Modeling Stem/Progenitor Cell-Induced Neovascularization and\ud Oxygenation around Solid Implants

Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O2) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O2-sensitive crystals, consisting of a polymeric capsule limited by a nano-porous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells (BMPC) in order to stimulate peri-implant neovascularization. The sensor provided local partial O2 pressure (pO2) using non-invasive electron paramagnetic resonance (EPR) signal measurements. A consistently higher level of per-implant oxygenation was observed in the cell-treatment case as compared to the control over a 10-week period. In order to provide a mechanistic explanation of these experimental observations, we present in this paper a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a Foreign Body Reaction (FBR) while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO2 to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem celltreated cases

Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications

Extreme value distributions for weakly correlated fitnesses in block model

We study the limit distribution of the largest fitness for two models of weakly correlated and identically distributed random fitnesses. The correlated fitness is given by a linear combination of a fixed number of independent random variables drawn from a common parent distribution. We find that for certain class of parent distributions, the extreme value distribution for correlated random variables can be related either to one of the known limit laws for independent variables or the parent distribution itself. For other cases, new limiting distributions appear. The conditions under which these results hold are identified.Comment: Expanded, added reference

Gravitational lensing constraint on the cosmic equation of state

Recent redshift-distance measurements of Type Ia supernovae (SNe Ia) at cosmological distances suggest that two-third of the energy density of the universe is dominated by dark energy component with an effective negative pressure. This dark energy component is described by the equation of state $p_{x} = w \rho_{x}$ $(w \geq -1)$. We use gravitational lensing statistics to constrain the equation of state of this dark energy. We use $n(\Delta\theta)$, image separation distribution function of lensed quasars, as a tool to probe $w$. We find that for the observed range of $\Omega_m \sim 0.2 - 0.4$, $w$ should lie between $-0.8 \leq w \leq -0.4$ in order to have five lensed quasars in a sample of 867 optical quasars. This limit is highly sensitive to lens and Schechter parameters and evolution of galaxies.Comment: Modified results and inclusion of calculations with new set of parameter

Standard Model with Cosmologically Broken Quantum Scale Invariance

We argue that scale invariance is not anomalous in quantum field theory, provided it is broken cosmologically. We consider a locally scale invariant extension of the Standard Model of particle physics and argue that it fits both the particle and cosmological observations. The model is scale invariant both classically and quantum mechanically. The scale invariance is broken cosmologically producing all the dimensionful parameters. The cosmological constant or dark energy is a prediction of the theory and can be calculated systematically order by order in perturbation theory. It is expected to be finite at all orders. The model does not suffer from the hierarchy problem due to absence of scalar particles, including the Higgs, from the physical spectrum.Comment: 13 pages, no figures significant revisions, no change in results or conclusion

Magneto-Seebeck effect in spin-valve with in-plane thermal gradient

We present measurements of magneto-Seebeck effect on a spin valve with in-plane thermal gradient. We measured open circuit voltage and short circuit current by applying a temperature gradient across a spin valve stack, where one of the ferromagnetic layers is pinned. We found a clear hysteresis in these two quantities as a function of magnetic field. From these measurements, the magneto-Seebeck effect was found to be 0.82%.Comment: 10 Pages, 7 figure

Possible Pairing-Induced Even-Denominator Fractional Quantum Hall Effect in the Lowest Landau Level

We report on our theoretical investigations that point to the possibility of a fractional quantum Hall effect with partial spin polarization at $\nu=3/8$. The physics of the incompressible state proposed here involves p-wave pairing of composite fermions in the spin reversed sector. The temperature and magnetic field regimes for the realization of this state are estimated