SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

Chimeric RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncoproteins are constitutively active tyrosine kinases found in thyroid papillary carcinoma and nonneoplastic Hashimoto's thyroiditis. Although several proteins have been identified to be substrates of RET/PTC kinases, the pathogenic roles played by RET/PTC in malignant and benign thyroid diseases and the molecular mechanisms that are involved are not fully understood. We found that RET/PTC expression phosphorylates the Y701 residue of STAT1, a type II interferon (IFN)-responsive protein. RET/PTC-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation requires RET/PTC kinase activity to be intact but other tyrosine kinases, such as Janus kinases or c-Src, are not involved. RET/PTC-induced STAT1 transcriptional activation was not inhibited by suppressor of cytokine signaling-1 or -3, or protein inhibitors of activated STAT3 [(protein inhibitor of activated STAT (PIAS3)], but PIAS1 strongly repressed the RET/PTC-induced transcriptional activity of STAT1. RET/PTC-induced STAT1 activation caused IFN regulatory factor-1 expression. We found that STAT1 and IFN regulatory factor-1 cooperated to significantly increase transcription from type IV IFN-gamma responsive promoters of class II transactivator genes. Significantly, cells stably expressing RET/PTC expressed class II transactivator and showed enhanced de novo membrane expression of major histocompatibility complex (MHC) class II proteins. Furthermore, RET/PTC1-bearing papillary thyroid carcinoma cells strongly expressed MHC class II (human leukocyte-associated antigen-DR alpha) genes, whereas the surrounding normal tissues did not. Thus, RET/PTC is able to phosphorylate and activate STAT1. This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes. Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto's thyroiditis.

Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.

Background: This study examined the cardiovascular responses to double-lumen endobronchial intubation during rapid sequence induction of anesthesia, and compared the effect of remifentanil and alfentanil in a randomized, double-blind, placebo-controlled study in three groups of 20 elderly patients each.Methods: Anesthesia was induced with intravenous thiopental (4-6 mg/kg) immediately followed by either remifentanil 2 μg/kg, alfentanil 30μg/kg, or saline (placebo) given over 30 sec. Succinylcholine 1.5 mg/kg was given for neuromuscular block.The laryngoscopy and intubation were performed 60 sec later.Results: The intubation significantly increased systolic arterial pressure (SAP) and heart rate (HR) in all groups. The maximum pressure changes in the remifentanil and alfentanil groups (36 ± 26 and 33 ± 30 mmHg, respectively) were significantly lower than the 83 ± 35 mmHg in the control group. The maximum HR in the remifentanil (77 ± 13 bpm) and alfentanil (80 ± 13 bpm) groups was lower when compared to controls (93 ± 11 bpm). The norepinephrine and epinephrine concentrations increased after intubation in the control group but remained unaltered in both the alfentanil and remifentanil groups. There were no significant differences between the remifentanil and alfentanil groups in HR, SAP or catecholamines at any time. Five patients in the remifentanil group and three in the alfentanil group received ephedrine for hypotension.Conclusions: Endobronchial intubation elicited a significant pressor response, and that both remifentanil and alfentanil similarly attenuated the pressor response. However, the incidence of hypotension confirms that both drugs should be used with caution in elderly patients.

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