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"Marshall, F J"
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Proton Radiography of Inertial Fusion Implosions
A distinctive way of quantitatively imaging inertial fusion implosions has resulted in the characterization of two different types of electromagnetic configurations and in the measurement of the temporal evolution of capsule size and areal density. Radiography with a pulsed, monoenergetic, isotropic proton source reveals field structures through deflection of proton trajectories, and areal densities are quantified through the energy lost by protons while traversing the plasma. The two field structures consist of (i) many radial filaments with complex striations and bifurcations, permeating the entire field of view, of magnetic field magnitude 60 tesla and (ii) a coherent, centrally directed electric field of order 10⁹ volts per meter, seen in proximity to the capsule surface. Although the mechanism for generating these fields is unclear, their effect on implosion dynamics is potentially consequential.
Journal Article
Psoriasin (S100A7) associates with integrin β6 subunit and is required for αvβ6-dependent carcinoma cell invasion
Expression of the integrin αvβ6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvβ6 composed of wild-type αv and a mutant β6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvβ6-dependent adhesion or migration, are essential for αvβ6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the β6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant β6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous β6 and colocalised with αvβ6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvβ6-dependent adhesion or migration but abrogated αvβ6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the β6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of β6, bound directly to recombinant Psor and inhibited cellular Psor binding to β6; this blocked αvβ6-dependent, but not αvβ6-independent, invasion. These data identify a novel interaction between Psor and β6 and demonstrate that it is required for αvβ6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion.
Journal Article
Visualizing fast electron energy transport into laser-compressed high-density fast-ignition targets
Recent progress in kilojoule-scale high-intensity lasers has opened up new areas of research in radiography, laboratory astrophysics, high-energy-density physics, and fast-ignition (FI) laser fusion. FI requires efficient heating of pre-compressed high-density fuel by an intense relativistic electron beam produced from laser–matter interaction. Understanding the details of electron beam generation and transport is crucial for FI. Here we report on the first visualization of fast electron spatial energy deposition in a laser-compressed cone-in-shell FI target, facilitated by doping the shell with copper and imaging the K-shell radiation. Multi-scale simulations accompanying the experiments clearly show the location of fast electrons and reveal key parameters affecting energy coupling. The approach provides a more direct way to infer energy coupling and guide experimental designs that significantly improve the laser-to-core coupling to 7%. Our findings lay the groundwork for further improving efficiency, with 15% energy coupling predicted in FI experiments using an existing megajoule-scale laser driver.
Fast-ignition laser fusion involves directing an intense relativistic electron beam onto a fuel target. Experiments and simulations now enable a visualization of the location of fast electrons and the energy-coupling mechanisms at play.
Journal Article
A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo
αvβ6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvβ6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvβ6, and inhibits binding to all ligands including the latency-associated peptide of TGF-β. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin αvβ8, but not the integrins α5β1, αvβ3, αvβ5 and α4β1.
In vitro
264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and αvβ6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-β-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-β by NCI-H358 tumour cells in a tumour cell−fibroblast co-culture assay.
In vivo
264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of αvβ6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of αvβ6 integrin, with some activity against αvβ8 integrin, that reduces both tumour growth and metastasis.
Journal Article
Time-resolved compression of a capsule with a cone to high density for fast-ignition laser fusion
The advent of high-intensity lasers enables us to recreate and study the behaviour of matter under the extreme densities and pressures that exist in many astrophysical objects. It may also enable us to develop a power source based on laser-driven nuclear fusion. Achieving such conditions usually requires a target that is highly uniform and spherically symmetric. Here we show that it is possible to generate high densities in a so-called fast-ignition target that consists of a thin shell whose spherical symmetry is interrupted by the inclusion of a metal cone. Using picosecond-time-resolved X-ray radiography, we show that we can achieve areal densities in excess of 300 mg cm
−2
with a nanosecond-duration compression pulse—the highest areal density ever reported for a cone-in-shell target. Such densities are high enough to stop MeV electrons, which is necessary for igniting the fuel with a subsequent picosecond pulse focused into the resulting plasma.
One of the challenges in fast-ignition fusion is to laser-compress an asymmetric cone-in-shell target to a density at which it can be ignited by a second laser. Theobald
et al
. report the achievement of areal densities in excess of 300 mg cm
−2
, to a point at which ignition might soon be possible.
Journal Article
A human monoclonal antibody 264RAD targeting alpha v beta 6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo
alpha v beta 6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits alpha v beta 6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey alpha v beta 6, and inhibits binding to all ligands including the latency-associated peptide of TGF- beta . Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin alpha v beta 8, but not the integrins alpha 5 beta 1, alpha v beta 3, alpha v beta 5 and alpha 4 beta 1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and alpha v beta 6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF- beta -mediated activation of dermal skin fibroblasts by preventing local activation of TGF- beta by NCI-H358 tumour cells in a tumour cell-fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of alpha v beta 6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of alpha v beta 6 integrin, with some activity against alpha v beta 8 integrin, that reduces both tumour growth and metastasis.
Journal Article
Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells
The integrin αvβ6 is not detectable on normal keratinocytes
in vivo
but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, αvβ6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, αvβ6 has also been shown to have high affinity for the TGF-β1 latency associated peptide and to participate in the activation of the TGF-β1 latent complex. Since TGF-β1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-β signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an αvβ6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to αvβ6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 μg ml
−1
) inhibited αvβ6-dependent adhesion, migration and invasion. Thus αvβ6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.
Journal Article
RCVS Council elections
The changes in general practice, with corporate and joint-venture partnerships seeming to dominate, the emergence of increasingly specialised referral practices, the threats to livestock agriculture from bovine TB, Schmallenberg virus (not to mention decreased profit margins), the horse DNA in meat products, the increase in paraveterinary occupations and the promised (threatened?) increase in veterinary schools, are all matters which, it seems to me, should occupy the minds of those individuals who wish to represent us.
Journal Article