Mechanistically Coupled PK (MCPK) Model to Describe Enzyme Induction and Occupancy Dependent DDI of Dabrafenib Metabolism.

Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug-drug interaction mechanisms. The prediction suggests an eight-fold increase in the steady-state concentration of potent desmethyl-dabrafenib and its inactive precursor carboxy-dabrafenib within four weeks upon 150 mg b.d. dabrafenib. While it is generally assumed that a higher dose is not critical, we found experimentally that a high physiological dabrafenib concentration fails to induce cell death in embedded 451LU melanoma spheroids

Critical Temperature of the Deconfining Phase Transition in (2+1)d Georgi-Glashow Model

We find the temperature of the phase transition in the (2+1)d Georgi-Glashow model. The critical temperature is shown to depend on the gauge coupling and on the ratio of Higgs and gauge boson masses. In the BPS limit of light Higgs the previous result by Dunne, Kogan, Kovner, and Tekin is reproduced.Comment: 17 pages, 3 figures, REVTeX

Universal Aspects of Gravity Localized on Thick Branes

We study gravity in backgrounds that are smooth generalizations of the Randall-Sundrum model, with and without scalar fields. These generalizations include three-branes in higher dimensional spaces which are not necessarily Anti-de Sitter far from the branes, intersecting brane configurations and configurations involving negative tension branes. We show that under certain mild assumptions there is a universal equation for the gravitational fluctuations. We study both the graviton ground state and the continuum of Kaluza-Klein modes and we find that the four-dimensional gravitational mode is localized precisely when the effects of the continuum modes decouple at distances larger than the fundamental Planck scale. The decoupling is contingent only on the long-range behaviour of the metric from the brane and we find a universal form for the corrections to Newton's Law. We also comment on the possible contribution of resonant modes. Given this, we find general classes of metrics which maintain localized four-dimensional gravity. We find that three-brane metrics in five dimensions can arise from a single scalar field source, and we rederive the BPS type conditions without any a priori assumptions regarding the form of the scalar potential. We also show that a single scalar field cannot produce conformally-flat locally intersecting brane configurations or a p-brane in greater than (p+2)-dimensions.Comment: 31 pages, 6 figures, latex, JHEP.cls, amsmath, epsf.sty. Comment on the Lykken-Randall scenario added. Minor changes and references adde

Asymptotic structure of Poynting dominated jets

In relativistic, Poynting dominated outflows, acceleration and collimation are intimately connected. An important point is that the Lorentz force is nearly compensated by the electric force therefore the acceleration zone spans a large range of scales. We derived the asymptotic equations describing relativistic, axisymmetric MHD flows far beyond the light cylinder. These equations do not contain either intrinsic small scales (like the light cylinder radius) or terms that nearly cancel each other (like the electric and magnetic forces) therefore they could be easily solved numerically. They also suit well for qualitative analysis of the flow and in many cases, they could even be solved analytically or semi-analytically. We show that there are generally two collimation regimes. In the first regime, the residual of the hoop stress and the electric force is counterbalanced by the pressure of the poloidal magnetic field so that at any distance from the source, the structure of the flow is the same as the structure of an appropriate cylindrical equilibrium configuration. In the second regime, the pressure of the poloidal magnetic field is negligible small so that the flow could be conceived as composed from coaxial shrinking magnetic loops. In the two collimation regimes, the flow is accelerated in different ways. We study in detail the structure of jets confined by the external pressure with a power law profile. In particular, we obtained simple scalings for the extent of the acceleration zone, for the terminal Lorentz factor and for the collimation angle.Comment: Submitted to ApJ; the second version: corrected typos, minor changes in the tex

Dickkopf1 Regulates Fate Decision and Drives Breast Cancer Stem Cells to Differentiation: An Experimentally Supported Mathematical Model

BACKGROUND: Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintained by quorum sensing (QS). METHODOLOGY/PRINCIPAL FINDINGS: To explore the mechanism by which putative QS cellular signals in mammary stem cells (SCs) may regulate SC fate decisions, we developed a multi-scale mathematical model, integrating extra-cellular and intra-cellular signal transduction within the mammary tissue dynamics. Preliminary model analysis of the single cell dynamics indicated that Dickkopf1 (Dkk1), a protein known to negatively regulate the Wnt pathway, can serve as anti-proliferation and pro-maturation signal to the cell. Simulations of the multi-scale tissue model suggested that Dkk1 may be a QS factor, regulating SC density on the level of the whole tissue: relatively low levels of exogenously applied Dkk1 have little effect on SC numbers, whereas high levels drive SCs into differentiation. To verify these model predictions, we treated the MCF-7 cell line and primary breast cancer (BC) cells from 3 patient samples with different concentrations and dosing regimens of Dkk1, and evaluated subsequent formation of mammospheres (MS) and the mammary SC marker CD44(+)CD24(lo). As predicted by the model, low concentrations of Dkk1 had no effect on primary BC cells, or even increased MS formation among MCF-7 cells, whereas high Dkk1 concentrations decreased MS formation among both primary BC cells and MCF-7 cells. CONCLUSIONS/SIGNIFICANCE: Our study suggests that Dkk1 treatment may be more robust than other methods for eliminating CSCs, as it challenges a general cellular homeostasis mechanism, namely, fate decision by QS. The study also suggests that low dose Dkk1 administration may be counterproductive; we showed experimentally that in some cases it can stimulate CSC proliferation, although this needs validating in vivo

Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models

Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols

XIPE: the x-ray imaging polarimetry explorer

XIPE, the X-ray Imaging Polarimetry Explorer, is a mission dedicated to X-ray Astronomy. At the time of writing XIPE is in a competitive phase A as fourth medium size mission of ESA (M4). It promises to reopen the polarimetry window in high energy Astrophysics after more than 4 decades thanks to a detector that efficiently exploits the photoelectric effect and to X-ray optics with large effective area. XIPE uniqueness is time-spectrally-spatially- resolved X-ray polarimetry as a breakthrough in high energy astrophysics and fundamental physics. Indeed the payload consists of three Gas Pixel Detectors at the focus of three X-ray optics with a total effective area larger than one XMM mirror but with a low weight. The payload is compatible with the fairing of the Vega launcher. XIPE is designed as an observatory for X-ray astronomers with 75 % of the time dedicated to a Guest Observer competitive program and it is organized as a consortium across Europe with main contributions from Italy, Germany, Spain, United Kingdom, Poland, Sweden