Thyroid malignancies are the most common type of endocrine tumors. Of the various histological sub-types, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF proto-oncogene is detected in ~40% of papillary thyroid cancers (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3-kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we previously developed a model of PTC. However, as in humans, BRAFV600E-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CAH1047R is unable to drive transformation on its own, when combined with BRAFV600E in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAFV600E cooperates with either PIK3CAH1074R or with silencing of the tumor suppressor PTEN, to promote development of anaplastic thyroid cancer.

Edited by Michael R. SussmanKeywords: AAE15/16 Acyl chain activating enzyme Cuphea Medium chain fatty acid Thioesterase Triacylglycerol a b s t r a c t Engineering transgenic plants that accumulate high levels of medium-chain fatty acids (MCFA) has been least successful for shorter chain lengths (e.g., C8). We demonstrate that one limitation is the activity of acyl-ACP synthetase (AAE) that re-activates fatty acids released by acyl-ACP thioesterases. Seed expression of Cuphea pulcherrima FATB acyl-ACP thioesterase in a double mutant lacking AAE15/16 increased 8:0 accumulation almost 2-fold compared to expression in wild type. These results also provide an in planta demonstration that AAE enzymes participate not only in activation of exogenously added MCFA but also in activation of MCFA synthesized in plastids.

IgG subclasses differ in their effector functions in a variety of in vitro assays. To assess the effect of antibody subclass differences on in vivo protective efficacy against herpes simplex virus (HSV), a series of subclass switch mutants was made from an anti-HSV glycoprotein D monoclonal antibody. Purified antibody was examined for the ability to protect against HSV-2 challenge in mice. IgG2a was found to be more effective than IgG1. This correlated both with activity in antibody-dependent cell-mediated cytotoxicity and with efficiency of complement-mediated neutralization. These data suggest that optimization of passive immunization against HSV requires consideration of antibody subclass.

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