2,410 research outputs found
Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer
Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer
Diffuse-Charge Dynamics in Electrochemical Systems
The response of a model micro-electrochemical system to a time-dependent
applied voltage is analyzed. The article begins with a fresh historical review
including electrochemistry, colloidal science, and microfluidics. The model
problem consists of a symmetric binary electrolyte between parallel-plate,
blocking electrodes which suddenly apply a voltage. Compact Stern layers on the
electrodes are also taken into account. The Nernst-Planck-Poisson equations are
first linearized and solved by Laplace transforms for small voltages, and
numerical solutions are obtained for large voltages. The ``weakly nonlinear''
limit of thin double layers is then analyzed by matched asymptotic expansions
in the small parameter , where is the
screening length and the electrode separation. At leading order, the system
initially behaves like an RC circuit with a response time of
(not ), where is the ionic diffusivity, but nonlinearity
violates this common picture and introduce multiple time scales. The charging
process slows down, and neutral-salt adsorption by the diffuse part of the
double layer couples to bulk diffusion at the time scale, . In the
``strongly nonlinear'' regime (controlled by a dimensionless parameter
resembling the Dukhin number), this effect produces bulk concentration
gradients, and, at very large voltages, transient space charge. The article
concludes with an overview of more general situations involving surface
conduction, multi-component electrolytes, and Faradaic processes.Comment: 10 figs, 26 pages (double-column), 141 reference
A mathematical model of tumour & blood pHe regulation: The HCO-3/CO2 buffering system
Malignant tumours are characterised by a low, acidic extracellular pH (pHe) which facilitates invasion and metastasis. Previous research has proposed the potential benefits of manipulating systemic pHe, and recent experiments have highlighted the potential for buffer therapy to raise tumour pHe, prevent metastases, and prolong survival in laboratory mice. To examine the physiological regulation of tumour buffering and investigate how perturbations of the buffering system (via metabolic/respiratory disorders or changes in parameters) can alter tumour and blood pHe, we develop a simple compartmentalised ordinary differential equation model of pHe regulation by the View the MathML source buffering system. An approximate analytical solution is constructed and used to carry out a sensitivity analysis, where we identify key parameters that regulate tumour pHe in both humans and mice. From this analysis, we suggest promising alternative and combination therapies, and identify specific patient groups which may show an enhanced response to buffer therapy. In addition, numerical simulations are performed, validating the model against well-known metabolic/respiratory disorders and predicting how these disorders could change tumour pHe
Distinct Transmission Cycles of Leishmania tropica in 2 Adjacent Foci, Northern Israel
TOC summary for table of contents: Infection with Leishmania tropica is emerging because of encroachment of rock hyraxes and transmission by multiple vector species
Dynamic Phase Transition in a Time-Dependent Ginzburg-Landau Model in an Oscillating Field
The Ginzburg-Landau model below its critical temperature in a temporally
oscillating external field is studied both theoretically and numerically. As
the frequency or the amplitude of the external force is changed, a
nonequilibrium phase transition is observed. This transition separates
spatially uniform, symmetry-restoring oscillations from symmetry-breaking
oscillations. Near the transition a perturbation theory is developed, and a
switching phenomenon is found in the symmetry-broken phase. Our results confirm
the equivalence of the present transition to that found in Monte Carlo
simulations of kinetic Ising systems in oscillating fields, demonstrating that
the nonequilibrium phase transition in both cases belongs to the universality
class of the equilibrium Ising model in zero field. This conclusion is in
agreement with symmetry arguments [G. Grinstein, C. Jayaprakash, and Y. He,
Phys. Rev. Lett. 55, 2527 (1985)] and recent numerical results [G. Korniss,
C.J. White, P. A. Rikvold, and M. A. Novotny, Phys. Rev. E (submitted)].
Furthermore, a theoretical result for the structure function of the local
magnetization with thermal noise, based on the Ornstein-Zernike approximation,
agrees well with numerical results in one dimension.Comment: 16 pp. RevTex, 9 embedded ps figure
Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study
Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud
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Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud
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Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud
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Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising
Random walk with barriers: Diffusion restricted by permeable membranes
Restrictions to molecular motion by barriers (membranes) are ubiquitous in
biological tissues, porous media and composite materials. A major challenge is
to characterize the microstructure of a material or an organism
nondestructively using a bulk transport measurement. Here we demonstrate how
the long-range structural correlations introduced by permeable membranes give
rise to distinct features of transport. We consider Brownian motion restricted
by randomly placed and oriented permeable membranes and focus on the
disorder-averaged diffusion propagator using a scattering approach. The
renormalization group solution reveals a scaling behavior of the diffusion
coefficient for large times, with a characteristically slow inverse square root
time dependence. The predicted time dependence of the diffusion coefficient
agrees well with Monte Carlo simulations in two dimensions. Our results can be
used to identify permeable membranes as restrictions to transport in disordered
materials and in biological tissues, and to quantify their permeability and
surface area.Comment: 8 pages, 3 figures; origin of dispersion clarified, refs adde
Genetic, serological and biochemical characterization of Leishmania tropica from foci in northern Palestine and discovery of zymodeme MON-307
Background
Many cases of cutaneous leishmaniasis (CL) have been recorded in the Jenin District based on their clinical appearance. Here, their parasites have been characterized in depth.
Methods
Leishmanial parasites isolated from 12 human cases of CL from the Jenin District were cultured as promastigotes, whose DNA was extracted. The ITS1 sequence and the 7SL RNA gene were analysed as was the kinetoplast minicircle DNA (kDNA) sequence. Excreted factor (EF) serotyping and multilocus enzyme electrophoresis (MLEE) were also applied.
Results
This extensive characterization identified the strains as Leishmania tropica of two very distinct sub-types that parallel the two sub-groups discerned by multilocus microsatellite typing (MLMT) done previously. A high degree of congruity was displayed among the results generated by the different analytical methods that had examined various cellular components and exposed intra-specific heterogeneity among the 12 strains.
Three of the ten strains subjected to MLEE constituted a new zymodeme, zymodeme MON-307, and seven belonged to the known zymodeme MON-137. Ten of the 15 enzymes in the profile of zymodeme MON-307 displayed different electrophoretic mobilities compared with the enzyme profile of the zymodeme MON-137. The closest profile to that of zymodeme MON-307 was that of the zymodeme MON-76 known from Syria.
Strains of the zymodeme MON-307 were EF sub-serotype A2 and those of the zymodeme MON-137 were either A9 or A9B4. The sub-serotype B4 component appears, so far, to be unique to some strains of L. tropica of zymodeme MON-137. Strains of the zymodeme MON-137 displayed a distinctive fragment of 417 bp that was absent in those of zymodeme MON-307 when their kDNA was digested with the endonuclease RsaI. kDNA-RFLP after digestion with the endonuclease MboI facilitated a further level of differentiation that partially coincided with the geographical distribution of the human cases from which the strains came.
Conclusions
The Palestinian strains that were assigned to different genetic groups differed in their MLEE profiles and their EF types. A new zymodeme, zymodeme MON-307 was discovered that seems to be unique to the northern part of the Palestinian West Bank. What seemed to be a straight forward classical situation of L. tropica causing anthroponotic CL in the Jenin District might be a more complex situation, owing to the presence of two separate sub-types of L. tropica that, possibly, indicates two separate transmission cycles involving two separate types of phlebotomine sand fly vector
Dynamic Phase Transition, Universality, and Finite-size Scaling in the Two-dimensional Kinetic Ising Model in an Oscillating Field
We study the two-dimensional kinetic Ising model below its equilibrium
critical temperature, subject to a square-wave oscillating external field. We
focus on the multi-droplet regime where the metastable phase decays through
nucleation and growth of many droplets of the stable phase. At a critical
frequency, the system undergoes a genuine non-equilibrium phase transition, in
which the symmetry-broken phase corresponds to an asymmetric stationary limit
cycle for the time-dependent magnetization. We investigate the universal
aspects of this dynamic phase transition at various temperatures and field
amplitudes via large-scale Monte Carlo simulations, employing finite-size
scaling techniques adopted from equilibrium critical phenomena. The critical
exponents, the fixed-point value of the fourth-order cumulant, and the critical
order-parameter distribution all are consistent with the universality class of
the two-dimensional equilibrium Ising model. We also study the cross-over from
the multi-droplet to the strong-field regime, where the transition disappears
Canine leishmaniosis and its relationship to human visceral leishmaniasis in Eastern Uzbekistan
<p>Abstract</p> <p>Background</p> <p>The Namangan Region in the Pap District, located in Eastern Uzbekistan is the main focus of visceral leishmaniasis (VL) in Uzbekistan. In total, 28 cases of human VL were registered during 2006-2008 in this region. A study on the epidemiology of VL in this area was carried out in 2007-2008 in the villages of Chodak, Oltinkan, Gulistan and Chorkesar located at elevations of 900-1200 above sea level.</p> <p>Results</p> <p>A total of 162 dogs were tested for <it>Leishmania </it>infection. Blood was drawn for serology and PCR. When clinical signs of the disease were present, aspirates from lymph nodes and the spleen were taken. Forty-two dogs (25.9%) had clinical signs suggestive of VL and 51 (31.5%) were sero-positive. ITS-1 PCR was performed for 135 dogs using blood and tissue samples and 40 (29.6%) of them were PCR-positive. Leishmanial parasites were cultured from lymph node or spleen aspirates from 10 dogs.</p> <p>Eight <it>Leishmania </it>strains isolated from dogs were typed by multi-locus microsatellite typing (MLMT) and by multilocus enzyme electrophoretic analysis (MLEE), using a 15 enzyme system. These analyses revealed that the strains belong to the most common zymodeme of <it>L. infantum</it>, i.e., MON-1, and form a unique group when compared to MON-1 strains from other geographical regions.</p> <p>Conclusions</p> <p>The data obtained through this study confirm the existence of an active focus of VL in the Namangan region of Uzbekistan. The fact that <it>L. infantum </it>was the causative agent of canine infection with typical clinical signs, and also of human infection affecting only infants, suggests that a zoonotic form of VL similar in epidemiology to Mediterranean VL is present in Uzbekistan.</p
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