Georgios Lolas

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Distributed Learning in Healthcare

Trends of Artificial Intelligence and Big Data for E-Health

Mathematical Modelling of Cancer Cell Invasion of Tissue: The Role of the Urokinase Plasminogen Activation System

Mathematical Models and Methods in Applied Sciences, Nov 1, 2005

The growth of solid tumours proceeds through two distinct phases: the avascular and the vascular ... more The growth of solid tumours proceeds through two distinct phases: the avascular and the vascular phase. It is during the latter stage that the insidious process of cancer invasion of peritumoral tissue can and does take place. Vascular tumours grow rapidly allowing the cancer cells to establish a new colony in distant organs, a process that is known as metastasis. The progression from a single, primary tumour to multiple tumours in distant sites throughout the body is known as the metastatic cascade. This is a multistep process that first involves the over-expression by the cancer cells of proteolytic enzyme activity, such as the urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). uPA itself initiates the activation of an enzymatic cascade that primarily involves the activation of plasminogen and subsequently its matrix degrading protein plasmin. Degradation of the matrix then enables the cancer cells to migrate through the tissue and subsequently to spread to secondary sites in the body. In this paper we consider a mathematical model of cancer cell invasion of tissue (extracellular matrix) which focuses on the role of the plasminogen activation system. The model consists of a system of reaction-diffusion-taxis partial differential equations describing the interactions between cancer cells, urokinase plasminogen activator (uPA), uPA inhibitors, plasmin and the host tissue. The focus of the modelling is on the spatiotemporal dynamics of the uPA system and how this influences the migratory properties of the cancer cells through random motility, chemotaxis and haptotaxis. The results obtained from numerical computations carried out on the model equations produce rich, dynamic heterogeneous spatio-temporal solutions and demonstrate the ability of rather simple models to produce complicated dynamics, all of which are associated with tumour heterogeneity and cancer cell progression and invasion.

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AI and Big Data for Drug Discovery

Integrated Science, 2022

AI and Big Data for Drug Discovery

Springer eBooks, 2022

AI and Big Data for Cancer Segmentation, Detection and Prevention

Integrated Science, 2022

Mathematical Biology Mathematical modeling of cancer cell invasion of tissue: biological insight from mathematical analysis and computational simulation

The ability of cancer cells to break out of tissue compartments and invade locally gives solid tu... more The ability of cancer cells to break out of tissue compartments and invade locally gives solid tumours a defining deadly characteristic. One of the first steps of invasion is the remodelling of the surrounding tissue or extracellular matrix (ECM) and a major part of this process is the over-expression of proteolytic enzymes, such as the urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), by the cancer cells to break down ECM proteins. Degradation of the matrix enables the cancer cells to migrate through the tissue and subsequently to spread to secondary sites in the body, a process known as metastasis. In this paper we undertake an analysis of a mathematical model of cancer cell invasion of tissue, or ECM, which focuses on the role of the urokinase plasminogen activation system. The model consists of a system of five reaction-diffusion-taxis partial differential equations describing the interactions between cancer cells, uPA, uPA inhibitors, plasmin and ...

Additional file 1 of Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer

Additional file 1: Supplemental Figure S1. Histological assessment of patient samples and PDX mod... more Additional file 1: Supplemental Figure S1. Histological assessment of patient samples and PDX models. Histological features of the selected NSCLC PDX and corresponding patient tissue. H&E stains were prepared from FFPE samples of donor patient tissue as well as the fourth passage of PDX derived thereof. Whole slides were scanned and 10x magnification jpegs extracted of the scans (scale bar included). Supplemental Figure S2. EGFR gene-expression levels correlate with Erlotinib response. EGFR gene-expression measured in the microarray HGU133 (left graph) or by RNA-sequencing (right graph) plotted against the relative tumor size of Erlotinib-treated versus control ZTX models (low values indicate stronger response to Erlotinib). Blue dashed regression lines indicate logarithmic regressions based on the values within the blue dashed circles.

Mathematical Modelling of Proteolysis and Cancer Cell Invasion of Tissue

Lecture Notes in Mathematics, 2005

The growth of solid tumors proceeds through two distinct phases: the avascular and the vascular p... more The growth of solid tumors proceeds through two distinct phases: the avascular and the vascular phase. It is during the latter stage that the insidious process of cancer invasion of peritumoral tissue can and does take place. Vascular tumors grow rapidly allowing the cancer cells to establish a new colony in distant organs, a process known as metastasis. The metastatic cascade is a multistep process that involves the over-expression of proteolytic enzyme activity such as the urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). uPA initiates the activation of an enzymatic cascade that primarily involves the activation of plasminogen and subsequently its matrix degrading protein plasmin. Degradation of the peritumoral tissue enables the cancer cells to migrate through the tissue and subsequently to spread to secondary sites in the body.

The role of VEGF-C and CCR7/CCL21 in Tumor Lymphangiogenesis

9Th European Conference on Mathematical and Theoretical Biology, Jun 9, 2014

Tumor survival, growth and dissemination are associated with the formation of both new blood vess... more Tumor survival, growth and dissemination are associated with the formation of both new blood vessels (angiogenesis) and new lymph vessels (lymphangiogenesis). Despite the longstanding recognition of the presence of the lymphatic system in several clinical studies, experimental demonstration of its role in lymphedema, lymphangiogenesis or tumor cell metastasis was until recently hindered by the lack of unique markers for the lymphatic vessels. In the current work we present an in silico model for lymphangiogenesis in tumor. The modeling focuses on key events associated with the migratory response of lymphatic endothelial cells to auto- and tumor secreted growth factors. Using parameter values based on experimental data we present numerical results, which demonstrate the process of tumor lymphangiogenesis based on VEGF-C secretion and its correlation with peritumoral and intratumoral lymphatic presence and penetration. Furthermore, we present a 3D multi-cell simulation as a generic simplification of tumour lymphovascular invasion through the activation of CCR7/CCL21 axis in order to provide a glimpse of what may be a more active role of chemokines in lymphovascular invasion.

Influence of accelerated aging on nanomechanical properties, creep behaviour and adhesive forces of PDMS

Plastics, Rubber and Composites, 2012

In the present study, the nanoindentation creep behaviour of untreated and ultraviolet (UV) treat... more In the present study, the nanoindentation creep behaviour of untreated and ultraviolet (UV) treated polydimethylsiloxane (PDMS) samples was investigated, accompanied with adhesion analysis and Fourier transform infrared spectroscopy (FTIR) characterisation. Different hold times, in the range of 5-2000 s (at 10 mN of applied load), were incorporated into each nanoindentation measurement. The increase in hold time results in an increase in change in depth of the indenter in both samples. The error in hardness/modulus due to creep can be neglected for hold times of y400 s or more for untreated PDMS and y200 s or more for UV treated PDMS. The FTIR obtained data revealed surface deterioration, while the bulk nanomechanical properties were almost identical. A decrease in adhesive energy in the case of UV treated PDMS was observed, indicating that adhesive forces play a significant role at the nanometre scale in the indentation tests (real contact area determination during nanoindentation measurements).

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Retinal Plasticity: Mathematical modelling of positional information of sub-apical neurons

9Th European Conference on Mathematical and Theoretical Biology, Jun 9, 2014

The coordination between further proliferation, differentiation and cell cycle exit in retina dev... more The coordination between further proliferation, differentiation and cell cycle exit in retina development is a complex and fully coordinated process. More specifically it involves cell cycle exit, migration as well as multiple regulatory pathways which involve transcription factors and cell-cell signaling events. The plethora of retina cell types develop form a common pool of progenitor cells. Pluripotent retinal progenitors produce a varied number of clones of heterogeneous size and cell types. However up until now little is known regarding the involvement of non-apical progenitors in retinal development. We developed a mathematical model to assess that increasing apical precursors overcrowding leads to non-apical divisions. The model describes a basic lineage relationship between pluripotent progenitors, committed progenitors and neurons located apically and non-apically. We further estimate the maximum transition rate with which an apical progenitor becomes a sub-apically dividing precursor. In addition, we formulate a qualitative mathematical model using a combination of experimentally measured and model selected parameters.

Mathematical modeling of cancer cell invasion of tissue: biological insight from mathematical analysis and computational simulation

Journal of Mathematical Biology, 2010

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Microbiomics in Collusion with the Nervous System in Carcinogenesis: Diagnosis, Pathogenesis and Treatment

Microorganisms, 2021

The influence of the naturally occurring population of microbes on various human diseases has bee... more The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood–brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripher...

format_quoteNeoneurogenesis supports cancer growth by providing pathways for tumor cells to metastasize and invade new tissues.format_quote

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Storage tank for injection device of liquid reducing agent into exhaust gas after-treatment device, has suction hoses guided into multiple intake manifolds distributed over total base area of storage tank

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer

Journal of Experimental & Clinical Cancer Research

Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are c... more Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responde...

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Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

Cancers

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous ... more During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute t...

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Genomics and molecular analysis of RPL9 and LIAS in lung cancer: Emerging implications in carcinogenesis

Informatics in Medicine Unlocked

Adjustable delivery of pro-angiogenic FGF-2 by collagen-alginate microspheres

Biology open, Jan 15, 2018

Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great poten... more Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here we demonstrate that collagen:alginate hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded pro-angiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate:collagen microspheres were completely biocompatible and did not cause any adverse reactions when inje...

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Modeling Proteolytically Driven Tumor Lymphangiogenesis

Advances in Experimental Medicine and Biology, 2016

With the exception of a limited number of sites in the body, primary tumors infrequently lead to ... more With the exception of a limited number of sites in the body, primary tumors infrequently lead to the demise of cancer patients. Instead, mortality and a significant degree of morbidity result from the growth of secondary tumors in distant organs. Tumor survival, growth and dissemination are associated with the formation of both new blood vessels (angiogenesis) and new lymph vessels (lymphagenesis or lymphangiogenesis). Although intensive research in tumor angiogenesis has been going on for the past four decades, experimental results in tumor lymphangiogenesis began to appear only in the last 10 years. In this chapter we expand the models proposed by Friedman, Lolas and Pepper on tumor lymphangiogenesis mediated by proteolytically and un-proteolytically processed growth factors (Friedman and Lolas G, Math Models Methods Appl Sci 15(01):95-107, 2005; Pepper and Lolas G, Selected topics in cancer modeling: genesis, evolution, immune competition, and therapy. In: The lymphatic vascular system in lymphangiogenesis invasion and metastasis a mathematical approach. Birkhäuser Boston, Boston, pp 1-22, 2008). The variables represent different cell densities and growth factors concentrations, and where possible the parameters are estimated from experimental and clinical data. The results obtained from computational simulations carried out on the model equations produce dynamic heterogeneous (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;anarchic&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;) spatio-temporal solutions. More specifically, we observed coherent masses of tumor clusters migrating around and within the lymphatic network. Our findings are in line with recent experimental evidence that associate cluster formation with the minimization of cell loss favoring high local extracellular matrix proteolysis and thus protecting cancer invading cells from an immunological assault driven by the lymphatic network.

Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach

Scientific Reports, 2016

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