Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia

BACKGROUND: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings. METHODS: The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA. RESULTS: Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation. CONCLUSIONS: Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.1U01 CA168409 - NCI NIH HHS; P01 CA 87497 - NCI NIH HHS; P30 CA008748 - NCI NIH HHS; MOP-106530 - Canadian Institutes of Health Research; P01 CA013106 - NCI NIH HH

A Critical Assessment of Protection for Key Wildlife and Salmon Habitats under the Proposed British Columbia Central Coast Land and Resource Management Plan

The Central Coast Land and Resource Management Plan (CCLRMP) table recently declared a consensus1 on proposed protected areas for British Columbia’s Central Coast. This region is recognized for its globally rare and largely intact mainland and island ecosystems and land use decisions should reflect this importance. We evaluated the efficacy of this proposal using a spatial assessment of habitat. We focus on protected areas in the context of the overall CCLRMP. We examined the level of protection provided by the CCLRMP in three key coastal habitats: deer winter range, wolf reproductive habitat, and salmon reproductive and rearing habitat. Assessment of deer winter range was limited to Heiltsuk Territory, which comprises a large proportion of the CCLRMP region

Ecology of Conflict: Marine Food Supply Affects Human-Wildlife Interactions on Land

Human-wildlife conflicts impose considerable costs to people and wildlife worldwide. Most research focuses on proximate causes, offering limited generalizable understanding of ultimate drivers. We tested three competing hypotheses (problem individuals, regional population saturation, limited food supply) that relate to underlying processes of human-grizzly bear (Ursus arctos horribilis) conflict, using data from British Columbia, Canada, between 1960–2014. We found most support for the limited food supply hypothesis: in bear populations that feed on spawning salmon (Oncorhynchus spp.), the annual number of bears/km2killed due to conflicts with humans increased by an average of 20% (6–32% [95% CI]) for each 50% decrease in annual salmon biomass. Furthermore, we found that across all bear populations (with or without access to salmon), 81% of attacks on humans and 82% of conflict kills occurred after the approximate onset of hyperphagia (July 1st), a period of intense caloric demand. Contrary to practices by many management agencies, conflict frequency was not reduced by hunting or removal of problem individuals. Our finding that a marine resource affects terrestrial conflict suggests that evidence-based policy for reducing harm to wildlife and humans requires not only insight into ultimate drivers of conflict, but also management that spans ecosystem and jurisdictional boundaries

A preliminary study of university disclosures

Disclosures, such as financial statements and annual reports, provide relevant and reliable information for decision-making and general interest. This study evaluates the disclosures by universities to the public using analysis based on general accounting theory and index items from previous studies. The objective is to determine the accountability of the eight universities sampled to their stakeholders through these disclosures. The findings indicate a need for much improvement and further research on the use of information disclosures

Human Activity Mediates a Trophic Cascade Caused by Wolves

Experimental evidence of trophic cascades initiated by large vertebrate predators is rare in terrestrial ecosystems. A serendipitous natural experiment provided an opportunity to test the trophic cascade hypothesis for wolves (Canis lupus) in Banff National Park, Canada. The first wolf pack recolonized the Bow Valley of Banff National Park in 1986. High human activity partially excluded wolves from one area of the Bow Valley (low-wolf area), whereas wolves made full use of an adjacent area (high-wolf area). We investigated the effects of differential wolf predation between these two areas on elk (Cervus elaphus) population density, adult female survival, and calf recruitment; aspen (Populus tremuloides) recruitment and browse intensity; willow (Salix spp.) production, browsing intensity, and net growth; beaver (Castor canadensis) density; and riparian songbird diversity, evenness, and abundance. We compared effects of recolonizing wolves on these response variables using the log response ratio between the low-wolf and high-wolf treatments. Elk population density diverged over time in the two treatments, such that elk were an order of magnitude more numerous in the low-wolf area compared to the high-wolf area at the end of the study. Annual survival of adult female elk was 62% in the high-wolf area vs. 89% in the low-wolf area. Annual recruitment of calves was 15% in the high-wolf area vs. 27% without wolves. Wolf exclusion decreased aspen recruitment, willow production, and increased willow and aspen browsing intensity. Beaver lodge density was negatively correlated to elk density, and elk herbivory had an indirect negative effect on riparian songbird diversity and abundance. These alternating patterns across trophic levels support the wolf-caused trophic cascade hypothesis. Human activity strongly mediated these cascade effects, through a depressing effect on habitat use by wolves. Thus, conservation strategies based on the trophic importance of large carnivores have increased support in terrestrial ecosystems. Read More: http://www.esajournals.org/doi/full/10.1890/04-126

HOXA3 Modulates Injury-Induced Mobilization and Recruitment of Bone Marrow-Derived Cells

The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor κB pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds

Differences in Reversion of Resistance Mutations to Wild-Type under Structured Treatment Interruption and Related Increase in Replication Capacity

The CPCRA 064 study examined the effect of structured treatment interruption (STI) of up to 4 months followed by salvage treatment in patients failing therapy with multi-drug resistant HIV. We examined the relationship between the reversion rate of major reverse transcriptase (RT) resistance-associated mutations and change in viral replication capacity (RC). The dataset included 90 patients with RC and genotypic data from virus samples collected at 0 (baseline), 2 and 4 months of STI.Rapid shift towards wild-type RC was observed during the first 2 months of STI. Median RC increased from 47.5% at baseline to 86.0% at 2 months and to 97.5% at 4 months. Between baseline and 2 months of STI, T215F had the fastest rate of reversion (41%) and the reversion of E44D and T69D was associated with the largest changes in RC. Among the most prevalent RT mutations, M184V had the fastest rate of reversion from baseline to 2 months (40%), and its reversion was associated with the largest increase in RC. Most rates of reversion increased between 2 months and 4 months, but the change in RC was more limited as it was already close to 100%. The highest frequency of concurrent reversion was found for L100I and K103N. Mutagenesis tree models showed that M184V, when present, was overall the first mutation to revert among all the RT mutations reported in the study.Longitudinal analysis of combined phenotypic and genotypic data during STI showed a large amount of variability in prevalence and reversion rates to wild-type codons among the RT resistance-associated mutations. The rate of reversion of these mutations may depend on the extent of RC increase as well as the co-occurring reversion of other mutations belonging to the same mutational pathway

Salmon for Terrestrial Protected areas

Although managers safeguard protected areas for migratory species, little consideration has been given to how migratory species might benefit parks. Additionally, whereas land‐sea connections are considered in management of protected areas, most effort has focused on reducing negative “downstream” processes. Here, we offer a proposal to promote positive “upstream” processes by safeguarding the seasonal pulse of marine nutrients imported into freshwater and riparian ecosystems by spawning migrations of Pacific salmon. Currently, high rates of fishing limit this important contribution to species and processes that terrestrial parks were designed to protect. Accordingly, we propose limiting exploitation in areas and periods through which salmon runs bound for terrestrial protected areas can migrate. Best suited for less commercially valuable but relatively abundant and widespread pink and chum salmon (O. gorbuscha and keta), our proposal thus considers ecosystem and societal needs for salmon. We conclude by outlining strategies to overcome socio‐economic barriers to implementation

Confronting Uncertainty in Wildlife Management: Performance of Grizzly Bear Management

Scientific management of wildlife requires confronting the complexities of natural and social systems. Uncertainty poses a central problem. Whereas the importance of considering uncertainty has been widely discussed, studies of the effects of unaddressed uncertainty on real management systems have been rare. We examined the effects of outcome uncertainty and components of biological uncertainty on hunt management performance, illustrated with grizzly bears (Ursus arctos horribilis) in British Columbia, Canada. We found that both forms of uncertainty can have serious impacts on management performance. Outcome uncertainty alone – discrepancy between expected and realized mortality levels – led to excess mortality in 19% of cases (population-years) examined. Accounting for uncertainty around estimated biological parameters (i.e., biological uncertainty) revealed that excess mortality might have occurred in up to 70% of cases. We offer a general method for identifying targets for exploited species that incorporates uncertainty and maintains the probability of exceeding mortality limits below specified thresholds. Setting targets in our focal system using this method at thresholds of 25% and 5% probability of overmortality would require average target mortality reductions of 47% and 81%, respectively. Application of our transparent and generalizable framework to this or other systems could improve management performance in the presence of uncertainty. &nbsp