Pharmacokinetic Modeling of an Induction Regimen for In Vivo Combined Testing of Novel Drugs against Pediatric Acute Lymphoblastic Leukemia Xenografts

Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL), or for re-induction post relapse, use a combination of vincristine (VCR), a glucocorticoid, and l-asparaginase (ASP) with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX) and ASP (VXL) against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL

Historic and Recent Distributions of Elk in Nebraska

Elk (Cervus elaphus) were historically found throughout North America but were extirpated from Nebraska and much of the Great Plains in the 1880s due to consumptive uses by settlers, miners, market hunters, and others. Elk began to reappear in Nebraska in the 1950s and 1960s, and established a stable, nonmigratory population that currently consists of seven herds and an estimated 1,400 individuals throughout western and central Nebraska. The reappearance and subsequent persistence of elk in Nebraska suggests there is adequate habitat to support a self-sustaining population. The general movement of elk eastward may lead to an eventual statewide distribution, and populations being established in states to the east and south of Nebraska, where elk populations were historically present and suitable habitat still exists. We examined published historic accounts, museum and archeological records, and current literature to determine historic and current distribution of elk in Nebraska and the Great Plains

Effect of selected factors on reproductive characteristics of dairy cows

The aim of the thesis was to evaluate the effect of selected factors on the reproductive characteristics of Montbeliard dairy cows. Hypothesis said that high milk production, poor health and high air temperatures have a negative effect on reproductive indicators of cows. In the literature review, there were summarized knowledge about the factors affecting fertility, reproductive indicators and a description of the breed. Observation was carried out on the farm Osičky, which is one of the centers of the company Agrodružstvo Lhota pod Libčany. To assess the influence of milk yield and health were monitored all standard lactations of dairy cows, which were completed in the period from 1. 1. 2014 to 31. 12. 2015. This gave rise to a set of 632 lactations. To evaluate the milk production was data set divided by the number of lactation, quarter of calving and the rate of milk production into three groups. As a disease with an expected negative impact on fertility, mastitis was selected. Besides air temperature, the relative humidity was assessed too. Indicators such as days open, days from calving to calving and services per conception were evaluated. In order to assess the impact of climate change on fertility data file was divided into 3 groups of air temperature, by quarter, according to the category of cows and by calendar year. Services per conception, pregnancy after the first insemination and pregnancy after all insemination, were assessed. Data could be obtained only from a whole herd of cows and heifers. For statistical evaluation has been used SAS 9.3 software (SAS / STAT 9.3, 2011). Achieved an average length of days open was 98.07 days, days from calving to calving 380.62 days, services per conception was 1.94, pregnancy after the first insemination in heifers 54.28% and 48.43% in cows, yield per lactation was 8 407, 98 kg of milk with fat contents of 3.65 % and a protein contents of 3.53 %. Mastitis occurred only in 17.72 % of cases. The average monthly air temperature during the year 2014 ranged from 1.3 ° C to 21.2 ° C, in 2015 it was 1.5 ° C - 23.2 ° C. From the results of the regression analysis, it was found that the milk production per lactation had a statistically significant effect on the length of the days open (r = 0.214; P 0.05). Effect of air temperature on services per conception, pregnancy after the first insemination and pregnancy after all insemination, was not statistically proven (P > 0.05). Furthermore it has been approved many correlations between different parameters at the levels of significance (P < 0.001, P < 0.05). The hypothesis was confirmed only for the negative impact of high milk production, but the impact of poor health and high air temperatures on reproduction was not approved. The results indicate a healthy herd in terms of mastitis, good management of breeding, which minimizes heat stress and which is of relatively high milk yield and proven negative impact of high milk production to reproduction, achieved a good level of reproduction

Heliopause explorer: a sailcraft mission to the outer boundaries of the solar system

Solar sail technology holds the promise of enhancing the interplanetary transportation infrastructure for low-cost space exploration missions in the new millennium, by exploiting the freely available, space-pervading resource of solar radiation pressure for primary propulsion. Despite the large distances to the Sun and the reduced solar radiation pressure, fast missions to the outer edge of our solar system belong to the promising mission applications of solar sails. In order to realize such a mission, the sailcraft would first perform a so-called "solar photonic assist", approaching the Sun to less than 0.3 AU thus exploiting the increased solar radiation pressure, to pick up enough orbital energy to enter a hyperbolic orbit. This concept has been extended to a double and triple solar approach which reduces the requirement for very high area-to-mass ratios of the sailcraft. The target distance of the Heliopause Explorer mission is set to 200 AU. The science objective was defined as to allow the Heliopause Explorer to perform in situ observations which cannot be obtained within the remaining life time of the two Voyager spacecraft. A first feasibility study was initiated to derive technology requirements for the realization of such a challenging deep space mission

Estimated pharmacokinetic parameters.

‡<p>Abbreviations. AUC_0-∞: Area under the concentration-time curve from zero to infinity; C_max: actual maximum concentration observed after drug administration; T_max: time of maximum drug concentration.</p

Synergy between VCR, DEX and ASP against ALL cell lines <i>in vitro</i>.

<p>Cell lines were exposed to VCR (open circles), DEX (open triangles), ASP (open squares), or the triple combination VXL (closed circles), at fixed ratios, and dose-responses were assessed using the DIMSCAN assay as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033894#s4" target="_blank">Materials and methods</a>. Fractional survival of treated vs. untreated control cells is shown. Each condition included 12 replicates and error bars represent standard deviation. The data shown are representative of two independent experiments.</p

<i>In vivo</i> sensitivity of ALL xenografts to VXL and VXL/ABT-737 combination treatments.

<p>Female mice were engrafted with: ALL-2 (<b>A</b>); ALL-8 (<b>B</b>); ALL-10 (<b>C</b>); or ALL-17 (<b>D</b>) and treated with a diluent vehicle (controls, dashed black lines), ABT-737 (25 mg/kg, solid grey lines), VXL combination (solid black lines), or VXL+ABT-737 quadruple combination (dashed grey lines). Engraftment kinetics indicated by %huCD45⁺ cells in PB of individual mice (left panel) and Kaplan-Meier survival curves (EFS) (right panel) are shown. Shaded boxes represent the treatment period. All events were leukemia-related except for 1 and 4 in the VXL/ABT-737-treated group of the ALL-8, and ALL-10, respectively. In the ALL-17 quadruple drug combination cohort all mice were culled due to leukemia or toxicity unrelated morbidity.</p