A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery.

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.

Assisting digital forensic analysis via exploratory information visualisation

Background: Digital forensics is a rapidly expanding field, due to the continuing advances in computer technology and increases in data stage capabilities of devices. However, the tools supporting digital forensics investigations have not kept pace with this evolution, often leaving the investigator to analyse large volumes of textual data and rely heavily on their own intuition and experience. Aim: This research proposes that given the ability of information visualisation to provide an end user with an intuitive way to rapidly analyse large volumes of complex data, such approached could be applied to digital forensics datasets. Such methods will be investigated; supported by a review of literature regarding the use of such techniques in other fields. The hypothesis of this research body is that by utilising exploratory information visualisation techniques in the form of a tool to support digital forensic investigations, gains in investigative effectiveness can be realised. Method:To test the hypothesis, this research examines three different case studies which look at different forms of information visualisation and their implementation with a digital forensic dataset. Two of these case studies take the form of prototype tools developed by the researcher, and one case study utilises a tool created by a third party research group. A pilot study by the researcher is conducted on these cases, with the strengths and weaknesses of each being drawn into the next case study. The culmination of these case studies is a prototype tool which was developed to resemble a timeline visualisation of the user behaviour on a device. This tool was subjected to an experiment involving a class of university digital forensics students who were given a number of questions about a synthetic digital forensic dataset. Approximately half were given the prototype tool, named Insight, to use, and the others given a common open-source tool. The assessed metrics included: how long the participants took to complete all tasks, how accurate their answers to the tasks were, and how easy the participants found the tasks to complete. They were also asked for their feedback at multiple points throughout the task. Results:The results showed that there was a statistically significant increase in accuracy for one of the six tasks for the participants using the Insight prototype tool. Participants also found completing two of the six tasks significantly easier when using the prototype tool. There were no statistically significant different difference between the completion times of both participant groups. There were no statistically significant differences in the accuracy of participant answers for five of the six tasks. Conclusions: The results from this body of research show that there is evidence to suggest that there is the potential for gains in investigative effectiveness when information visualisation techniques are applied to a digital forensic dataset. Specifically, in some scenarios, the investigator can draw conclusions which are more accurate than those drawn when using primarily textual tools. There is also evidence so suggest that the investigators found these conclusions to be reached significantly more easily when using a tool with a visual format. None of the scenarios led to the investigators being at a significant disadvantage in terms of accuracy or usability when using the prototype visual tool over the textual tool. It is noted that this research did not show that the use of information visualisation techniques leads to any statistically significant difference in the time taken to complete a digital forensics investigation.

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.

The color blind test

Conceived as an investigation into theories and practices of visual perception, these prints explore the idea that artwork can be intentionally created to be experienced differently dependent on one's visual abilities. The software facilitates the embedding of messages revealed only to those with particular visual acuities or viewed using a smart device to digitally simulate those acuities.

North Sea Oil and Genuine Saving in the Scottish Economy

The World Bank has published estimates of sustainability of consumption paths by adjusting saving rates to take account of the depletion of non-renewable resources. During the period of North Sea oil production Scotland has been in a fiscal union with the rest of the UK. The present paper adjusts the World Bank data to produce separate genuine saving estimates for Scotland and the rest of the UK for 1970-2009, based on a ‘derivation’ principle for oil revenues. The calculations indicate that Scotland has had a negative genuine saving rate for most of the period of exploitation of North Sea oil resources, with genuine saving being positive in the rest of the UK during this period.

‘All the places we were not supposed to go’: a case study of formative class and gender habitus in adventure climbing

This paper explores the origins of meaning in adventurous activities. Specifically, the paper reports on a study of 10 adventure climbers in the Scottish mountaineering community. The study explores how formative experiences have influenced engagement in adventure climbing. Work has been done on the phenomenology of adventure and how individuals interpret and find meaning in the activity—this paper goes a step further and asks where do these dispositions come from? Using Bourdieu’s ideas of field, habitus and forms of capital to frame these experiences in the wider social environment, early experiences are identified that, for the subjects of this study, provide a framework for their later adoption of the ‘adventure habitus’. Among these influences are mainstream education, adventure education in particular, as well as broader formative experiences relating to factors such as gender and class. In addition, the study suggests that accounts differ between males and females in terms of their attitudes and dispositions towards adventure. This may relate to their respective experiences as well as expanding opportunities for both males and females. However, while the ‘adventure field’ provides a context where women can develop transformative identities, these are nearly always subject to male validation.

Rainfall infiltration and soil hydrological characteristics below ancient forest, planted forest, and grassland in a temperate northern climate

How rainfall infiltration rate and soil hydrological characteristics develop over time under forests of different ages in temperate regions is poorly understood. In this study, infiltration rate and soil hydrological characteristics were investigated under forests of different ages and under grassland. Soil hydraulic characteristics were measured at different scales under a 250 year old grazed grassland (GL), a six (6 yr) and 48 (48 yr) year old Scots pine (Pinus sylvestris) plantation, remnant 300 year old individual Scots pines (OT) and a 4000 year old Caledonian Forest (AF). In-situ field saturated hydraulic conductivity (Kfs) was measured and visible root:soil area was estimated from soil pits. Macroporosity, pore structure, and macropore connectivity were estimated from X-ray tomography of soil cores, and from water-release characteristics. At all scales the median values for Kfs, root fraction, macro-porosity and connectivity values tended to AF > OT > 48 yr > GL > 6 yr, indicating that infiltration rates and water storage increased with forest age. The remnant Caledonian Forest had a huge range of Kfs (12 to > 4922 mm h-1), with maximum Kfs values 7 to 15 times larger than 48-year-old Scots pine plantation, suggesting that undisturbed old forests, with high rainfall and minimal evapotranspiration in winter, may act as important areas for water storage and sinks for storm rainfall to infiltrate and transport to deeper soil layers via preferential flow. The importance of the development of soil hydrological characteristics under different aged forests is discussed.