1,721,011 research outputs found
Multi-scale based software for effective analysis of anticancer drug efficacy in a computer simulated target environment
No full textEfficacy of chemotherapeutic cancer treatment varies from patient to patient. This variability can be attributed to the differences in the biological characteristics of the cancer cells. The effects of the biological characteristics on chemotherapy outcomes are widely studied. In most cases, such as in drug testing, it is assumed that a drug working on a biological cell type will continue to work with the same efficacy on patients having the same cell type. However, even in patients having phenotypically and genotypically identical cancer cells, the treatment efficacies vary between each other. These deviations arise from the cell-level biophysical characteristic variations in the cells that make up the tumor microenvironment. In addition to affecting the treatment outcomes, the microenvironment also alters the evasive capability of cancer cells. The tumor microenvironment therefore acts as a modifier of chemotherapeutic effects and enabler of chemotherapy evasion of the cancer cells. To completely understand the effects of microenvironment on chemotherapy outcomes, it is necessary to analyse the cell-level and tissue level biophysical evasion mechanisms of the cancer cells. These mechanisms aid in drug effect evasion and/or promote metastases. In this thesis, a simulation framework is developed for numerical modelling and simulation of interactions between cancerous tumor cells and their microenvironment. Three computational and experimental studies are included. They include, study of the, effects of chemotherapy on homogenous tumor population, influence of tumor microenvironment on the development of invadopodia structures and the transformation of benign tumor to a malignant tumor.
The mechanisms of action and efficacy of chemotherapy drugs, at cell population levels are well studied in literature. However, the localized spatio-temporal effects of the drugs are less well understood. The emergence of spatially preferential drug efficacy of cisplatin and paclitaxel resulting from variations in mechanisms of cell-drug interactions is explored. Using lab-grown 3D spheroids of HeLa-C3 cells and mechanistic model simulations, it is shown that cell repair probability, intracellular drug concentration and cell’s mitosis phase interact to determine the outcomes of drug actions on a local cell population. In spheroids treated with cisplatin, the drug induced apoptosis is found to be scattered throughout the volume of the spheroids. The efficacy of cisplatin is dependent on the stochastic cell repair probability. In contrast, the effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. The preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis in the spheroids based on the scheduling strategy. Treatments initiated with paclitaxel are found to be more efficacious than its counterpart due to the cascading of spatial effects of the drugs. Short time drug alternation strategies produce largely similar treatment outcomes irrespective of the drug ordering.
Invadopodia of tumor cells have been sufficiently documented for their role in tumor progression and distant metastasis. Invadopodia formation is found to promote extravasation of circulating tumor cells, which has been verified by different experiment models. The influence of microenvironment on invadopodia formation of circulating tumor cells is largely unknown. The fluidic shear stress, which is an important physiological factor in the microenvironment of circulating tumor cells, is investigated for its effects on invadopodia formation. By utilizing a microfluidic system, shear stress is applied on tumor cells. Shear stress is found to promote invadopodia formation of tumor cells. The mechanism study using biological experiments and Glazier-Graner-Hogeweg method-based numerical model simulations shows that shear stress-generated reactive oxygen species is able to activate tyrosine kinase 5 and enhance invadopodia formation. This study provides insights on the invasiveness of metastatic cells and has important implications for cancer prognosis and therapy development.
Ductal carcinoma in-situ (DCIS) presents a risk of transformation to malignant intraductal carcinoma (IDC) of the breast. Three tumor suppressor genes RB, BRCA1 and TP53 are critical in curtailing the progress of DCIS to IDC. The complex transition process from DCIS to IDC involves acquisition of intracellular genomic aberrations and consequent changes in phenotypic characteristics and protein expression level of the cells. There is a lack of proper understanding of the spatiotemporal dynamics associated with breech of epithelial basement membrane and subsequent invasion of stromal tissues during the transition. Therefore, the emergence of invasive behavior in benign tumor, emanating from altered expression levels of the three critical genes is explored in this thesis. A multiscale mechanistic model is used to unravel the phenotypical and biophysical dynamics promoting the invasive nature of DCIS. Ductal morphologies including comedo, hyperplasia and DCIS evolve spontaneously from the interplay between the gene activity parameters in the simulations. The model elucidates the cause and effect relationship between cell-level biological signaling and tissue-level biophysical response in the ductal microenvironment. The model predicts that BRCA1 mutations will act as a facilitator for DCIS to IDC transitions while mutations in RB act as initiator of such transitions.
Overall, the three model studies highlight the importance of tumor microenvironment in determining the treatment outcomes and cancer progression. Tumor microenvironment drives the non-linear response of tumor cells to chemotherapy. The studies indicate a heterogenous response to chemotherapy from a genetically homogenous tumor population. The DCIS to IDC transformation study suggests RB as a crucial drug target candidate to prevent tumor growth and arrest further metastases. Similarly, the extravasation study proposes ROS as an external environmental factor promoting cancer cell extravasation and therefore, consequently, a critical drug candidate. Thus, this thesis successfully identifies significant biophysical and chemical targets in the tumor microenvironment landscape which enable evasion and reduction of chemotherapeutic efficacy in cancer treatment.Doctor of Philosoph
8th Workshop on Biomedical and Bioinformatics Challenges for Computer Science – BBC2015. Introduction
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Genetic commerce: intelligent share trading
No full textIn time, it seems feasible that genetic algorithms will help to achieve similar levels of productivity gains in many service domains as has been achieved in line and, more recently, batch manufacture. And e-commerce will embody the standards and guidelines necessary to enable managers to make the most of the possibilities offered by this development. It will help them to both satisfy and retain the custom of their clients; and make it possible to operate in a highly efficient and effective manner. The paper discusses the nature of these changes and it assesses some of their implications for organisations and their management. It introduces the concept of intelligent share trading; a future manifestation of these developments. And it talks about the important role artificial intelligence, particularly genetic algorithms, will play in these systems
Experiences with deploying legacy code applications as grid services using GEMLCA
No full textOne of the biggest obstacles in the wide-spread industrial take-up of Grid technology is the existence of a large amount of legacy code programs that is not accessible as Grid Services. On top of that, Grid technology challenges the user in order to intuitively interconnect and utilize resources in a friendly environment. This paper describes how legacy code applications were transformed into Grid Services using GEMLCA providing a user-friendly high-level Grid environment for deployment, and running them through the P-GRADE Grid portal. GEMLCA enables the use of legacy code programs as Grid services without modifying the original code. Using the P-GRADE Grid portal with GEMLCA it is possible to deploy legacy code applications as Grid services and use them in the creation and execution of complex workflows. This environment is tested by deploying and executing several legacy code applications on different sites of the UK e-Science OGSA testbed.
The work presented in this paper was initially supported by EPSRC funded project (Grant No: GR/S77509/01): A proposal to evaluate OGSA/GT3 on a UK multisided testbed.
The integration of GEMLCA, P+Grade and other Grid tools and projects is currently supported by "CoreGrid", network of excellence in "Foundations, Software Infrastructures and Applications for large scale distributed, Grid and Peer-to-Peer Technologies"
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
