Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-γ is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-γ selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-γ is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-β/γ selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma

Enhancing the effectiveness of interdisciplinary mental health treatment teams

Mental health administrators often lack guidelines for promoting and evaluating the effectiveness of interdisciplinary clinical treatment teams. This article describes the use of a model of group effectiveness that elucidates several aspects of team effectiveness. Also discussed are how administrators can support such teams by reviewing their initial set-up, how the organization influences the team's productivity and longevity, and how team members can better understand one another's personal and professional frames of reference to improve mutual collaboration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44090/1/10488_2005_Article_BF02106536.pd

Spike Patterning by Ca2-Dependent Regulation of a Muscarinic Cation Current in Entorhinal Cortex Layer II Neurons

In entorhinal cortex layer-II neurons, muscarinic receptor stimulation promotes depolarization via activation of a non-specific cation current (INCM). Under muscarinic influence, these neurons also develop changes in excitability that result in activity-dependent induction of delayed firing and bursting activity. In order to identify the membrane processes underlying these phenomena, we examined whether INCM may undergo activity-dependent regulation. Our voltage-clamp experiments revealed that appropriate depolarizing protocols increased the basal level of inward current activated during muscarinic stimulation, and suggested that this effect was due to INCM up-regulation. In the presence of low buffering for intracellular Ca2+, this up-regulation was transient and its decay could be followed by a phase of INCM down-regulation. Both up- and down-regulation were elicited by depolarizing stimuli able to activate voltage-gated Ca2+ channels (VGCC); both were sensitive to increasing concentrations of intracellular Ca2+-chelating agents, with down-regulation being abolished at lower Ca2+-buffering capacities; both were reduced or suppressed by VGCC block or in the absence of extracellular Ca2+. These data indicate that relatively small increases in [Ca2+]i driven by firing activity can induce up-regulation of a basal muscarinic depolarizing-current level, whereas more pronounced [Ca2+]i elevations can result in INCM down-regulation. We propose that the interaction of activity-dependent positive and negative feedback mechanisms on INCM allows entorhinal cortex layer-II neurons to exhibit emergent properties, such as delayed firing and enhanced or suppressed responses to repeated stimuli, that may be of importance in the memory functions of the temporal lobe and in the pathophysiology of epilepsy