Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease

In the last decade, treatment for castration-resistant prostate cancer has changed markedly, impacting symptom control and longevity for patients. However, a large proportion of cases progress despite androgen deprivation therapy and chemotherapy, while still being fit enough for several more lines of treatment. Overstimulation of the androgen receptor (AR) activity is the main driver of this cancer. Targeting biological functions of the AR or its co-regulators has proven very effective in this disease and led to the development of several highly effective drugs targeting the AR signalling axis. Drugs such as enzalutamide demonstrated that the improvement in anti-tumour efficacy is closely correlated with an affinity for the AR and its activity and have established the paradigm that AR remains activity in aggressive disease. However, as importantly, key insights into mechanisms of resistance are guiding the development of the next generation of AR-targeted drugs. This review outlines the historical development of these highly specific agents, their mechanism of action in the context of defective AR activity, and explores the potential for the upcoming next-generation AR inhibitors (ARI) for prostate cancer by targeting the alternative domains of AR, rather than by the conventional ligand-binding domain approach. There is huge potential in these approaches to develop new drugs with high clinical activity and further improve the outlook for patients.     

Migration and Dependency: Mexican Countryside Proletarianization and the Seasonal Agricultural Worker Program

Dialectical Anthropology - This article addresses the Seasonal Agricultural Worker Program (SAWP) between Mexico and Canada by examining the forms of disposability and job insecurity of Mexicans...     

Synthesis of tastes other than the 'primaries': implications for neural coding theories and the concept of 'suppression'

It has been demonstrated that mixtures of ‘primary’tastes may be perceived as singular rather than as multiple(Erickson and Covey, 1980). This finding may be accounted forin two different and testable ways. First, suppression: oneof the tastes in the mixture may be suppressed by the other(i.e., in a mixture of A and B, A suppresses the taste of B);the prediction which follows from this hypothesis is that asolution of A (the suppressing component) should be indistinguishablefrom the AB mixture. Secondly, synthesis: the singularity ofthe mixture may arise from the formation of a new taste, andin this case both components should be distinguishable fromtheir mixture. The present data indicate that the latter istrue in some cases. Since the taste of these mixtures must beother than the primary tastes used to form them, these findingsquestion the presumption that only four ‘primaries’are adequate to describe the range of tastes.