Two-Type Age-Dependent Branching Processes with Inhomogeneous Immigration as Models of Renewing Cell Population

2000 Mathematics Subject Classification: primary 60J80; secondary 60J85, 92C37.Two-type reducible age-dependent branching processes with inhomogeneous immigration are considered to describe the kinetics of renewing cell populations. This class of processes can be used to model the generation of oligodendrocytes in the central nervous system in vivo or the kinetics of leukemia cells. The asymptotic behavior of the first and second moments, including the correlation, of the process is investigated.This research was supported by NIH grants 2R01 NS039511, R01 CA134839, and 1R01 AI069351

An age-dependent branching process model for the analysis of CFSE-labeling experiments

<p>Abstract</p> <p>Background</p> <p>Over the past decade, flow cytometric CFSE-labeling experiments have gained considerable popularity among experimentalists, especially immunologists and hematologists, for studying the processes of cell proliferation and cell death. Several mathematical models have been presented in the literature to describe cell kinetics during these experiments.</p> <p>Results</p> <p>We propose a multi-type age-dependent branching process to model the temporal development of populations of cells subject to division and death during CFSE-labeling experiments. We discuss practical implementation of the proposed model; we investigate a competing risk version of the process; and we identify the classes of cellular dependencies that may influence the expectation of the process and those that do not. An application is presented where we study the proliferation of human CD8+ T lymphocytes using our model and a competing risk branching process.</p> <p>Conclusions</p> <p>The proposed model offers a widely applicable approach to the analysis of CFSE-labeling experiments. The model fitted very well our experimental data. It provided reasonable estimates of cell kinetics parameters as well as meaningful insights into the processes of cell division and cell death. In contrast, the competing risk branching process could not describe the kinetics of CD8+ T cells. This suggested that the decision of cell division or cell death may be made early in the cell cycle if not in preceding generations. Also, we show that analyses based on the proposed model are robust with respect to cross-sectional dependencies and to dependencies between fates of linearly filiated cells.</p> <p>Reviewers</p> <p>This article was reviewed by Marek Kimmel, Wai-Yuan Tan and Peter Olofsson.</p

Poisson Random Measures and Noncritical Multitype Markov Branching Processes

We investigate noncritical multi-type Markov branching processes with immigration generated by Poisson measures. Limiting distributions are obtained when the rates of the Poisson measures are asymptotically equivalent to exponential or regularly varying functions. In particular, results analogous to a strong LLN are presented, and limiting normal distributions are obtained when the rates increase. When the rates decrease, then conditional limiting distributions are established. A stationary limiting distribution is obtained when the mean Poisson measure grows linearly. The asymptotic behaviour of the first and second moments of the processes is also investigated.NFSR of the Ministry of Education and Science of Bulgaria, grant No. KP–06-H22/3

Preclinical and Pilot Clinical Studies of Docetaxel Chemoradiation for Stage III Non–Small-Cell Lung Cancer

Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for stage III non-small cell lung cancer (NSCLC). We conducted preclinical studies of docetaxel cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications

A Flexible Copula Model for Bivariate Survival Data

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biostatistics and Computational Biology, 2012.Copulas are bevariate distributions with uniform marginals. They provide a general method for binding several univariate marginal distributions together to form a multivariate distribution. Following Clayton (1978), several families of single-parameter copula models have been proposed for analyzing survival data. This dissertation explores the use of a flexible two-parameter copula family for bivariate survival data. The two parameters reflect respectively lower and upper tail dependence, allowing these two important aspects of a bivariate distribution to be modeled separately. The basic properties of this family are described and investigated. Under parametric assumptions on the univariate marginals, besides the commonly used one-stage M.L.E., a two-stage parametric estimator is developed for the dependence parameters. In addition we study a semi-parametric generalization of the two-stage approach in which the two marginal distributions are estimated nonparametrically. The asymptotic properties of all proposed estimators are derived and finite sample properties under different censorship scenarios are assessed by simulation. We find that the one-stage and two-stage parametric estimators perform similarly, with somewhat lower variances than the two-stage semi-parametric estimator. Robustness of the parametric estimator to the specification of the marginals is explored. We also design and implement a goodness-of-fit test for model checking, and a model selection test for choosing the best model among commonly used copula families. The practical application of the proposed two-parameter model is illustrated through a data example

Molecular Accessibility in Relation to Cell Surface Topography and Compression Against a Flat Substrate

The recruitment of cells to the vascular wall in vivo or the capture of cell subpopulations at the surface of a fabricated device requires the formation of bonds between specific molecular pairs on the cell and the substrate. The ability of a molecule to form a bond depends critically on its localization relative to the cell surface topography. In this report, we present a framework for the quantitative assessment of molecular availability that accounts for the deformability of the cell surface and the balance of forces in the interface, as well as the variability of surface protrusion lengths and the preference for molecules to reside at or away from the tips of surface projections. We also examined how molecular availability should change with increasing compression of the cell against the substrate. Finally, we convolved the distribution of molecules at the interface with a decaying evanescent excitation to predict the fluorescence intensity in total internal reflectance fluorescence microscopy, which can provide a quantitative measure of the relative availability of different molecules at a cell-substrate interface. Model predictions show good agreement with measurements of fluorescence intensity of different molecules labeled fluorescently on the surface of a human neutrophil compressed against a glass surface