262 research outputs found
The role of spatial variations of abiotic factors in mediating intratumour phenotypic heterogeneity
We present here a space- and phenotype-structured model of selection dynamics between cancer cells within a solid tumour. In the framework of this model, we combine formal analyses with numerical simulations to investigate in silico the role played by the spatial distribution of abiotic components of the tumour microenvironment in mediating phenotypic selection of cancer cells. Numerical simulations are performed both on the 3D geometry of an in silico multicellular tumour spheroid and on the 3D geometry of an in vivo human hepatic tumour, which was imaged using computerised tomography. The results obtained show that inhomogeneities in the spatial distribution of oxygen, currently observed in solid tumours, can promote the creation of distinct local niches and lead to the selection of different phenotypic variants within the same tumour. This process fosters the emergence of stable phenotypic heterogeneity and supports the presence of hypoxic cells resistant to cytotoxic therapy prior to treatment. Our theoretical results demonstrate the importance of integrating spatial data with ecological principles when evaluating the therapeutic response of solid tumours to cytotoxic therapy
Micro-Capsules in Shear Flow
This paper deals with flow-induced shape transitions of elastic capsules. The
state of the art concerning both theory and experiments is briefly reviewed
starting with dynamically induced small deformation of initially spherical
capsules and the formation of wrinkles on polymerized membranes. Initially
non-spherical capsules show tumbling and tank-treading motion in shear flow.
Theoretical descriptions of the transition between these two types of motion
assuming a fixed shape are at variance with the full capsule dynamics obtained
numerically. To resolve the discrepancy, we expand the exact equations of
motion for small deformations and find that shape changes play a dominant role.
We classify the dynamical phase transitions and obtain numerical and analytical
results for the phase boundaries as a function of viscosity contrast, shear and
elongational flow rate. We conclude with perspectives on timedependent flow, on
shear-induced unbinding from surfaces, on the role of thermal fluctuations, and
on applying the concepts of stochastic thermodynamics to these systems.Comment: 34 pages, 15 figure
Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model
Practically, all chemotherapeutic agents lead to drug resistance. Clinically,
it is a challenge to determine whether resistance arises prior to, or as a
result of, cancer therapy. Further, a number of different intracellular and
microenvironmental factors have been correlated with the emergence of drug
resistance. With the goal of better understanding drug resistance and its
connection with the tumor microenvironment, we have developed a hybrid
discrete-continuous mathematical model. In this model, cancer cells described
through a particle-spring approach respond to dynamically changing oxygen and
DNA damaging drug concentrations described through partial differential
equations. We thoroughly explored the behavior of our self-calibrated model
under the following common conditions: a fixed layout of the vasculature, an
identical initial configuration of cancer cells, the same mechanism of drug
action, and one mechanism of cellular response to the drug. We considered one
set of simulations in which drug resistance existed prior to the start of
treatment, and another set in which drug resistance is acquired in response to
treatment. This allows us to compare how both kinds of resistance influence the
spatial and temporal dynamics of the developing tumor, and its clonal
diversity. We show that both pre-existing and acquired resistance can give rise
to three biologically distinct parameter regimes: successful tumor eradication,
reduced effectiveness of drug during the course of treatment (resistance), and
complete treatment failure
Influence of shear flow on vesicles near a wall: a numerical study
We describe the dynamics of three-dimensional fluid vesicles in steady shear
flow in the vicinity of a wall. This is analyzed numerically at low Reynolds
numbers using a boundary element method. The area-incompressible vesicle
exhibits bending elasticity. Forces due to adhesion or gravity oppose the
hydrodynamic lift force driving the vesicle away from a wall. We investigate
three cases. First, a neutrally buoyant vesicle is placed in the vicinity of a
wall which acts only as a geometrical constraint. We find that the lift
velocity is linearly proportional to shear rate and decreases with increasing
distance between the vesicle and the wall. Second, with a vesicle filled with a
denser fluid, we find a stationary hovering state. We present an estimate of
the viscous lift force which seems to agree with recent experiments of Lorz et
al. [Europhys. Lett., vol. 51, 468 (2000)]. Third, if the wall exerts an
additional adhesive force, we investigate the dynamical unbinding transition
which occurs at an adhesion strength linearly proportional to the shear rate.Comment: 17 pages (incl. 10 figures), RevTeX (figures in PostScript
Establishment of a murine epidermal cell line suitable for in vitro and in vivo skin modelling
<p>Abstract</p> <p>Background</p> <p>Skin diseases are a major health problem. Some of the most severe conditions involve genetic disorders, including cancer. Several of these human diseases have been modelled in genetically modified mice, thus becoming a highly valuable preclinical tool for the treatment of these pathologies. However, development of three-dimensional models of skin using keratinocytes from normal and/or genetically modified mice has been hindered by the difficulty to subculture murine epidermal keratinocytes.</p> <p>Methods</p> <p>We have generated a murine epidermal cell line by serially passaging keratinocytes isolated from the back skin of adult mice. We have termed this cell line COCA. Cell culture is done in fully defined media and does not require feeder cells or any other coating methods.</p> <p>Results</p> <p>COCA retained its capacity to differentiate and stratify in response to increased calcium concentration in the cell culture medium for more than 75 passages. These cells, including late passage, can form epidermis-like structures in three-dimensional <it>in vitro </it>models with a well-preserved pattern of proliferation and differentiation. Furthermore, these cells form epidermis in grafting assays <it>in vivo</it>, and do not develop tumorigenic ability.</p> <p>Conclusions</p> <p>We propose that COCA constitutes a good experimental system for <it>in vitro </it>and <it>in vivo </it>skin modelling. Also, cell lines from genetically modified mice of interest in skin biology could be established using the method we have developed. COCA keratinocytes would be a suitable control, within a similar background, when studying the biological implications of these alterations.</p
Interactions between proteins bound to biomembranes
We study a physical model for the interaction between general inclusions
bound to fluid membranes that possess finite tension, as well as the usual
bending rigidity. We are motivated by an interest in proteins bound to cell
membranes that apply forces to these membranes, due to either entropic or
direct chemical interactions. We find an exact analytic solution for the
repulsive interaction between two similar circularly symmetric inclusions. This
repulsion extends over length scales of order tens of nanometers, and contrasts
with the membrane-mediated contact attraction for similar inclusions on
tensionless membranes. For non circularly symmetric inclusions we study the
small, algebraically long-ranged, attractive contribution to the force that
arises. We discuss the relevance of our results to biological phenomena, such
as the budding of caveolae from cell membranes and the striations that are
observed on their coats.Comment: 22 pages, 2 figure
Predicting Residential Exposure to Phthalate Plasticizer Emitted from Vinyl Flooring: Sensitivity, Uncertainty, and Implications for Biomonitoring
A Functional Role of RB-Dependent Pathway in the Control of Quiescence in Adult Epidermal Stem Cells Revealed by Genomic Profiling
Continuous cell renewal in mouse epidermis is at the expense of a pool of pluripotent cells that lie in a well defined niche in the hair follicle known as the bulge. To identify mechanisms controlling hair follicle stem cell homeostasis, we developed a strategy to isolate adult bulge stem cells in mice and to define their transcriptional profile. We observed that a large number of transcripts are underexpressed in hair follicle stem cells when compared to non-stem cells. Importantly, the majority of these downregulated genes are involved in cell cycle. Using bioinformatics tools, we identified the E2F transcription factor family as a potential element involved in the regulation of these transcripts. To determine their functional role, we used engineered mice lacking Rb gene in epidermis, which showed increased expression of most E2F family members and increased E2F transcriptional activity. Experiments designed to analyze epidermal stem cell functionality (i.e.: hair regrowth and wound healing) imply a role of the Rb-E2F axis in the control of stem cell quiescence in epidermis
- …