Enhancement of Tumor Cell Death by Combining gef Gene Mediated Therapy and New 1,4-Benzoxazepin-2,6-Dichloropurine Derivatives in Breast Cancer Cells

New treatment modalities are urgently needed to better manage advanced breast cancer. Combination therapies are usually more effective than monotherapy. In this context, the use of cyclic and acyclic O, N-acetals derivative compounds in combination with the suicide gef gene shown a potent anti-tumor activity and represent a new generation of anticancer agents. Here, we evaluate the use of the gef gene to promote and increase the anti-tumor effect of cyclic and acyclic O, N-acetals purine derivatives and elucidate their mechanisms of action. Among all compounds tested, those with a nitro group and a cyclic pattern structures (FC-30b2, FC-29c, and bozepinib) are the most benefited from the gef gene effect. These compounds, in combination with gef gene, were able to abolish tumor cell proliferation with a minimal dose leading to more effective and less toxic chemotherapy. The effect of this combined therapy is triggered by apoptosis induction which can be found deregulated in the later stage of breast cancer. Moreover, the combined therapy leads to an increase of cell post-apoptotic secondary necrosis that is able to promote the immunogenicity of cancer cells leading to a successful treatment. This data suggests that this novel combination therapy represents a promising candidate for breast cancer treatment.European Commission (AC-G Marie Curie Programme MERG-CT-2005-030616)Fundación Mutua Madrileña by the proyect FMM-AP16683-2017Consejería de Salud Junta de Andalucía (PI-0089-2017)Chair “Doctors Galera-Requena in cancer stem cell research

Contrasting effects of defaunation on aboveground carbon storage across the global tropics

Defaunation is causing declines of large-seeded animal-dispersed trees in tropical forests worldwide, but whether and how these declines will affect carbon storage across this biome is unclear. Here we show, using a pan-tropical dataset, that simulated declines of large-seeded animal-dispersed trees have contrasting effects on aboveground carbon stocks across Earth’s tropical forests. In our simulations, African, Neotropical and South Asian forests which have high proportions of animal-dispersed species consistently show carbon losses (2-12%), but Southeast Asian and Australian forests where there are more abiotically-dispersed species show little to no carbon losses or marginal gains (±1%). These patterns result primarily from changes in wood volume, and are underlain by consistent relationships in our empirical data (~2100 species), wherein, large-seeded animal-dispersed species are larger as adults than small-seeded animal-dispersed species, but are smaller than abiotically-dispersed species. Thus, floristic differences and distinct dispersal mode-seed size-adult size combinations can drive contrasting regional responses to defaunation

Quantifying the impacts of defaunation on natural forest regeneration in a global meta-analysis

Intact forests provide diverse and irreplaceable ecosystem services that are critical to human well-being, such as carbon storage to mitigate climate change. However, the ecosystem functions that underpin these services are highly dependent on the woody vegetation-animal interactions occurring within forests. While vertebrate defaunation is of growing policy concern, the effects of vertebrate loss on natural forest regeneration have yet to be quantified globally. Here we conduct a meta-analysis to assess the direction and magnitude of defaunation impacts on forests. We demonstrate that real-world defaunation caused by hunting and habitat fragmentation leads to reduced forest regeneration, although manipulation experiments provide contrasting findings. The extirpation of primates and birds cause the greatest declines in forest regeneration, emphasising their key role in maintaining carbon stores, and the need for national and international climate change and conservation strategies to protect forests from defaunation fronts as well as deforestation fronts

Dispersal vacuum in the seedling recruitment of a primate-dispersed Amazonian tree

Unregulated hunting of large-bodied frugivores is ubiquitous in tropical forests. Due to their low fecundity and complex social organization, large primates are often the first tropical forest vertebrates to be extirpated by hunting. Large primates are important seed dispersers and the only dispersal vectors of many large-seeded plants, leading to concerns that primate-dispersed trees will succumb to large-scale recruitment failure wherever they co-occur with overhunting. We used a field experiment in a remote, nonhunted region of the western Brazilian Amazon to test how the seedling recruitment success of a primate-dispersed Sapotaceae tree (Manilkara bidentata) is affected by distance from parent trees, protection from vertebrate seed predators, and gastro-intestinal seed cleaning associated with passage through frugivorous vertebrates. Only seed cleaning significantly increased the rate of seedling recruitment. Janzen-Connell effects have been widely purported as the central mechanism for recruitment failure, but our results suggest that for many tropical forest plant species Janzen-Connell effects are a second-order effect that acts once seeds have been successfully cleaned of fruit pulp by gut treatment. As an illustration of the relative importance of the sheer quantity of seeds ingested by woolly monkeys (Lagothrix cana), we further estimate the density and dispersal services provided by a complete primate assemblage to show that L. cana cleans and disperses nearly one million seeds per km2 per 24-day Manilkara fruiting season, amounting to over 71% of the seed dispersal services provided by the entire primate assemblage. The disperser vacuum in the absence of L. cana greatly reduces the quantity of cleaned seeds deposited on the forest floor. For similar fleshy-fruited species where gut passage greatly increases survival, a simple lack of redundancy in seed consumption may be the primary driver of recruitment failure resulting from large-primate extirpation due to overhunting, with Janzen-Connell effects secondarily influencing recruitment success as a function of either dispersal distance or seed density