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      Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy

        1 , 2

      Endocrine Reviews

      Endocrine Society

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          Abstract

          Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.

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          Most cited references 286

          • Record: found
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          The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches.

          The RAS/RAF/MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) (MAPK) and the PI3K/AKT/mammalian target of rapamycin (mTOR) (PI3K) pathways are frequently deregulated in human cancer as a result of genetic alterations in their components or upstream activation of cell-surface receptors. These signalling cascades are regulated by complex feedback and cross-talk mechanisms. In this review the key components of the MAPK and AKT pathways and their molecular alterations are described. The complex interactions between these signalling cascades are also analysed. The observation that the MAPK and the PI3K pathways are often deregulated in human cancer makes the components of these signalling cascades interesting targets for therapeutic intervention. Recently, the presence of compensatory loops that activate one pathway following the blockade of the other signalling cascade has been demonstrated. Therefore, the blockade of both pathways with combinations of signalling inhibitors might result in a more efficient anti-tumor effect as compared with a single agent. In addition, the MAPK and PI3K pathways are activated by mutations that coexist or can be mutually exclusive. In this regard, a large-scale characterization of the cancer genome might offer personalized cancer genomic information, which may improve the anti-tumor efficacy of signalling inhibitors.
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            • Record: found
            • Abstract: found
            • Article: not found

            Genomic responses in mouse models greatly mimic human inflammatory diseases.

            The use of mice as animal models has long been considered essential in modern biomedical research, but the role of mouse models in research was challenged by a recent report that genomic responses in mouse models poorly mimic human inflammatory diseases. Here we reevaluated the same gene expression datasets used in the previous study by focusing on genes whose expression levels were significantly changed in both humans and mice. Contrary to the previous findings, the gene expression levels in the mouse models showed extraordinarily significant correlations with those of the human conditions (Spearman's rank correlation coefficient: 0.43-0.68; genes changed in the same direction: 77-93%; P = 6.5 × 10(-11) to 1.2 × 10(-35)). Moreover, meta-analysis of those datasets revealed a number of pathways/biogroups commonly regulated by multiple conditions in humans and mice. These findings demonstrate that gene expression patterns in mouse models closely recapitulate those in human inflammatory conditions and strongly argue for the utility of mice as animal models of human disorders.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Signalling bias in new drug discovery: detection, quantification and therapeutic impact.

              Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure-activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide.
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                Author and article information

                Journal
                Endocr Rev
                Endocr. Rev
                edrv
                Endocrine Reviews
                Endocrine Society (Washington, DC )
                0163-769X
                1945-7189
                February 2019
                11 September 2018
                1 February 2020
                : 40
                : 1
                : 236-267
                Affiliations
                [1 ]Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
                [2 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
                Author notes
                Correspondence and Reprint Requests:  Terry J. Smith, MD, Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Brehm Tower, 1000 Wall Street, Ann Arbor, Michigan 48105. E-mail: terrysmi@ 123456med.umich.edu .
                Article
                PMC6338478 PMC6338478 6338478 edrv_201800066
                10.1210/er.2018-00066
                6338478
                30215690
                Copyright © 2019 Endocrine Society
                Page count
                Pages: 32
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: EY008976
                Award ID: 5UMIA110557
                Award ID: DK063121
                Award ID: EY11708
                Funded by: National Eye Institute 10.13039/100000053
                Award ID: EY007003
                Categories
                Reviews
                Thyroid

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