A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment.

Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRα/β, FLT3 and c-KIT. In this study a multi-parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges of identifying appropriate quantitative imaging response biomarkers in heterogeneous models, particularly considering the multifaceted roles of angiogenic growth factors

Continuous safe water monitoring using 3G telemetry in IDP camp water supply systems: Iraq trial

Water quality monitoring for disinfection using chlorine in humanitarian settings is predominantly measured through low-resolution manual sampling and analysis methods, that is subject to human error, as well as being highly dependent on accessibility of sites, capacity and availability of human resources. The Chloroclam, a small high-resolution chlorine analyser that transmits continuous real-time data through a 2G/3G mobile network, was trialled over a 7-month period in an IDP camp in Northern Iraq to determine its functionality and ease of use in a crisis context. The results validated the data produced by the Chloroclam, with datasets highlighting significant seasonal and diurnal variances in chlorine concentrations and noting that manual sampling was not representative of the functionality of the water supply system. The data was able to suggest adjustments to dosing regimes to ensure sufficient levels of chlorine is available throughout collection periods and across the year

The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent

Geomorphological controls on fluvial carbon storage in headwater peatlands

Geomorphological controls and catchment sediment characteristics control the formation of floodplains and affect their capacity to sequester carbon. Organic carbon stored in floodplains is typically a product of pedogenic development between periods of mineral sediment deposition. However, in organically‐dominated upland catchments with a high sediment load, eroded particulate organics may also be fluvially deposited with potential for storage and/or oxidation. Understanding the redistribution of terrestrial carbon laterally, beyond the bounds of river channels is important, especially in eroding peatland systems where fluvial particulate organic carbon exports are often assumed to be oxidised. Floodplains have the potential to be both carbon cycling hotspots and areas of sequestration. Understanding of the interaction of carbon cycling and the sediment cascade through floodplain systems is limited. This paper examines the formation of highly organic floodplains downstream of heavily eroded peatlands in the Peak District, UK. Reconstruction of the history of the floodplains suggests that they have formed in response to periods of erosion of organic soils upstream. We present a novel approach to calculating a carbon stock within a floodplain, using XRF and radiograph data recorded during Itrax core scanning of sediment cores. This carbon stock is extrapolated to the catchment scale, to assess the importance of these floodplains in the storage and cycling of organic carbon in this area. The carbon stock estimate for the floodplains across the contributing catchments is between 3482‐13460 tonnes, equating on an annualised basis to 0.8‐4.5% of the modern‐day POC flux. Radiocarbon analyses of bulk organic matter in floodplain sediments revealed that a substantial proportion of organic carbon was associated with re‐deposited peat and has been used as a tool for organic matter source determination. The average age of these samples (3010 years BP) is substantially older than Infrared Stimulated Luminesence dating which demonstrated that the floodplains formed between 430 and 1060 years ago. Our data suggest that floodplains are an integral part of eroding peatland systems, acting as both significant stores of aged and eroded organic carbon and as hotspots of carbon turnover

Type II Endoleak after Endovascular Aneurysm Repair: natural history and treatment outcomes

Published online April 2017Abstract not availableLiana Kumar, Prue Cowled, Margaret Boult, Stuart Howell, and Robert Fitridg

Design for Social Value: Using design to improve the impact of CSR

This paper discusses the meaning of social value from the design perspective, especially in Corporate Social Responsibility practices, and the contextual issues and values derived from design, considering how companies could better use design for social value creation. The research identified consumer attitudes to corporate social value and where companies are perceived to have generated social value, and explored where design has contributed to such social value. The research illustrates that design has great potential to add value to the triple bottom line, mostly related directly to organisations, but also to areas relating to society, including the ‘lower levels of environmental degradation’ and ‘more solutions for social issues’, indicating design plays an influential role in creating socially responsible products/services. However, this research suggests that a clear definition of ‘social value’ from various perspectives and its relationship with CSR is required due to the complex and subjective nature of ‘social value’.Arts and Humanities Research Council (AHRC

Wittgensteinian Anti-Scepticism and Epistemic Vertigo

status: publishe

26.1 MOTOR SUBTYPES AND PREDICTION OF COURSE IN PSYCHOSIS RISK YOUTH

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R2, before and during carbogen (95% O2/5% CO2) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R2 were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R2 response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P < 0.05) different median baseline R2, ΔR2carbogen, and fractional blood volume. CUSPIO imaging showed that small subcutaneous tumors predominantly exhibited a negative ΔR2carbogen followed by a positive ΔR2USPIO, consistent with a well perfused tumor vasculature. Large subcutaneous tumors exhibited a small positive ΔR2carbogen and relatively low fractional blood volume, suggesting less functional vasculature. Orthotopic tumors revealed a large, positive ΔR2carbogen, consistent with vascular steal, and which may indicate that vascular function is more dependent on site of implantation than tumor size. Regions exhibiting significant ΔR2carbogen, but no significant ΔR2USPIO, suggesting transient vascular shutdown over the experimental timecourse, were apparent in all 3 cohorts. CUSPIO imaging can inform on efficient drug delivery via functional vasculature in vivo, and on appropriate tumor model selection for pre-clinical therapy trials