Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence

Parton cascade description of relativistic heavy-ion collisions at CERN SPS energies ?

We examine Pb+Pb collisions at CERN SPS energy 158 A GeV, by employing the earlier developed and recently refined parton-cascade/cluster-hadronization model and its Monte Carlo implementation. This space-time model involves the dynamical interplay of perturbative QCD parton production and evolution, with non-perturbative parton-cluster formation and hadron production through cluster decays. Using computer simulations, we are able to follow the entwined time-evolution of parton and hadron degrees of freedom in both position and momentum space, from the instant of nuclear overlap to the final yield of particles. We present and discuss results for the multiplicity distributions, which agree well with the measured data from the CERN SPS, including those for K mesons. The transverse momentum distributions of the produced hadrons are also found to be in good agreement with the preliminary data measured by the NA49 and the WA98 collaboration for the collision of lead nuclei at the CERN SPS. The analysis of the time evolution of transverse energy deposited in the collision zone and the energy density suggests an existence of partonic matter for a time of more than 5 fm.Comment: 16 pages including 7 postscript figure

Simulation of Light Antinucleus-Nucleus Interactions

Creations of light anti-nuclei (anti-deuterium, anti-tritium, anti-He3 and anti-He4) are observed by collaborations at the LHC and RHIC accelerators. Some cosmic ray experiments are aimed to find the anti-nuclei in cosmic rays. To support the experimental studies of the anti-nuclei a Monte Carlo simulation of anti-nuclei interactions with matter is implemented in the Geant4 toolkit. The implementation combines practically all known theoretical approaches to the problem of antinucleon-nucleon interactions.Comment: 8 pages, 5 figure

Synergistic and antagonistic effects of land use and non‐native species on community responses to climate change

Climate change, land‐use change and introductions of non‐native species are key determinants of biodiversity change worldwide. However, the extent to which anthropogenic drivers of environmental change interact to affect biological communities is largely unknown, especially over longer time periods. Here, we show that plant community composition in 996 Swedish landscapes has consistently shifted to reflect the warmer and wetter climate that the region has experienced during the second half of the 20th century. Using community climatic indices, which reflect the average climatic associations of the species within each landscape at each time period, we found that species compositions in 74% of landscapes now have a higher representation of warm‐associated species than they did previously, while 84% of landscapes now host more species associated with higher levels of precipitation. In addition to a warmer and wetter climate, there have also been large shifts in land use across the region, while the fraction of non‐native species has increased in the majority of landscapes. Climatic warming at the landscape level appeared to favour the colonization of warm‐associated species, while also potentially driving losses in cool‐associated species. However, the resulting increases in community thermal means were apparently buffered by landscape simplification (reduction in habitat heterogeneity within landscapes) in the form of increased forest cover. Increases in non‐native species, which generally originate from warmer climates than Sweden, were a strong driver of community‐level warming. In terms of precipitation, both landscape simplification and increases in non‐natives appeared to favour species associated with drier climatic conditions, to some extent counteracting the climate‐driven shift towards wetter communities. Anthropogenic drivers can act both synergistically and antagonistically to determine trajectories of change in biological communities over time. Therefore, it is important to consider multiple drivers of global change when trying to understand, manage and predict biodiversity in the future

Relativistic Heavy--Ion Collisions in the Dynamical String--Parton Model

We develop and extend the dynamical string parton model. This model, which is based on the salient features of QCD, uses classical Nambu-Got\=o strings with the endpoints identified as partons, an invariant string breaking model of the hadronization process, and interactions described as quark-quark interactions. In this work, the original model is extended to include a phenomenological quantization of the mass of the strings, an analytical technique for treating the incident nucleons as a distribution of string configurations determined by the experimentally measured structure function, the inclusion of the gluonic content of the nucleon through the introduction of purely gluonic strings, and the use of a hard parton-parton interaction taken from perturbative QCD combined with a phenomenological soft interaction. The limited number of parameters in the model are adjusted to $e^+e^-$ and $p$--$p$ data. Utilizing these parameters, the first calculations of the model for $p$--$A$ and $A$--$A$ collisions are presented and found to be in reasonable agreement with a broad set of data.Comment: 26 pages of text with 23 Postscript figures placed in tex

Evaluation of rate law approximations in bottom-up kinetic models of metabolism.

BackgroundThe mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question.ResultsIn this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations.ConclusionsOverall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches

Determinants of serum levels of vitamin D: a study of life-style, menopausal status, dietary intake, serum calcium, and PTH

Background: Low blood levels of vitamin D (25-hydroxy D3, 25OHD3) in women have been associated with an increased risk of several diseases. A large part of the population may have suboptimal 25OHD3 levels but high-risk groups are not well known. The aim of the present study was to identify determinants for serum levels of 25OHD3 in women, i.e. factors such as lifestyle, menopausal status, diet and selected biochemical variables. Methods: The study was based on women from the Malmo Diet and Cancer Study (MDCS), a prospective, population-based cohort study in Malmo, Sweden. In a previous case-control study on breast cancer, 25OHD3 concentrations had been measured in 727 women. In these, quartiles of serum 25OHD3 were compared with regard to age at baseline, BMI (Body Max Index), menopausal status, use of oral contraceptives or menopausal hormone therapy (MHT), life-style (e. g. smoking and alcohol consumption), socio-demographic factors, season, biochemical variables (i.e. calcium, PTH, albumin, creatinine, and phosphate), and dietary intake of vitamin D and calcium. In order to test differences in mean vitamin D concentrations between different categories of the studied factors, an ANOVA test was used followed by a t-test. The relation between different factors and 25OHD3 was further investigated using multiple linear regression analysis and a logistic regression analysis. Results: We found a positive association between serum levels of 25OHD3 and age, oral contraceptive use, moderate alcohol consumption, blood collection during summer/autumn, creatinine, phosphate, calcium, and a high intake of vitamin D. Low vitamin D levels were associated with obesity, being born outside Sweden and high PTH levels. Conclusions: The present population-based study found a positive association between serum levels of 25OHD3 and to several socio-demographic, life-style and biochemical factors. The study may have implications e. g. for dietary recommendations. However, the analysis is a cross-sectional and it is difficult to suggest Lifestyle changes as cause-effect relationships are difficult to assess

Lower Blood Calcium Associates with Unfavorable Prognosis and Predicts for Bone Metastasis in NSCLC

Ionized calcium was involved in various cellular signal pathways,and regulates many cellular processes, including those relevant to tumorigenesis. We hypothesis that imbalance of calcium homeostasis is correlated with development of lung carcinomas. We collected the clinical data of 1084 patients with non small cell lung cancer (NSCLC) treated in Shandong Provincial Hospital, Shandong University. Logistic regression was used to determine the association between calcium levels and clinical characteristics, and COX regression and Kaplan-Meier model were applied to analyze risk factors on overall survival. Blood electrolytes were tested before treatment; and nearly 16% patients with NSCLC were complained with decreased blood calcium, which is more frequent than that in other electrolytes. Further, Multivariate logistic regression analysis disclosed that there were significant correlation between blood calcium decrease and moderate and poor differentiation (P = 0.012, OR = 1.926 (1.203–4.219)), squamous cell carcinoma (P = 0.024, OR = 1.968(1.094–3.540)), and bone metastasis (P = 0.032, OR = 0.396(0.235–0.669)). In multivariate COX regression analysis, advanced lymph node stage and decreased blood calcium were significantly and independent, unfavorable prognostic factors (P<0.001). Finally, the Kaplan-Meier Survival curve revealed that blood calcium decrease was associated with shorter survival (Log-rank; χ2 = 26.172,P<0.001). Our finding indicates that lower blood calcium levels are associated with a higher risk of unfavorable prognosis and bone metastasis of NSCLC