Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G2/M arrest. G2/M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bcl-xL and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G2/M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-xL. Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer.

The United Kingdom, the United Nations Human Rights Council and the first cycle of the Universal Periodic Review

The introduction of the Universal Periodic Review (UPR) mechanism as an innovative component of the new Human Rights Council in 2006 has suffered little academic scrutiny. This is partly because it holds as its objective an improvement in human rights situations on the ground, a goal that is difficult to test amongst so many possible causal factors attributable to law reform and policy change, and partly due to the fact that the mechanism has only completed one full cycle of review. This article seeks to remedy this absence of analysis by examining the experience of the United Kingdom during its first review. In doing so, the article first considers the conception of the UPR, before progressing to examine the procedure and recommendations made to the UK by its peers. Finally, the article considers the five year review of the UPR which occurred as a subset of the Human Rights Council Review in 2011 and the resulting changes to the process modalities.

Techno-Economic and Life Cycle Assessment on Lignocellulosic Biomass Thermochemical Conversion Technologies: A Review

Bioenergy derived from biomass provides a promising energy alternative and can reduce the greenhouse gas (GHG) emissions generated from fossil fuels. Biomass-based thermochemical conversion technologies have been acknowledged as apt options to convert bioresources into bioenergy; this bioenergy includes electricity, heat, and fuels/chemicals in solid, liquid, and gaseous phases. In this review, the techno-economic and life cycle assessment of these technologies (combustion, gasification, pyrolysis, liquefaction, carbonization, and co-firing) are summarized. Specific indicators (production costs in a techno-economic analysis, functional units and environmental impacts in a life cycle analysis) for different technologies were compared. Finally, gaps in research and future trends in biomass thermochemical conversion were identified. This review could be used to guide future research related to economic and environmental benefits of bioenergy.

HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

The synapsin cycle:a view from the synaptic endocytic zone

Although the synapsin phosphoproteins were discovered more than 30 years ago and are known to play important roles in neurotransmitter release and synaptogenesis, a complete picture of their functions within the nerve terminal is lacking. It has been shown that these proteins play an important role in the clustering of synaptic vesicles (SVs) at active zones and function as modulators of synaptic strength by acting at both pre- and postdocking levels. Recent studies have demonstrated that synapsins migrate to the endocytic zone of central synapses during neurotransmitter release, which suggests that there are additional functions for these proteins in SV recycling.

A magnetic cycle of τ Bootis? The coronal and chromospheric view

τ Bootis is a late F-type main sequence star orbited by a Hot Jupiter. During the last years spectropolarimetric observations led to the hypothesis that this star may host a global magnetic field that switches its polarity once per year, indicating a very short activity cycle of only one year duration. In our ongoing observational campaign, we have collected several X-ray observations with XMM-Newton and optical spectra with TRES/FLWO in Arizona to characterize τ Boo's corona and chromosphere over the course of the supposed one-year cycle. Contrary to the spectropolarimetric reconstructions, our observations do not show indications for a short activity cycle.