs.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2006-0752
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2007
    detail.hit.zdb_id: 2011695-0
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  • 8
    Online Resource
    Online Resource
    Identification of Constitutively Activating Somatic Thyrotropin Receptor Mutations in a Subset of Toxic Multinodular Goiters
    The Endocrine Society ; 1997
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 ( 1997-12-01), p. 4229-4233
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 82, No. 12 ( 1997-12-01), p. 4229-4233
    Abstract: Constitutively activating mutations in the TSH receptor (TSHR) gene and in the Gsα gene are frequent molecular causes for solitary toxic nodules of the thyroid. However, the etiology of toxic multinodular goiter is still largely unknown. Therefore, DNA from nodular and quiescent surrounding tissue of six patients with toxic multinodular goiters was screened for mutations in exons 9 and 10 of the TSHR gene and exons 7–10 of the Gsα gene by direct automated sequencing. In one patient, two different somatic TSHR mutations were identified in two different toxic nodules (L632I and F631L). In another patient, two different toxic nodules harbored the same TSHR mutation (I630L), whereas only one TSHR mutation (F631L) was identified in one of the two toxic nodules of an additional patient. In the other three patients, no mutations could be found in exons 9 and 10 of the TSHR gene or in exons 7–10 of the Gsα gene. Our results demonstrate that not only solitary toxic adenomas but also toxic multinodular goiters can be caused by constitutively activating mutations of the TSHR. In addition to mutations in the TSHR and possibly in Gsα, there are probably other still unknown mechanisms that cause hot nodules in toxic multinodular goiters.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.82.12.4441
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1997
    detail.hit.zdb_id: 2026217-6
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  • 9
    Online Resource
    Online Resource
    Proteomics in Thyroid Tumor Research
    The Endocrine Society ; 2009
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 94, No. 8 ( 2009-08-01), p. 2717-2724
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 94, No. 8 ( 2009-08-01), p. 2717-2724
    Abstract: Background: In recent years, “OMICS” technologies have paved novel ways for the broad-scale identification of molecular signatures and signaling pathways specific to tumorigenesis. Related to this are high hopes for the discovery of biomarkers facilitating diagnosis and prognosis of cancer as well as the option for pathway-targeted tumor treatment. Among the different OMICS methods, the potential of proteomics is just beginning to emerge, and according to the current literature, the proteome is to date the most feasible tool to reflect tumor biology. Objective: In this review we discuss the application of proteomics to the field of thyroid tumor research. Context: First, we provide an overview of different methods for protein expression profiling and then discuss specific requirements and challenges of thyroid proteomics. Furthermore, we summarize results of published proteomics studies on human thyroid tumors and finally explore perspectives of thyroid proteomics, which, combined with mRNA expression profiling and traditional biochemical methods, is increasingly contributing to an improved understanding of thyroid tumorigenesis and may in the future open novel avenues in thyroid cancer therapy.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2009-0308
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2009
    detail.hit.zdb_id: 2026217-6
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  • 10
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    Online Resource
    FOXO3 Is Inhibited by Oncogenic PI3K/Akt Signaling but Can Be Reactivated by the NSAID Sulindac Sulfide
    The Endocrine Society ; 2011
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 96, No. 9 ( 2011-09-01), p. E1361-E1371
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 96, No. 9 ( 2011-09-01), p. E1361-E1371
    Abstract: Overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a pivotal trigger of thyroid carcinogenesis. Recent findings from other tumor entities revealed that PI3K/Akt-driven carcinogenesis critically involves the inactivation of the tumor-suppressive transcription factor Forkhead box O (FOXO)-3. However, little is known about FOXO3 in the thyroid context. Aims: We sought to investigate the influence of the thyroid oncogenes BRAFV600E, H-RASV12, and p110α (H1074R) on the regulation of the PI3K downstream target FOXO3 in vitro. Furthermore, the impact of the expression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) on the transcriptional activity of FOXO3 was assessed in a panel of 44 human thyroid tumors. Finally, we tried to modulate FOXO3 activity pharmacologically with help of the nonsteroidal antiinflammatory drug sulindac sulfide (SS). Results: We found that the overexpression of p110α H1074R results in the inactivation of FOXO3 via its nuclear exclusion. In vivo, we observed a direct correlation between PTEN expression and the transcriptional activation of FOXO3. In vitro, we found that stimulation with SS reversed PI3K/Akt-driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45α and p27kip1 and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133). In agreement with this, SS promoted the cell cycle arrest and apoptosis in thyroid cells, which could be amplified by the transfection of exogenous FOXO3. Conclusion: Our data suggest that deregulation of proapoptotic FOXO3 represents a central step in PI3K/Akt-mediated thyroid carcinogenesis. Thus, SS might represent an attractive pharmacological tool for targeting thyroid neoplasia with aberrant PI3K/Akt/FOXO3 signaling.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2010-2453
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2011
    detail.hit.zdb_id: 2026217-6
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