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

Performance Comparison of Dual Connectivity and Hard Handover for LTE-5G Tight Integration in mmWave Cellular Networks

MmWave communications are expected to play a major role in the Fifth generation of mobile networks. They offer a potential multi-gigabit throughput and an ultra-low radio latency, but at the same time suffer from high isotropic pathloss, and a coverage area much smaller than the one of LTE macrocells. In order to address these issues, highly directional beamforming and a very high-density deployment of mmWave base stations were proposed. This Thesis aims to improve the reliability and performance of the 5G network by studying its tight and seamless integration with the current LTE cellular network. In particular, the LTE base stations can provide a coverage layer for 5G mobile terminals, because they operate on microWave frequencies, which are less sensitive to blockage and have a lower pathloss. This document is a copy of the Master's Thesis carried out by Mr. Michele Polese under the supervision of Dr. Marco Mezzavilla and Prof. Michele Zorzi. It will propose an LTE-5G tight integration architecture, based on mobile terminals' dual connectivity to LTE and 5G radio access networks, and will evaluate which are the new network procedures that will be needed to support it. Moreover, this new architecture will be implemented in the ns-3 simulator, and a thorough simulation campaign will be conducted in order to evaluate its performance, with respect to the baseline of handover between LTE and 5G.Comment: Master's Thesis carried out by Mr. Michele Polese under the supervision of Dr. Marco Mezzavilla and Prof. Michele Zorz

Control-data separation architecture for cellular radio access networks: a survey and outlook

Conventional cellular systems are designed to ensure ubiquitous coverage with an always present wireless channel irrespective of the spatial and temporal demand of service. This approach raises several problems due to the tight coupling between network and data access points, as well as the paradigm shift towards data-oriented services, heterogeneous deployments and network densification. A logical separation between control and data planes is seen as a promising solution that could overcome these issues, by providing data services under the umbrella of a coverage layer. This article presents a holistic survey of existing literature on the control-data separation architecture (CDSA) for cellular radio access networks. As a starting point, we discuss the fundamentals, concepts, and general structure of the CDSA. Then, we point out limitations of the conventional architecture in futuristic deployment scenarios. In addition, we present and critically discuss the work that has been done to investigate potential benefits of the CDSA, as well as its technical challenges and enabling technologies. Finally, an overview of standardisation proposals related to this research vision is provided