A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum

Expansion of the Vortex Cores in YBa2Cu3O6.95 at Low Magnetic Fields

Muon spin rotation spectroscopy has been used to measure the effective size of the vortex cores in optimally doped YBa2Cu3O6.95 as a function of temperature and magnetic field deep in the superconducting state. While the core size at H=2T is close to 20 angstroms and consistent with that measured by STM at 6T, we find a striking increase in the core size at lower magnetic fields, where it approaches an extraordinarily large value of about 100 angstroms. This suggests that the average value of the superconducting coherence length in cuprate superconductors may be larger than previously thought at low magnetic fields.Comment: 9 pages, 4 figures, 1 text fil

Correlations Between Charge Ordering and Local Magnetic Fields in Overdoped YBa2_2Cu3_3O6+x_{6+x}

Zero-field muon spin relaxation (ZF-$\mu$SR) measurements were undertaken on under- and overdoped samples of superconducting YBa$_2$Cu$_3$O$_{6+x}$ to determine the origin of the weak static magnetism recently reported in this system. The temperature dependence of the muon spin relaxation rate in overdoped crystals displays an unusual behavior in the superconducting state. A comparison to the results of NQR and lattice structure experiments on highly doped samples provides compelling evidence for strong coupling of charge, spin and structural inhomogeneities.Comment: 4 pages, 4 figures, new data, new figures and modified tex

Muon spin rotation measurement of the fundamental length scales in the vortex state of YBa2Cu3O6.60

The internal field distribution in the vortex state of YBa2Cu3O6.60 is shown to be a sensitive measure of both the magnetic penetration depth and the vortex-core radius. The temperature dependence of the vortex core radius is found to be weaker than in the conventional superconductor NbSe2 and much weaker than theoretical predictions for an isolated vortex. The effective vortex-core radius decreases sharply with increasing H, whereas the penetration depth is found to be much stronger than in NbSe2.Comment: 5 pages, RevTeX, 4 encapsulated postscript figures, submitted to Phys. Rev. Let

Muon-spin-rotation study of the effect of Zn substitution on magnetism in YBa2Cu3Ox

The magnetic properties of YBa2(Cu0.96Zn0.04)3Ox were studied in detail by means of muon spin rotation and relaxation for 6.0≤x≤6.92. The complete magnetic phase diagram was mapped out and a disordered magnetic state was found to persist between x=6.4 and x≃6.7 (metallic transition), in contrast with pure YBa2Cu3Ox. The appearance of this magnetic state is attributed to the effect of Zn on the doped hole dynamics and might be associated with the freezing of local moments due to Zn (6.43≤x≤6.88), which were also detected here, in the paramagnetic state

Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

Background: Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods: We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results: We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m(2) with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions: We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation

Unsettling boundaries in making a space for research

In engaging in research we draw upon and develop meanings and concepts that help to frame what we do, how we do it and the meaning we make of it. In the process of framing, we exclude other possibilities from our research practices. To do research then is to engage in the fashioning of conceptual boundaries. This article explores the dilemmas of boundary-making in the context of a research project aimed at exploring the border literacy practices of students in UK further education, those boundary crossing practices which relate to the everyday and more formal demands of the curriculum. This discussion is related to wider debates in the social sciences on the significance of boundaries and borders and their powerful effects on identities and actions

Involvement of Skeletal Muscle Gene Regulatory Network in Susceptibility to Wound Infection Following Trauma

Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear. A Drosophila melanogaster/Pseudomonas aeruginosa injury and infection model was used to identify host genetic components that contribute to the hyper-susceptibility to infection that follows severe trauma. We show that P. aeruginosa compromises skeletal muscle gene (SMG) expression at the injury site to promote infection. We demonstrate that activation of SMG structural components is under the control of cJun-N-terminal Kinase (JNK) Kinase, Hemipterous (Hep), and activation of this pathway promotes local resistance to P. aeruginosa in flies and mice. Our study links SMG expression and function to increased susceptibility to infection, and suggests that P. aeruginosa affects SMG homeostasis locally by restricting SMG expression in injured skeletal muscle tissue. Local potentiation of these host responses, and/or inhibition of their suppression by virulent P. aeruginosa cells, could lead to novel therapies that prevent or treat deleterious and potentially fatal infections in severely injured individuals