Conditional mouse models demonstrate oncogene-dependent differences in tumor maintenance and recurrence

Diversity in the pathophysiology of breast cancer frustrates therapeutic progress. We need to understand how mechanisms activated by specific combinations of oncogenes, tumor suppressors, and hormonal signaling pathways govern response to therapy and prognosis. A recent series of investigations conducted by Chodosh and colleagues offers new insights into the similarities and differences between specific oncogenic pathways. Expression of three oncogenes relevant to pathways activated in human breast cancers (c-myc, activated neu and Wnt1) were targeted to murine mammary epithelial cells using the same transgenic tetracycline-responsive conditional gene expression system. While the individual transgenic lines demonstrate similarly high rates of tumor penetrance, rates of oncogene-independent tumor maintenance and recurrence following initial regression are significantly different, and are modifiable by mutations in specific cooperating oncogenes or loss of tumor suppressor gene expression. The experiments make three notable contributions. First, they illustrate that rates of tumor regression and recurrence following initial regression are dependent upon the pathways activated by the initiating oncogene. The experiments also demonstrate that altered expression or mutation of specific cooperating oncogenes or tumor suppressor genes results in different rates of tumor regression and recurrence. Finally, they exemplify the power of conditional mouse models for elucidating how specific molecular mechanisms give rise to the complexity of human cancer

A comparison of baseline methodologies for 'Reducing Emissions from Deforestation and Degradation'

<p>Abstract</p> <p>Background</p> <p>A mechanism for emission reductions from deforestation and degradation (REDD) is very likely to be included in a future climate agreement. The choice of REDD baseline methodologies will crucially influence the environmental and economic effectiveness of the climate regime. We compare three different historical baseline methods and one innovative dynamic model baseline approach to appraise their applicability under a future REDD policy framework using a weighted multi-criteria analysis.</p> <p>Results</p> <p>The results show that each baseline method has its specific strengths and weaknesses. Although the dynamic model allows for the best environmental and for comparatively good economic performance, its high demand for data and technical capacity limit the current applicability in many developing countries.</p> <p>Conclusion</p> <p>The adoption of a multi-tier approach will allow countries to select the baseline method best suiting their specific capabilities and data availability while simultaneously ensuring scientific transparency, environmental effectiveness and broad political support.</p

Formation and inactivation of endogenous cannabinoid anandamide in central neurons

Anandamide (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phosphodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger