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Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro
(2011)
Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.
The present article introduces a model based on cognitive consistency principles to predict how new identities become integrated into the self-concept, with consequences for intergroup attitudes. The model specifies four concepts (self-concept, stereotypes, identification, and group compatibility) as associative connections. The model builds on two cognitive principles, balance-congruity and imbalance-dissonance, to predict identification with social groups that people currently belong to, belonged to in the past, or newly belong to. More precisely, the model suggests that the relative strength of self-group associations (i.e., identification) depends in part on the (in)compatibility of the different social groups. Combining insights into cognitive representation of knowledge, intergroup bias, and explicit/implicit attitude change, we further derive predictions for intergroup attitudes. We suggest that intergroup attitudes alter depending on the relative associative strength between the social groups and the self, which in turn is determined by the (in)compatibility between social groups. This model unifies existing models on the integration of social identities into the self-concept by suggesting that basic cognitive mechanisms play an important role in facilitating or hindering identity integration and thus contribute to reducing or increasing intergroup bias.