Brevican knockdown reduces late-stage glioma tumor aggressiveness

Growing evidence supports the important role of the tumor microenvironment (TME) in cancer biology. A defining aspect of the glioma TME is the unique composition and structure of its extracellular matrix (ECM), which enables tumor cells to overcome the inhibitory barriers of the adult central nervous system (CNS). In this way, the TME plays a role in glioma invasion and the cellular heterogeneity that distinguishes these tumors. Brain Enriched Hyaluronan Binding (BEHAB)/brevican (B/b), is a CNS-specific ECM constituent and is upregulated in the glioma TME. Previous studies have shown B/b exerts a pro-invasive function, suggesting it may represent a target to reduce glioma pathogenesis. Herein, we also provide evidence that B/b expression is enriched in the glioma initiating cell (GIC) niche. We demonstrate that B/b plays roles in the pathological progression, aggressiveness, and lethality of tumors derived from human GICs and traditional glioma cell lines. Interestingly, we found that B/b is not required to maintain the defining phenotypic properties of GICs and thereby acts primarily in late stages of glioma progression. This study suggests that the increased expression of B/b in the TME is a valuable therapeutic target for glioma.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

Translational Research in South Africa: Evaluating Implementation Quality Using a Factorial Design

Background  

HealthWise South Africa: Life Skills for Adolescents (HW) is an evidence-based substance use and sexual risk prevention program that emphasizes the positive use of leisure time. Since 2000, this program has evolved from pilot testing through an efficacy trial involving over 7,000 youth in the Cape Town area. Beginning in 2011, through 2015, we are undertaking a new study that expands HW to all schools in the Metro South Education District.