Anti-epidermal growth factor receptor (EGFR) therapy modelled in the mouse

Despite advances in response prediction to epidermal growth factor receptor (EGFR) targeted therapy in colorectal cancer there remain unknown factors determining the clinical outcome in patients with K-RAS wild type tumours in the absence of mutations activating B-RAF or PIK3CA/PTEN signalling. In addition, therapeutic agents for K-RAS mutant colorectal cancer and advances in the treatment of K-RAS wild type tumours are needed. Here the Apcmm/+ mouse has been used to define mRNA transcripts altered in response to Egfr receptor inhibition based upon the hypothesis that early gene expression changes will predict response to EGFR targeted therapy in K-RAS wild type colon cancer and thus identify novel biomarkers of response. In addition, the Apcmm/+ mouse and a model including endogenous K-ras activated colon tumourigenesis have been used to examine the consequences of dual Egfr/lgflr signalling inhibition, short term interruption of the Ras/Raf/Mek/Erk pathway with Mek inhibition and Egfr signalling inhibition combined with the induction of apoptosis. Gene expression microarray analysis and qRT-PCR validated 3 genes (IKBKG, CXCL9 and CCNE2) which, upon probing of transcript datasets from patients with K-RAS wild type colorectal cancer, identified their discriminatory value in terms of clinical responses to cetuximab monotherapy. Apcmm/+ intestinal adenomas acutely exposed to a small molecular inhibitor of Egfr (gefitinib) showed concurrent suppression of downstream signalling and induction of Igf signalling. To test the hypothesis that blockade of Egfr signalling was tempered by compensatory activation of the Igf pathway, the effect of chronic suppression of Igflr using AZD12253801, a small molecular tyrosine kinase inhibitor of IGF1R, was examined alone and in combination with gefitinib. Compared to either drug alone, combined dosing with gefitinib and AZ12253801 suppressed small intestinal tumourigenesis more effectively, but this failed to translate into a survival advantage possibly due to an increased incidence of intra-abdominal abscess formation. Nonetheless, this data provides preliminary evidence in support of combinatorial therapy. Examination of Mek inhibition using AZD6244 revealed induction of immediate cell death and perturbation of the cell cycle in intestinal tumours. These changes were not limited to K-ras mutant tumours suggesting a potential application to K-ras wild type intestinal cancer. Finally the addition of a BH3 mimetic, ABT737, to gefitinib induced a 3-fold increase in cell death indicating that short term pathway inhibition combined with induction of apoptosis is a rational treatment strategy for malignancy, and should also be extended in future experiments with Mek inhibition. This work has demonstrated the value of these mouse models in relation to target validation, biomarker prediction, resistance mechanisms and therapeutic utility

The nature and role of trap states in a dendrimer-based organic field-effect transistor explosive sensor

We report the fabrication and charge transport characterization of carbazole dendrimer-based organic field-effect transistors (OFETs) for the sensing of explosive vapors. After exposure to para-nitrotoluene (pNT) vapor, the OFET channel carrier mobility decreases due to trapping induced by the absorbed pNT. The influence of trap states on transport in devices before and after exposure to pNT vapor has been determined using temperature-dependent measurements of the field-effect mobility. These data clearly show that the absorption of pNT vapor into the dendrimer active layer results in the formation of additional trap states. Such states inhibit charge transport by decreasing the density of conducting states. (C) 2013 AIP Publishing LLC

Characterization and Quantification of Isoprene-Derived Epoxydiols in Ambient Aerosol in the Southeastern United States

Isoprene-derived epoxydiols (IEPOX) are identified in ambient aerosol samples for the first time, together with other previously identified isoprene tracers (i.e., 2-methyltetrols, 2-methylglyceric acid, C5-alkenetriols, and organosulfate derivatives of 2-methyltetrols). Fine ambient aerosol collected in downtown Atlanta, GA and rural Yorkville, GA during the 2008 August Mini-Intensive Gas and Aerosol Study (AMIGAS) was analyzed using both gas chromatography/quadrupole mass spectrometry (GC/MS) and gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) with prior trimethylsilylation. Mass concentrations of IEPOX ranged from ~1 to 24 ng m^(−3) in the aerosol collected from the two sites. Detection of particle-phase IEPOX in the AMIGAS samples supports recent laboratory results that gas-phase IEPOX produced from the photooxidation of isoprene under low-NO_x conditions is a key precursor of ambient isoprene secondary organic aerosol (SOA) formation. On average, the sum of the mass concentrations of IEPOX and the measured isoprene SOA tracers accounted for about 3% of the organic carbon, demonstrating the significance of isoprene oxidation to the formation of ambient aerosol in this region

The effect of sodium species on methanol synthesis and water-gas shift Cu/ZnO catalysts: utilising high purity zincian georgeite

The effect of sodium species on the physical and catalytic properties of Cu/ZnO catalysts derived from zincian georgeite has been investigated. Catalysts prepared with <100 ppm to 2.1 wt% Na+, using a supercritical CO2 antisolvent technique, were characterised and tested for the low temperature water–gas shift reaction and also CO2 hydrogenation to methanol. It was found that zincian georgeite catalyst precursor stability was dependent on the Na+ concentration, with the 2.1 wt% Na+-containing sample uncontrollably ageing to malachite and sodium zinc carbonate. Samples with lower Na+ contents (<100–2500 ppm) remained as the amorphous zincian georgeite phase, which on calcination and reduction resulted in similar CuO/Cu particle sizes and Cu surface areas. The aged 2.1 wt% Na+ containing sample, after calcination and reduction, was found to comprise of larger CuO crystallites and a lower Cu surface area. However, calcination of the high Na+ sample immediately after precipitation (before ageing) resulted in a comparable CuO/Cu particle size to the lower (<100–2500 ppm) Na+ containing samples, but with a lower Cu surface area, which indicates that Na+ species block Cu sites. Activity of the catalysts for the water–gas shift reaction and methanol yields in the methanol synthesis reaction correlated with Na+ content, suggesting that Na+ directly poisons the catalyst. In situ XRD analysis showed that the ZnO crystallite size and consequently Cu crystallite size increased dramatically in the presence of water in a syn-gas reaction mixture, showing that stabilisation of nanocrystalline ZnO is required. Sodium species have a moderate effect on ZnO and Cu crystallite growth rate, with lower Na+ content resulting in slightly reduced rates of growth under reaction conditions

Quark Mass Textures Within a Finite Non-Abelian Dicyclic Group

Using as a flavor symmetry a finite nonabelian dicyclic $Q_{2N}$ group, we show how to derive quark mass matrices with two arrangements of symmetric texture zeros which are phenomenologically viable. Three other such acceptable textures in the recent literature are unattainable in this approach and hence disfavored. We assume massive vector-like fermions and Higgs singlets transforming as judiciously-chosen $Q_{2N}$ doublets and use the tree-level mass generation mechanism of Froggatt and Nielsen.Comment: 11 pages latex including two figures. published version. New title. Slight modificatio

Dicyclic Horizontal Symmetry and Supersymmetric Grand Unification

It is shown how to use as horizontal symmetry the dicyclic group $Q_6 \subset SU(2)$ in a supersymmetric unification $SU(5)\otimes SU(5)\otimes SU(2)$ where one $SU(5)$ acts on the first and second families, in a horizontal doublet, and the other acts on the third. This can lead to acceptable quark masses and mixings, with an economic choice of matter supermultiplets, and charged lepton masses can be accommodated.Comment: 10 pages, LaTe

Differentiating between V‐ and G‐series nerve agent and simulant vapours using fluorescent film responses

In-field rapid and reliable identification of nerve agents is critical for the protection of Defence and National Security personnel as well as communities. Fluorescence-based detectors can be portable and provide rapid detection of chemical threats. However, most current approaches cannot differentiate between dilute vapors of nerve agent classes and are susceptible to false positives due to the presence of common acids. Here a fluorescence-based method is shown for rapid differentiation between the V-series and phosphonofluoridate G-series nerve agents and avoids false positives due to common acids. Differentiation is achieved through harnessing two different mechanisms. Detection of the V-series is achieved using photoinduced hole transfer whereby the fluorescence of the sensing material is quenched in the presence of the V-series agent. The G-series is detected using a turn-on mechanism in which a silylated excited state intramolecular proton transfer sensing molecule is selectively deprotected by hydrogen fluoride, which is typically found as a contaminant and/or breakdown product in G-series agents such as sarin. The strategy provided discrimination between classes, as the sensor for the G-series agent class is insensitive to the V-series agent, and vice versa, and neither responded to common acids

Origin and Biology of Simian Immunodeficiency Virus in Wild-Living Western Gorillas

Western lowland gorillas (Gorilla gorilla gorilla) are infected with a simian immunodeficiency virus (SIVgor) that is closely related to chimpanzee and human immunodeficiency viruses (SIVcpz and HIV-1, respectively) in west central Africa. Although existing data suggest a chimpanzee origin for SIVgor, a paucity of available sequences has precluded definitive conclusions. Here, we report the molecular characterization of one partial (BQ664) and three full-length (CP684, CP2135, and CP2139) SIVgor genomes amplified from fecal RNAs of wild-living gorillas at two field sites in Cameroon. Phylogenetic analyses showed that all SIVgor strains clustered together, forming a monophyletic lineage throughout their genomes. Interestingly, the closest relatives of SIVgor were not SIVcpzPtt strains from west central African chimpanzees (Pan troglodytes troglodytes) but human viruses belonging to HIV-1 group O. In trees derived from most genomic regions, SIVgor and HIV-1 group O formed a sister clade to the SIVcpzPtt lineage. However, in a tree derived from 5' pol sequences (similar to 900 bp), SIVgor and HIV-1 group O fell within the SIVcpzPtt radiation. The latter was due to two SIVcpzPtt strains that contained mosaic pol sequences, pointing to the existence of a divergent SIVcpzPtt lineage that gave rise to SIVgor and HIV-1 group O. Gorillas appear to have acquired this lineage at least 100 to 200 years ago. To examine the biological properties of SIVgor, we synthesized a full-length provirus from fecal consensus sequences. Transfection of the resulting clone (CP2139.287) into 293T cells yielded infectious virus that replicated efficiently in both human and chimpanzee CD4(+) T cells and used CCR5 as the coreceptor for viral entry. Together, these results provide strong evidence that P. t. troglodytes apes were the source of SIVgor. These same apes may also have spawned the group O epidemic; however, the possibility that gorillas served as an intermediary host cannot be excluded

Oh, Jeremy Corbyn! Why did Labour Party membership soar after the 2015 general election?

This article investigates the remarkable surge in individual membership of the Labour Party after the general election of May 2015, particularly after Jeremy Corbyn was officially nominated as a candidate for the leadership in June of that year. Using both British Election Study and Party Members Project data, we explain the surge by focussing on the attitudinal, ideological and demographic characteristics of the members themselves. Findings suggest that, along with support for the leader and yearning for a new style of politics, feelings of relative deprivation played a significant part: many ‘left-behind’ voters (some well-educated, some less so) joined Labour for the first time when a candidate with a clearly radical profile appeared on the leadership ballot. Anti-capitalist and left-wing values mattered too, particularly for those former members who decided to return to the party