Platinum resistant cancer cells conserve sensitivity to BH3 domains and obatoclax induced mitochondrial apoptosis

Resistance to cisplatin chemotherapy remains a major hurdle preventing effective treatment of many solid cancers. BAX and BAK are pivotal regulators of the mitochondrial apoptosis pathway, however little is known regarding their regulation in cisplatin resistant cells. Cisplatin induces DNA damage in both sensitive and resistant cells, however the latter exhibits a failure to initiate N-terminal exposure of mitochondrial BAK or mitochondrial SMAC release. Both phenotypes are highly sensitive to mitochondrial permeabilisation induced by exogenous BH3 domain peptides derived from BID, BIM, NOXA (which targets MCL-1 and A1), and there is no significant change in their prosurvival BCL2 protein expression profiles. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 family proteins including MCL-1, decreases cell viability irrespective of platinum resistance status across a panel of cell lines selected for oxaliplatin resistance. In summary, selection for platinum resistance is associated with a block of mitochondrial death signalling upstream of BAX/BAK activation. Conservation of sensitivity to BH3 domain induced apoptosis can be exploited by agents such as obatoclax, which directly target the mitochondria and BCL-2 family.

Vaughan Williams and contemporary music: composers' forum

Like many long-lived composers, Vaughan Williams suffered a decline in his reputation immediately following his death, as the emergence in the 1960s of a younger generation of composers rendered much of his work outmoded in the eyes of many critics. In recent years, however, the reception of Vaughan Williams's music among composers has improved markedly, a combination of the ebbing of the tide of high modernism and greater pluralism in contemporary music, and a growing awareness that Vaughan Williams was perhaps more modernist (or at least progressive) than had previously been thought. In interviews with four leading British composers (two of whom were part of the 1960s generation mentioned above), I investigate the nature and extent of Vaughan Williams's legacy to his successors, both musical and social. What emerges is a near consensus on Vaughan Williams's greatest works, but a diversity of views on his compositional techniques and on his place among his European contemporaries.

Comparison of the binding specificity of two bacterial metalloproteases, LasB of Pseudomonas aeruginosa and ZapA of Proteus mirabilis, using N-alpha mercaptoamide template-based inhibitor analogues

The metalloproteases ZapA of Proteus mirabilis and LasB of Pseudomonas aeruginosa are known to be virulence factors their respective opportunistic bacterial pathogens, and are members of the structurally related serralysin and thermolysin families of bacterial metalloproteases respectively. Secreted at the site of infection, these proteases play a key role in the infection process, contributing to tissue destruction and processing of components of the host immune system. Inhibition of these virulence factors may therefore represent an antimicrobial strategy, attenuating the virulence of the infecting pathogen. Previously we have screened a library of N-alpha mercaptoamide dipeptide inhibitors against both ZapA and LasB, with the aim of mapping the S1' binding site of the enzymes, revealing both striking similarities and important differences in their binding preferences. Here we report the design, synthesis, and screening of several inhibitor analogues, based on two parent inhibitors from the original library. The results have allowed for further characterization of the ZapA and LasB active site binding pockets, and have highlighted the possibility for development of broad-spectrum bacterial protease inhibitors, effective against enzymes of the thermolysin and serralysin metalloprotease families.

Multicentre randomised control trial comparing real time teledermatology with conventional outpatient dermatological care:societal cost-benefit analysis

Comparison of real time teledermatology with outpatient dermatology in terms of clinical outcomes, cost-benefits, and patient reattendance.

British Constructions with Constitutions:The Formal and Informal Nature of 'Island' Relations on Montserrat and Gibraltar

This article explores social, economic and political relations on two British Dependent Territories (BDTs) -- Montserrat and Gibraltar. This article notes that though BDTs are British colonial constructions, created, sustained and modelled upon and by Britain, they differ from Britain in that they have political constitutions. They also exhibit an ambiguous dependence and independence upon and with Britain. This article goes on to look at social and economic relations on Montserrat and Gibraltar before comparing and contrasting the political climates on each BDT. Throughout this article, it is suggested that there is a dynamic tension between formal and informal aspects to managing life. Finally, this article concludes with a discussion about the suitability of the split between Executive and Legislative Councils in these two BDTs.