Overcoming primary and acquired erlotinib resistance with epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K) co-inhibition in pancreatic cancer

PI3K/Akt is over-expressed in 50-70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR co-inhibition may be effective in PDAC with upregulated PI3K/Akt/mTOR (PAM) signaling. Five primary PDAC and two erlotinib acquired resistant (ER) cell lines with significantly over-expressed AKT2 gene, total Akt and pAkt, were used. Multiple inhibitors of the MAPK and PAM were tested alone or in combination by western blotting, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib acted synergistically with PI3Kα inhibitor BYL in both ER cell lines (synergy index, SI=1.71 and 1.44 respectively). Treatment of ER cell lines by this dual blockade caused significant G1 cell cycle arrest (71%, P<0.001; 58%, P=0.003), inhibition of colony formation (69% and 72%, both P<0.001), and necrosis and apoptosis (75% and 53%, both P<0.001), more so compared to parent cell lines. In primary patient-derived tumor subrenal capsule (n=90) and subcutaneous (n=22) xenografts, Erlotinib plus BYL significantly reduced tumor volume (P=0.005). Strong pEGFR and pAkt immunostaining (2+/3+) was correlated with high response to erlotinib and low response to erlotinib plus BYL respectively. In conclusion, PDAC with increased expression of the PAM signaling were susceptible to PI3K/ EGFR co-inhibition suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential predictive biomarkers is warranted

Parallel and Distributed Execution of Model Management Programs

The engineering process of complex systems involves many stakeholders and development artefacts. Model-Driven Engineering (MDE) is an approach to development which aims to help curtail and better manage this complexity by raising the level of abstraction. In MDE, models are first-class artefacts in the development process. Such models can be used to describe artefacts of arbitrary complexity at various levels of abstraction according to the requirements of their prospective stakeholders. These models come in various sizes and formats and can be thought of more broadly as structured data. Since models are the primary artefacts in MDE, and the goal is to enhance the efficiency of the development process, powerful tools are required to work with such models at an appropriate level of abstraction. Model management tasks – such as querying, validation, comparison, transformation and text generation – are often performed using dedicated languages, with declarative constructs used to improve expressiveness. Despite their semantically constrained nature, the execution engines of these languages rarely capitalize on the optimization opportunities afforded to them. Therefore, working with very large models often leads to poor performance when using MDE tools compared to general-purpose programming languages, which has a detrimental effect on productivity. Given the stagnant single-threaded performance of modern CPUs along with the ubiquity of distributed computing, parallelization of these model management program is a necessity to address some of the scalability concerns surrounding MDE. This thesis demonstrates efficient parallel and distributed execution algorithms for model validation, querying and text generation and evaluates their effectiveness. By fully utilizing the CPUs on 26 hexa-core systems, we were able to improve performance of a complex model validation language by 122x compared to its existing sequential implementation. Up to 11x speedup was achieved with 16 cores for model query and model-to-text transformation tasks

Building information modeling – A game changer for interoperability and a chance for digital preservation of architectural data?

Digital data associated with the architectural design-andconstruction process is an essential resource alongside -and even past- the lifecycle of the construction object it describes. Despite this, digital architectural data remains to be largely neglected in digital preservation research – and vice versa, digital preservation is so far neglected in the design-and-construction process. In the last 5 years, Building Information Modeling (BIM) has seen a growing adoption in the architecture and construction domains, marking a large step towards much needed interoperability. The open standard IFC (Industry Foundation Classes) is one way in which data is exchanged in BIM processes. This paper presents a first digital preservation based look at BIM processes, highlighting the history and adoption of the methods as well as the open file format standard IFC (Industry Foundation Classes) as one way to store and preserve BIM data

Extending functional databases for use in text-intensive applications

This thesis continues research exploring the benefits of using functional databases based around the functional data model for advanced database applications-particularly those supporting investigative systems. This is a growing generic application domain covering areas such as criminal and military intelligence, which are characterised by significant data complexity, large data sets and the need for high performance, interactive use. An experimental functional database language was developed to provide the requisite semantic richness. However, heavy use in a practical context has shown that language extensions and implementation improvements are required-especially in the crucial areas of string matching and graph traversal. In addition, an implementation on multiprocessor, parallel architectures is essential to meet the performance needs arising from existing and projected database sizes in the chosen application area. [Continues.