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

        1 , 2

      Endocrine Reviews

      The 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 292

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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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            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.
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              Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.

              Fibrocytes are a distinct population of blood-borne cells that display a unique cell surface phenotype (collagen I+/CD11b+/CD13+/CD34+/CD45RO+/MHC class II+/CD86+) and exhibit potent immunostimulatory activities. Circulating fibrocytes rapidly enter sites of tissue injury, suggesting an important role for these cells in wound repair. However, the regulatory processes that govern the differentiation of blood-borne fibrocytes and the mechanisms that underlie the migration of these cells to wound sites are currently not known. We report herein that ex vivo cultured fibrocytes can differentiate from a CD14+-enriched mononuclear cell population and that this process requires contact with T cells. Furthermore, we demonstrate that TGF-beta1 (1-10 ng/ml), an important fibrogenic and growth-regulating cytokine involved in wound healing, increases the differentiation and functional activity of cultured fibrocytes. Because fibrocytes home to sites of tissue injury, we examined the role of chemokine/chemokine receptor interactions in fibrocyte trafficking. We show that secondary lymphoid chemokine, a ligand of the CCR7 chemokine receptor, acts as a potent stimulus for fibrocyte chemotaxis in vitro and for the homing of injected fibrocytes to sites of cutaneous tissue injury in vivo. Finally, we demonstrate that differentiated, cultured fibrocytes express alpha smooth muscle actin and contract collagen gels in vitro, two characteristic features of wound-healing myofibroblasts. These data provide important insight into the control of fibrocyte differentiation and trafficking during tissue repair and significantly expand their potential role during wound healing.
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                Author and article information

                Journal
                Endocrine Reviews
                The Endocrine Society
                0163-769X
                1945-7189
                February 2019
                February 01 2019
                September 11 2018
                February 2019
                February 01 2019
                September 11 2018
                : 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
                Article
                10.1210/er.2018-00066
                6338478
                30215690
                © 2018

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