Process Algebra with Layers: Multi-scale Integration Modelling applied to Cancer Therapy

We present a novel Process Algebra designed for multi-scale integration modelling: Process Algebra with Layers (PAL). The unique feature of PAL is the modularisation of scale into integrated layers: Object and Population. An Object can represent a molecule, organelle, cell, tissue, organ or any organism. Populations hold specific types of Object, for example, life stages, cell phases and infectious states. The syntax and semantics of this novel language are presented. A PAL model of the multi-scale system of cell growth and damage from cancer treatment is given. This model allows the analysis of different scales of the system. The Object and Population levels give insight into the length of a cell cycle and cell population growth respectively. The PAL model results are compared to wet laboratory survival fractions of cells given different doses of radiation treatment [1]. This comparison shows how PAL can be used to aid in investigations of cancer treatment in systems biology

Towards Predicting the Response of a Solid Tumour to Chemotherapy and Radiotherapy Treatments: Clinical Insights from a Computational Model

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules

Exploiting Clinical Trial Data Drastically Narrows the Window of Possible Solutions to the Problem of Clinical Adaptation of a Multiscale Cancer Model

The development of computational models for simulating tumor growth and response to treatment has gained significant momentum during the last few decades. At the dawn of the era of personalized medicine, providing insight into complex mechanisms involved in cancer and contributing to patient-specific therapy optimization constitute particularly inspiring pursuits. The in silico oncology community is facing the great challenge of effectively translating simulation models into clinical practice, which presupposes a thorough sensitivity analysis, adaptation and validation process based on real clinical data. In this paper, the behavior of a clinically-oriented, multiscale model of solid tumor response to chemotherapy is investigated, using the paradigm of nephroblastoma response to preoperative chemotherapy in the context of the SIOP/GPOH clinical trial. A sorting of the model's parameters according to the magnitude of their effect on the output has unveiled the relative importance of the corresponding biological mechanisms; major impact on the result of therapy is credited to the oxygenation and nutrient availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. The effect of a number of parameter combinations on the extent of chemotherapy-induced tumor shrinkage and on the tumor's growth rate are discussed. A real clinical case of nephroblastoma has served as a proof of principle study case, demonstrating the basics of an ongoing clinical adaptation and validation process. By using clinical data in conjunction with plausible values of model parameters, an excellent fit of the model to the available medical data of the selected nephroblastoma case has been achieved, in terms of both volume reduction and histological constitution of the tumor. In this context, the exploitation of multiscale clinical data drastically narrows the window of possible solutions to the clinical adaptation problem

The proportion of cancer-related entries in PubMed has increased considerably; is cancer truly "The Emperor of All Maladies"?

In this work, the public database of biomedical literature PubMed was mined using queries with combinations of keywords and year restrictions. It was found that the proportion of Cancer-related entries per year in PubMed has risen from around 6% in 1950 to more than 16% in 2016. This increase is not shared by other conditions such as AIDS, Malaria, Tuberculosis, Diabetes, Cardiovascular, Stroke and Infection some of which have, on the contrary, decreased as a proportion of the total entries per year. Organ-related queries were performed to analyse the variation of some specific cancers. A series of queries related to incidence, funding, and relationship with DNA, Computing and Mathematics, were performed to test correlation between the keywords, with the hope of elucidating the cause behind the rise of Cancer in PubMed. Interestingly, the proportion of Cancer-related entries that contain "DNA", "Computational" or "Mathematical" have increased, which suggests that the impact of these scientific advances on Cancer has been stronger than in other conditions. It is important to highlight that the results obtained with the data mining approach here presented are limited to the presence or absence of the keywords on a single, yet extensive, database. Therefore, results should be observed with caution. All the data used for this work is publicly available through PubMed and the UK's Office for National Statistics. All queries and figures were generated with the software platform Matlab and the files are available as supplementary material