Expansion of the structure-activity relationship of branched chain fatty acids: effect of unsaturation and branching group size on anticancer activity.

Branched chain fatty acids (BCFAs) are a class of fatty acid with promising anticancer activity. The BCFA 13-methyltetradecanoic acid (13-MTD) inhibits tumour growth in vivo without toxicity but efficacy is limited by moderate potency, a property shared by all known BCFAs. The mechanism of action of BCFAs has not been fully elucidated, and in the absence of a clearly defined target optimisation of BCFA potency must rely on structure-activity relationships. Our current understanding of the structural features that promote BCFA anticancer activity is limited by the low structural diversity of reported BCFAs. The aim of this study was to examine the effects of two new structural modifications- unsaturation and branching group size- on BCFA activity. Thus, homologous series of saturated and cis-Δ9 unsaturated BCFAs were synthesised bearing methyl, ethyl, propyl and butyl branching groups, and were screened in vitro for activity against three human cancer cell lines. Potencies of the new BCFAs were compared to 13-MTD and an unbranched monounstaurated fatty acid (MUFA) bearing a cis-Δ9 double bond. The principal findings to emerge were that the anticancer activity of BCFAs was adversly affected by larger branching groups but significantly improved by incorporation of a cis-Δ9 double bond into the BCFA alkyl chain. This study provides new structure-activity relationship insights that may be used to develop BCFAs with improved potency and therapeutic potential

Proteins regulating the intercellular transfer and function of P-glycoprotein in multidrug-resistant cancer

© the authors; Chemotherapy is an essential part of anticancer treatment. However, the overexpression of P-glycoprotein (P-gp) and the subsequent emergence of multidrug resistance (MDR) hampers successful treatment clinically. P-gp is a multidrug efflux transporter that functions to protect cells from xenobiotics by exporting them out from the plasma membrane to the extracellular space. P-gp inhibitors have been developed in an attempt to overcome P-gp-mediated MDR; however, lack of specificity and dose limiting toxicity have limited their effectiveness clinically. Recent studies report on accessory proteins that either directly or indirectly regulate P-gp expression and function and which are necessary for the establishment of the functional phenotype in cancer cells. This review discusses the role of these proteins, some of which have been recently proposed to comprise an interactive complex, and discusses their contribution towards MDR. We also discuss the role of other pathways and proteins in regulating P-gp expression in cells. The potential for these proteins as novel therapeutic targets provides new opportunities to circumvent MDR clinically

Cell-derived microparticles: New targets in the therapeutic management of disease

Intercellular communication is essential to maintain vital physiological activities and to regulate the organism's phenotype. There are a number of ways in which cells communicate with one another. This can occur via autocrine signaling, endocrine signaling or by the transfer of molecular mediators across gap junctions. More recently communication via microvesicular shedding has gained important recognition as a significant pathway by which cells can coordinate the spread and dominance of selective traits within a population. Through this communication apparatus, cells can now acquire and secure a survival advantage, particularly in the context of malignant disease. This review aims to highlight some of the functions and implications of microparticles in physiology of various disease states, and present a novel therapeutic strategy through the regulation of microparticle production

Idempotent ideals and non-finitely generated projective modules over integral group rings of polycyclic-by-finite groups

We prove that every non-finitely generated projective module over the integral group ring of a polycyclic-by-finite group G is free if and only if G is polycyclic.Comment: 15 pages, to appear in J. Algebr

Prime ideals in nilpotent Iwasawa algebras

Let G be a nilpotent complete p-valued group of finite rank and let k be a field of characteristic p. We prove that every faithful prime ideal of the Iwasawa algebra kG is controlled by the centre of G, and use this to show that the prime spectrum of kG is a disjoint union of commutative strata. We also show that every prime ideal of kG is completely prime. The key ingredient in the proof is the construction of a non-commutative valuation on certain filtered simple Artinian rings

Iridium-Catalyzed Asymmetric Hydrogenation of Benzo[b]thiophene 1,1-Dioxides

An efficient iridium-catalyzed asymmetric hydrogenation of substituted benzothiophene 1,1-dioxides is described. The use of iridium complexes with chiral pyridyl phosphinite ligands provides access to highly enantiomerically enriched sulfones with substituents at the 2- and 3-position. Sulfones of this type are of interest as core structures of agrochemicals and pharmaceuticals. Moreover, they can be further reduced to chiral 2,3-dihydrobenzothiophenes

Finitely presented wreath products and double coset decompositions

We characterize which permutational wreath products W^(X)\rtimes G are finitely presented. This occurs if and only if G and W are finitely presented, G acts on X with finitely generated stabilizers, and with finitely many orbits on the cartesian square X^2. On the one hand, this extends a result of G. Baumslag about standard wreath products; on the other hand, this provides nontrivial examples of finitely presented groups. For instance, we obtain two quasi-isometric finitely presented groups, one of which is torsion-free and the other has an infinite torsion subgroup. Motivated by the characterization above, we discuss the following question: which finitely generated groups can have a finitely generated subgroup with finitely many double cosets? The discussion involves properties related to the structure of maximal subgroups, and to the profinite topology.Comment: 21 pages; no figure. To appear in Geom. Dedicat

High resolution global climate modelling; the UPSCALE project, a large simulation campaign

The UPSCALE (UK on PRACE: weather-resolving Simulations of Climate for globAL Environmental risk) project constructed and ran an ensemble of HadGEM3 (Hadley Centre Global Environment Model 3) atmosphere only global climate simulations over the period 1985–2011, at resolutions of N512 (25 km), N216 (60 km) and N96 (130 km) as used in current global weather forecasting, seasonal prediction and climate modelling respectively. Alongside these present climate simulations a parallel ensemble looking at extremes of future climate was run, using a timeslice methodology to consider conditions at the end of this century. These simulations were primarily performed using a 144 million core hour, single year grant of computing time from PRACE (the Partnership for Advanced Computing in Europe) in 2012, with additional resources supplied by the Natural Environment Research Council (NERC) and the Met Office. Almost 400 terabytes of simulation data were generated on the HERMIT supercomputer at the High Performance Computing Center Stuttgart (HLRS), and transferred to the JASMIN super-data cluster provided by the Science and Technology Facilities Council Centre for Data Archival (STFC CEDA) for analysis and storage. In this paper we describe the implementation of the project, present the technical challenges in terms of optimisation, data output, transfer and storage that such a project involves and include details of the model configuration and the composition of the UPSCALE data set. This data set is available for scientific analysis to allow assessment of the value of model resolution in both present and potential future climate conditions

Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter

A new mitochondrial uncoupler that forms membrane permeable dimers through interactions of remote acidic and anion receptor groups.</p