Modeling Mechanisms of In Vivo Variability in Methotrexate Accumulation and Folate Pathway Inhibition in Acute Lymphoblastic Leukemia Cells

Methotrexate (MTX) is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL). The accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), in ALL cells is an important determinant of its antileukemic effects. We studied 194 of 356 patients enrolled on St. Jude Total XV protocol for newly diagnosed ALL with the goal of characterizing the intracellular pharmacokinetics of MTXPG in leukemia cells; relating these pharmacokinetics to ALL lineage, ploidy and molecular subtype; and using a folate pathway model to simulate optimal treatment strategies. Serial MTX concentrations were measured in plasma and intracellular MTXPG concentrations were measured in circulating leukemia cells. A pharmacokinetic model was developed which accounted for the plasma disposition of MTX along with the transport and metabolism of MTXPG. In addition, a folate pathway model was adapted to simulate the effects of treatment strategies on the inhibition of de novo purine synthesis (DNPS). The intracellular MTXPG pharmacokinetic model parameters differed significantly by lineage, ploidy, and molecular subtypes of ALL. Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes. In addition, the folate pathway model showed differential inhibition of DNPS relative to MTXPG accumulation, MTX dose, and schedule. This study has provided new insights into the intracellular disposition of MTX in leukemia cells and how it affects treatment efficacy

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Gamma-ray and radio properties of six pulsars detected by the fermi large area telescope

We report the detection of pulsed γ-rays for PSRs J0631+1036, J0659+1414, J0742-2822, J1420-6048, J1509-5850, and J1718-3825 using the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (formerly known as GLAST). Although these six pulsars are diverse in terms of their spin parameters, they share an important feature: their γ-ray light curves are (at least given the current count statistics) single peaked. For two pulsars, there are hints for a double-peaked structure in the light curves. The shapes of the observed light curves of this group of pulsars are discussed in the light of models for which the emission originates from high up in the magnetosphere. The observed phases of the γ-ray light curves are, in general, consistent with those predicted by high-altitude models, although we speculate that the γ-ray emission of PSR J0659+1414, possibly featuring the softest spectrum of all Fermi pulsars coupled with a very low efficiency, arises from relatively low down in the magnetosphere. High-quality radio polarization data are available showing that all but one have a high degree of linear polarization. This allows us to place some constraints on the viewing geometry and aids the comparison of the γ-ray light curves with high-energy beam models

ERRATUM: "FERMI DETECTION OF γ-RAY EMISSION FROM THE M2 SOFT X-RAY FLARE ON 2010 JUNE 12" (2012, ApJ, 745, 144)

Due to an error at the publisher, the times given for the major tick marks in the X-axis in Figure 1 of the published article are incorrect. The correctly labeled times should be "00:52:00," "00:54:00," ... , and "01:04:00." The correct version of Figure 1 and its caption is shown below. IOP Publishing sincerely regrets this error

Multiple Scenario Generation of Subsurface Models:Consistent Integration of Information from Geophysical and Geological Data throuh Combination of Probabilistic Inverse Problem Theory and Geostatistics

Neutrinos with energies above 1017 eV are detectable with the Surface Detector Array of the Pierre Auger Observatory. The identification is efficiently performed for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for Earth-skimming \u3c4 neutrinos with nearly tangential trajectories relative to the Earth. No neutrino candidates were found in 3c 14.7 years of data taken up to 31 August 2018. This leads to restrictive upper bounds on their flux. The 90% C.L. single-flavor limit to the diffuse flux of ultra-high-energy neutrinos with an E\u3bd-2 spectrum in the energy range 1.0 7 1017 eV -2.5 7 1019 eV is E2 dN\u3bd/dE\u3bd &lt; 4.4 7 10-9 GeV cm-2 s-1 sr-1, placing strong constraints on several models of neutrino production at EeV energies and on the properties of the sources of ultra-high-energy cosmic rays

Régulateurs supérieurs et valeurs spéciales de la fonction L de degré huit de GSp(4) x GL(2)

In order to prove Beilinson conjectures, we link the image of an element through the Beilinson regulator in the Deligne cohomology of a product of a Siegel variety and a modular curve respectively, to the special value in 1 of the degree-eight L- function of GSp(4)xGL(2) associated to a product of automorphic generic admissible cuspidal representations of GSp(4) and GL(2) respectively, in the case where this function is entire. After defining the objects we will use in this thesis, namely motivic cohomology, Beilinson regulator and Shimura varieties, we construct in chapter 3 a differential form based on certain automorphic representations, whose proprieties will be precised. This differential form will have a key role in constructing in chapter 5 a linear form defined on the Deligne cohomology, which will be useful in chapter 6 in order to pairing the Beilinson regulator with the differential form previously introduced. Finally, our work will conclude in chapter 7 where we will enlighten the link between the Beilinson regulator and our L-function.En vue des conjectures de Beilinson, nous relions l'image d'un élément par le régulateur de Beilinson dans la cohomologie de Deligne d'un produit d'une variété de Siegel et d'une courbe modulaire respectivement, à la valeur spéciale en 1 de la fonction L de degré huit de GSp(4)xGL(2) associée à un produit de représentations automorphes admissibles cuspidales génériques de GSp(4,A) et GL(2,A) respectivement, dans le cas où celle-ci est enière. Après avoir rappelé les définitions des objets que nous utiliserons dans cette thèse, notamment la cohomologie motivique, le régulateur de Beilinson et les variétés de Shimura, nous construisons dans le chapitre 3 une forme différentielle à partir de certaines représentations automorphes dont nous préciserons les propriétés. Cette forme différentielle sera au coeur de la construction dans le chapitre 5 d'une forme linéaire définie sur un certain espace de cohomologie de Deligne, laquelle nous permettra dans le chapitre 6d'accoupler le régulateur de Beilinson avec la forme différentielle précédemment construite. Enfin, notre travail trouvera sa conclusion dans le chapitre 7 où nous mettrons en évidence le lien entre le régulateur de Beilinson et la fonction L sus-mentionnée

Higher regulators and special values of the degree-eight L-function of GSp(4)xGL(2).

En vue des conjectures de Beilinson, nous relions l'image d'un élément par le régulateur de Beilinson dans la cohomologie de Deligne d'un produit d'une variété de Siegel et d'une courbe modulaire respectivement, à la valeur spéciale en 1 de la fonction L de degré huit de GSp(4)xGL(2) associée à un produit de représentations automorphes admissibles cuspidales génériques de GSp(4,A) et GL(2,A) respectivement, dans le cas où celle-ci est enière. Après avoir rappelé les définitions des objets que nous utiliserons dans cette thèse, notamment la cohomologie motivique, le régulateur de Beilinson et les variétés de Shimura, nous construisons dans le chapitre 3 une forme différentielle à partir de certaines représentations automorphes dont nous préciserons les propriétés. Cette forme différentielle sera au coeur de la construction dans le chapitre 5 d'une forme linéaire définie sur un certain espace de cohomologie de Deligne, laquelle nous permettra dans le chapitre 6d'accoupler le régulateur de Beilinson avec la forme différentielle précédemment construite. Enfin, notre travail trouvera sa conclusion dans le chapitre 7 où nous mettrons en évidence le lien entre le régulateur de Beilinson et la fonction L sus-mentionnée.In order to prove Beilinson conjectures, we link the image of an element through the Beilinson regulator in the Deligne cohomology of a product of a Siegel variety and a modular curve respectively, to the special value in 1 of the degree-eight L- function of GSp(4)xGL(2) associated to a product of automorphic generic admissible cuspidal representations of GSp(4) and GL(2) respectively, in the case where this function is entire. After defining the objects we will use in this thesis, namely motivic cohomology, Beilinson regulator and Shimura varieties, we construct in chapter 3 a differential form based on certain automorphic representations, whose proprieties will be precised. This differential form will have a key role in constructing in chapter 5 a linear form defined on the Deligne cohomology, which will be useful in chapter 6 in order to pairing the Beilinson regulator with the differential form previously introduced. Finally, our work will conclude in chapter 7 where we will enlighten the link between the Beilinson regulator and our L-function

Introduction

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