Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy

Purpose

PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase-9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo.

Experimental Design

We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitonealy administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated.

Results

We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT-C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed.

Conclusion

Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression.     

Cessation of Mass Drug Administration for Lymphatic Filariasis in Zanzibar in 2006: Was Transmission Interrupted?

BackgroundLymphatic filariasis (LF) is targeted for elimination through annual mass drug administration (MDA) for 4–6 years. In 2006, Zanzibar stopped MDA against LF after five rounds of MDA revealed no microfilaraemic individuals during surveys at selected sentinel sites. We asked the question if LF transmission was truly interrupted in 2006 when MDA was stopped.ConclusionsOur findings indicated ongoing transmission of LF on Pemba in 2012. Moreover, we presented evidence from previous studies that LF transmission was also active on Unguja shortly after stopping MDA in 2006. Based on these observations the government of Zanzibar decided to resume MDA against LF on both islands in 2013.     

Childbirth Moderates the Genetic and Environmental Influences on BMI in Adult Twins

We report a study of the moderating role that the number of childbirths has on the genetic and environmental influences on BMI variation. We used a classical twin design with a sample of 704 adult female twins (334 monozygotic and 370 dizygotic). A gene–environment interaction (G × E) model was applied to estimate the moderating effects of childbearing. Results show that age and number of children exert a significant positive main effect on BMI. Furthermore, we found significant moderating effects of childbearing, with a larger number of children associated with an increased sensitivity to environmental factors.     

The role of a spiny plant refuge in structuring grazed shortgrass steppe plant communities

This study evaluates the hypothesis that biological grazing refuges have an important role in plant-grazer interactions of grasslands with a long history of grazing. We assessed the hypothesis that clumps of the spiny cactus Opuntia polyacantha provide biological refuges from cattle grazing, affecting cover and seedhead production of associated vascular plants in the shortgrass steppe of the North America. The study was based on sampling inside and outside Opuntia clumps in eight long-term moderately grazed pastures established 60 yr ago and their respective ungrazed controls. Opuntia clumps provided a refuge for seedhead production of the dominant grass ( Bouteloua gracilis ) and for cover and seedhead production of many plant groups. Clumps were also a refuge for species sensitive to grazing (species that decrease with grazing) and barrel-cacti, but not for species preferred by cattle (species with greater proportion in the diet than in the field), exotics or weeds. Our results suggest that these effects were mainly through changes in the microenvironmental conditions resulting from protection effects, even though all potential microenvironmental effects could not be measured. Cacti promoted some negative effects on other plant groups, probably due to the space occupied by cladodes inside cactus clumps. The refuge effects observed at the group level did not translate into strong community level effects. Species diversity ( H' ) was greater in cactus clumps due to lower dominance rather than greater richness. The presence of Opuntia clumps increased landscape-scale diversity. This ecological role of Opuntia clumps as refuge from cattle grazing should be taken into consideration in management practices aimed at cactus eradication in order to increase forage availability for livestock. We discuss the potential role of plant community productivity and grazing history with regard to the importance of natural refuges in structuring grassland communities.     

Restoration and management for cliff‐nesting birds in Mediterranean mining sites: the Sand Martin case study

Habitat enhancement for birds is frequently implemented during mine site restoration. Cliff‐nesting birds often colonize anthropogenic environments such as mining areas (aggregate sites and quarries for aggregate and cement production). Mining activity can compromise breeding success, causing cliff‐nesting birds to depend on the management and restoration of mining areas. The objective of our study is to assess the importance of mine site habitats for Sand Martin conservation and reconcile mining activity with breeding success in Mediterranean environments. We studied Sand Martin breeding habitat preferences in mining areas at three spatial scales. At the mining site scale, we compared 10 mining sites with Sand Martin burrows with 19 mining sites without burrows. At the colony scale (vertical structures with colonies), we evaluated the relationships between the number of breeding pairs, number of burrows, and colony characteristics within 30 distinct Sand Martin colonies. At the burrow scale, we compared the characteristics of the available vertical structure with the areas used by Sand Martins. At the mining site scale, Sand Martins preferred more surface of water bodies, shorter distances to flowing water, older sites, and mining sites which produce aggregates instead of cement. At the colony scale, Sand Martins preferred southwest orientations and stockpiles to vertical extraction faces. At the burrow scale, birds preferred the most vertical areas of the face. Our results support the need for effective habitat restoration and improved management for more effective Sand Martin conservation within mining areas. Simple interventions can enhance habitat quality and conservation of cliff‐nesting birds.     

Wine yeast fermentation vigor may be improved by elimination of recessive growth-retarding alleles.

The presence of recessive growth-retarding alleles can reduce the fitness of industrial wine yeasts. In nature, these alleles are supposed to be eliminated through "genome renewal". We emulated this process in the laboratory to increase the fermentation vigor of wine yeasts. The procedure is simply to sporulate the yeast strains and select new homozygous single-spore descendants. Most of the yeasts achieve a faster onset of fermentation when recessive deleterious genes are eliminated. The increase of the degree of homozygosity has no relation, either direct or inverse, with the fermentation vigor of the yeasts or with the quality of the resulting wine. However, in some strains in which recessive growth-retarding alleles have been eliminated, the fermentation vigor and the quality of the wine were found to be improved simultaneously.     

Asterless is a centriolar protein required for centrosome function and embryo development in Drosophila

BACKGROUND: Centrosomes, the major organizers of the microtubule network in most animal cells, are composed of centrioles embedded in a web of pericentriolar material (PCM). Recruitment and stabilization of PCM on the centrosome is a centriole-dependent function. Compared to the considerable number of PCM proteins known, the molecular characterization of centrioles is still very limited. Only a few centriolar proteins have been identified so far in Drosophila, most related to centriole duplication. RESULTS: We have cloned asterless (asl) and found that it encodes a 120 kD highly coiled-coil protein that is a constitutive pancentriolar and basal body component. Loss of asl function impedes the stabilization/maintenance of PCM at the centrosome. In embryos deficient for Asl, development is arrested right after fertilization. Asl shares significant homology with Cep 152, a protein described as a component of the human centrosome for which no functional data is yet available. CONCLUSIONS: The cloning of asl offers new insight into the molecular composition of Drosophila centrioles and a possible model for the role of its human homolog. In addition, the phenotype of asl-deficient flies reveals that a functional centrosome is required for Drosophila embryo development.     

Transposable elements: not as quiet as a mouse

In this issue of Genome Biology, Nellåker et al. show massive purging of deleterious transposable element variants, through negative selection, in 18 mouse strains.