Impact of imagery-enhanced interpretation training on offline and online interpretations in worry.

Worry and rumination are forms of repetitive negative thinking (RNT) that are maintained by negative interpretations and a predominance of abstract, verbal thinking. Hence, facilitating more positive interpretations and imagery-based thinking in combination may reduce RNT. Study 1 administered interpretation training with and without enhanced imagery, and an active control condition (designed not to change interpretations), in individuals with high levels of RNT (worry and/or rumination). Combining interpretation training with sustained imagery resulted in the highest levels of positive interpretation bias using an offline test of interpretation bias (when individuals have time to reflect). Study 2 investigated whether imagery-enhanced interpretation training influences online interpretations when ambiguous information is first encountered, indexed by reaction times and amplitude of the N400 event-related potential, as well as enhances offline positive interpretations in high worriers. It also examined whether imagery-enhanced interpretation training reduces negative thought intrusions associated with worry. Both online (reaction time) and offline interpretations were more positive following imagery-enhanced interpretation training, and negative thoughts were reduced, compared to the active control. However, no differences emerged on neurophysiological markers during the online task. Hence, brief interpretation training encompassing sustained imagery modifies online and offline interpretations, but further training may be required to impact upon neurophysiological measures.

Intramuscular immunization with plasmid coexpressing tumour antigen and Flt-3L results in potent tumour regression.

Dendritic cells (DC) are professional antigen-presenting cells capable of initiating a potent primary immune response, making them an attractive target for cancer immunotherapy. Flt-3 ligand (Flt-3L) is a haematopoietic growth factor that efficiently induces DC expansion in vivo. To achieve a more efficient and effective method of priming tumour-specific, DC-mediated immune response, we generated a DNA vaccine comprising both human Flt-3L and the tumour antigen, MUC-1 (pNGVL-hFLex-MUC-1). We report that pNGVL-hFLex-MUC-1 is able to induce antigen-specific CTL immunity in vivo, resulting in a potent anti-tumour response, and that the Flt-3L component is essential to the efficacy of the DNA vaccine. Moreover, the route of immunization is critical in determining the type of immune response generated; intramuscular (i.m.) immunization with pNGVL-hFLex-MUC-1 conferred tumour protection in contrast to poor response with hydrodynamic-based intravenous delivery. Post-i.m. immunization, we observed a massive infiltration of mononuclear cells to the injection site, comprised predominantly of CD11c(+)/CD8alpha(-) DC. Therefore, we propose that Flt-3L acts as an adjuvant to recruit DC, thereby priming the anti-tumour response. However, systemic expansion of DC prior to immunization did not enhance the specific cellular response, suggesting that it is in situ recruitment or expansion of DC that is critical for pNGVL-hFLex-MUC-1 potency.

Elevated Bcl-2 is not a causal event in the positive selection of T cells.

T cell development is characterized by the induction of apoptosis in most immature thymocytes and the rescue from apoptosis of a small proportion of cells by the process of positive selection.Up-regulation of the anti-apoptotic molecule Bcl-2 is associated with thymocytes undergoing positive selection and a bcl-2 transgene promotes the generation of mature T cells. In contrast,mice transgenic for the pro-apoptotic molecule Bax show impaired T cell maturation. We have used fetal thymic organ culture to determine the action of Bcl-2 and Bax on positive selection of thymocytes. Our data show that Bcl-2 and Bax do not alter the number of thymocytes positively selected by a defined peptide ligand. This implies that Bcl-2 and Bax alter the production of mature T cells in vivo by influencing thymocyte viability rather than by direct action on positive selection. It also presents a solution to the 'chicken-and-egg' scenario relating to Bcl-2 up-regulation and positive selection. The data suggest that the up-regulation of Bcl-2 associated with T cell maturation is a consequence of positive selection rather than a cause of it.

Bad can act as a key regulator of T cell apoptosis and T cell development.

Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.