1,721,019 research outputs found
MULTISCALE COMPLEXITY OF CALCIUM SIGNALING: MODELING ANGIOGENESIS
Full text linkIntracellular calcium signaling is a universal, evolutionary conserved and versatile regulator of cell biochemistry. The complexity of calcium signaling and related cell machinery can be investigated by the use of experimental strategies, as well as by computational approaches. Vascular endothelium is a fascinating model to study the specific properties and roles of calcium signals at multiple biological levels. During the past 20 years, live cell imaging, patch clamp and other techniques have allowed us to detect and interfere with calcium signaling in endothelial cells (ECs), providing a huge amount of information on the regulation of vascularization (angiogenesis) in normal and tumoral tissues. These data range from the spatiotemporal dynamics of calcium within difffferent cell microcompartments to those in entire multicellular and organized EC networks. Beside experimental strategies, in silico endothelial models, specifically designed for simulating calcium signaling, are contributing to our knowledge of vascular physiology and pathology. They help to investigate and predict the quantitative features of proangiogenic events moving through subcellular, cellular and supracellular levels. This review focuses on some recent developments of computational approaches for proangiogenic endothelial calcium signaling. In particular, we discuss the creation of hybrid simulation environments, which combine and integrate discrete Cellular Potts Models. They are able to capture the phenomenological mechanisms of cell morphological reorganization, migration, and intercellular adhesion, with single-cell spatiotemporal models, based on reaction-diffffusion equations that describe the agonist-induced intracellular calcium events
MULTISCALE MODEL OF TUMOR-DERIVED CAPILLARY-LIKE NETWORK FORMATION
Full text linkSolid tumors recruit and form blood vessels, used for maintenance
and growth as well as for formation and spread of metastases. Vascularization
is therefore a pivotal switch in cancer malignancy: an accurate analysis of its
driving processes is a big issue for the development of treatments. In vitro
experiments have demonstrated that cultured tumor-derived endothelial cells
(TECs) are able to organize in a connected network, which mimics an in vivo
capillary-plexus. The process, called tubulogenesis, is promoted by the activity
of soluble peptides (such as VEGFs), as well as by the following intracellular
calcium signals. We here propose a multilevel approach, reproducing selected
features of the experimental system: it incorporates a continuous model of microscopic
VEGF-induced events in a discrete mesoscopic Cellular Potts Model
(CPM). The two components are interfaced, producing a multiscale framework
characterized by a constant
ux of information from ner to coarser
levels. The simulation results, in agreement with experimental analysis, allow
to identify the key mechanisms of network formation. In particular, we provide
evidence that the nascent pattern is characterized by precise topological
properties, regulated by the initial cell density in conjunction with the degree
of the chemotactic response and the directional persistence of cell migration
Computational approaches for translational oncology: Concepts and patents
Full text linkBackground: Cancer is a heterogeneous disease, which is based on an intricate network of processes at different spatiotemporal scales, from the genome to the tissue level. Hence the necessity for the biomedical and pharmaceutical research to work in a multiscale fashion. In this respect, a significant help derives from the collaboration with theoretical sciences. Mathematical models can in fact provide insights into tumor-related processes and support clinical oncologists in the design of treatment regime, dosage, schedule and toxicity. Objective and Method: The main objective of this article is to review the recent computational-based patents which tackle some relevant aspects of tumor treatment. We first analyze a series of patents concerning the purposing the purposing or repurposing of anti-tumor compounds. These approaches rely on pharmacokinetics and pharmacodynamics modules, that incorporate data obtained in the different phases of clinical trials. Similar methods are also at the basis of other patents included in this paper, which deal with treatment optimization, in terms of maximizing therapy efficacy while minimizing side effects on the host. A group of patents predicting drug response and tumor evolution by the use of kinetics graphs are commented as well. We finally focus on patents that implement informatics tools to map and screen biological, medical, and pharmaceutical knowledge. Results and Conclusions: Despite promising aspects (and an increasing amount of the relative literature), we found few computational-based patents: There is still a significant effort to do for allowing modelling approaches to become an integral component of the pharmaceutical research
Specificity of calcium signaling induced by hydrogen sulfide in different endothelial cell types
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A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue
Full text linkAngiogenesis, the formation of new blood vessel networks from existing capillary or post-capillary venules, is an intrinsically multiscale process occurring in several physio-pathological conditions. In particular, hypoxic tissue cells activate downstream cascades culminating in the secretion of a wide range of angiogenic factors, including VEGF isoforms. Such diffusive chemicals activate the endothelial cells (ECs) forming the external walls of the nearby vessels that chemotactically migrate toward the hypoxic areas of the tissue as multicellular sprouts. A functional network eventually emerges by further branching and anastomosis processes. We here propose a CPM-based approach reproducing selected features of the angiogenic progression necessary for the reoxygenation of a hypoxic tissue. Our model is able to span the different scale involved in the angiogenic progression as it incorporates reaction-diffusion equations for the description of the evolution of microenvironmental variables in a discrete mesoscopic cellular Potts model (CPM) that reproduces the dynamics of the vascular cells. A key feature of this work is the explicit phenotypic differentiation of the ECs themselves, distinguished in quiescent, stalk and tip. The simulation results allow identifying a set of key mechanisms underlying tissue vascularization. Further, we provide evidence that the nascent pattern is characterized by precise topological properties. Finally, we link abnormal sprouting angiogenesis with alteration in selected cell behavior
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