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( 3 kinase/FRAP/mTOR/p70 s6 kinase pathway and the induction of target genes encoding IL-16 and Regulated Upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES), two T cell chemoattractants ( Figure 4 IGF-IR is over-expressed by GD-OF ( As mentioned above, subsequent studies have disclosed the physical and functional interactions between IGF-IR and TSHR occurring in thyroid epithelial cells, GD-OF and in situ in TAO orbital fat ( Culmination of Evidence That IGF-IR Represents A Clinically Important Therapeutic Target in TAO To test the central hypothesis that IGF-IR represents not only a critical component in the pathogenesis of TAO, but can also be therapeutically targeted, two placebo-controlled, multicenter clinical trials of teprotumumab have been conducted ( The initial trial of teprotumumab in TAO was organized by River Vision Development starting in 2010