Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor.

Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Estimating Size and Trend of the North Interlake Woodland Caribou Population Using Fecal-DNA and Capture-Recapture Models.

A critical step in recovery efforts for endangered and threatened species is the monitoring of population demographic parameters. As part of these efforts, we evaluated the use of fecal-DNA based capture-recapture methods to estimate population sizes and population rate of change for the North Interlake woodland caribou herd (Rangifer tarandus caribou), Manitoba, Canada. This herd is part of the boreal population of woodland caribou, listed as threatened under the federal Species at Risk Act (2003) and the provincial Manitoba Endangered Species Act (2006). Between 2004 and 2009 (9 surveys), we collected 1,080 fecal samples and identified 180 unique genotypes (102 females and 78 males). We used a robust design survey plan with 2 surveys in most years and analysed the data with Program MARK to estimate encounter rates (p), apparent survival rates (ϕ), rates of population change (λ), and population sizes (N). We estimated these demographic parameters for males and females and for 2 genetic clusters within the North Interlake. The population size estimates were larger for the Lower than the Upper North Interlake area and the proportion of males was lower in the Lower (33%) than the Upper North Interlake (49%). Population rate of change for the entire North Interlake area (2005-2009) using the robust design Pradel model was significantly <1.0 (λ = 0.90, 95% CI: 0.82-0.99) and varied between sex and area with the highest being for males in Lower North Interlake (λ = 0.98, 95% CI: 0.83-1.13) and the lowest being for females in Upper North Interlake (λ = 0.83, 95% CI: 0.69-0.97). The additivity of λ between sex and area is supported on the log scale and translates into males having a λ that is 0.09 greater than females and independent of sex, Lower North Interlake having a λ that is 0.06 greater than Upper North Interlake. Population estimates paralleled these declining trends, which correspond to trends observed in other fragmented populations of woodland caribou along the southern part of their range. The results of this study clearly demonstrate the applicability and success of non-invasive genetic sampling in monitoring populations of woodland caribou. © 2012 The Wildlife Society.