In vitro and in silico multidimensional modeling of oncolytic tumor virotherapy dynamics.

Tumor therapy with replication competent viruses is an exciting approach to cancer eradication where viruses are engineered to specifically infect, replicate, spread and kill tumor cells. The outcome of tumor virotherapy is complex due to the variable interactions between the cancer cell and virus populations as well as the immune response. Oncolytic viruses are highly efficient in killing tumor cells in vitro, especially in a 2D monolayer of tumor cells, their efficiency is significantly lower in a 3D environment, both in vitro and in vivo.

Tumour and immune cell dynamics explain the PSA bounce after prostate cancer brachytherapy.

Background: Interstitial brachytherapy for localised prostate cancer may be followed by transient increases in prostate-specific antigen (PSA) that resolve without therapy. Such PSA bounces may be associated with an improved outcome but often cause alarm in the patient and physician, and have defied explanation.

Methods: We developed a mathematical model to capture the interactions between the tumour, radiation and anti-tumour immune response.

Controlled Delivery of Vancomycin via Charged Hydrogels.

Surgical site infection (SSI) remains a significant risk for any clean orthopedic surgical procedure. Complications resulting from an SSI often require a second surgery and lengthen patient recovery time. The efficacy of antimicrobial agents delivered to combat SSI is diminished by systemic toxicity, bacterial resistance, and patient compliance to dosing schedules.

A gamma variate model that includes stretched exponential is a better fit for gastric emptying data from mice.

Noninvasive breath tests for gastric emptying are important techniques for understanding the changes in gastric motility that occur in disease or in response to drugs. Mice are often used as an animal model; however, the gamma variate model currently used for data analysis does not always fit the data appropriately. The aim of this study was to determine appropriate mathematical models to better fit mouse gastric emptying data including when two peaks are present in the gastric emptying curve.

Plasma membrane Ca²⁺-ATPases can shape the pattern of Ca²⁺ transients induced by store-operated Ca²⁺ entry.

Calcium (Ca(2+)) is a critical cofactor and signaling mediator in cells, and the concentration of cytosolic Ca(2+) is regulated by multiple proteins, including the plasma membrane Ca(2+)-ATPases (adenosine triphosphatases) (PMCAs), which use ATP to transport Ca(2+) out of cells. PMCA isoforms exhibit different kinetic and regulatory properties; thus, the presence and relative abundance of individual isoforms may help shape Ca(2+) transients and cellular responses. We studied the effects of three PMCA isoforms (PMCA4a, PMCA4b, and PMCA2b) on Ca(2+) transients elicited by conditions that trigger store-operated Ca(2+) entry (SOCE) and that blocked Ca(2+) uptake into the endoplasmic reticulum in HeLa cells, human embryonic kidney (HEK) 293 cells, or primary endothelial cell isolated from human umbilical cord veins (HUVECs).

Regulatory T cell kinetics in the peripheral blood of patients with Crohn's disease.

Estimates of T regulatory cell populations in the periphery of patients with Crohn's disease are confounded by disease activity and concomitant immunotherapeutic agents known to affect T cell proliferation and survival. We performed deuterium pulse/chase experiments in patients with quiescent Crohn's disease on no immunotherapy and healthy control subjects to estimate T regulatory cell kinetics. Quantification of deuterated DNA isolated from T cell subsets over 10 days was determined by mass spectrophotometry.

Controlled release of doxorubicin from pH-responsive microgels.

Stimuli-responsive hydrogels have enormous potential in drug delivery applications. They can be used for site-specific drug delivery due to environmental variables in the body such as pH and temperature. In this study, we have developed pH-responsive microgels for the delivery of doxorubicin (DOX) in order to optimize its anti-tumor activity while minimizing its systemic toxicity.

About and beyond the Henri-Michaelis-Menten rate equation for single-substrate enzyme kinetics.

For more than a century the simple single-substrate enzyme kinetics model and related Henri-Michaelis-Menten (HMM) rate equation have been thoroughly explored in various directions. In the present paper we are concerned with a possible generalization of this rate equation recently proposed by F. Kargi (BBRC 382 (2009) 157-159), which is assumed to be valid both in the case that the total substrate or enzyme is in excess and the quasi-steady-state is achieved.

Functional consequences and structural interpretation of mutations of human choline acetyltransferase.

Choline acetyltransferase (ChAT; EC 2.3.1.

Validation of fractal-like kinetic models by time-resolved binding kinetics of dansylamide and carbonic anhydrase in crowded media.

Kinetic studies of biochemical reactions are typically carried out in a dilute solution that rarely contains anything more than reactants, products, and buffers. In such studies, mass-action-based kinetic models are used to analyze the progress curves. However, intracellular compartments are crowded by macromolecules.

Development of 41Ca-based pharmacokinetic model for the study of bone remodelling in humans.

Background And Objective: Initial studies show that 41Ca may be employed as a useful diagnostic bioassay for monitoring metabolic bone disease and its treatment management. The 41Ca-based pharmacokinetic model is developed to assess its feasibility in monitoring bone disease and clinical responsiveness to therapeutic regimens.

Methods: A four-compartment calcium kinetic model is developed to interpret the results of clinically measured 41Ca tracer kinetics for oral and intravenous dose.

Quantitative methods for measuring DNA flexibility in vitro and in vivo.

The double-helical DNA biopolymer is particularly resistant to bending and twisting deformations. This property has important implications for DNA folding in vitro and for the packaging and function of DNA in living cells. Among the outstanding questions in the field of DNA biophysics are the underlying origin of DNA stiffness and the mechanisms by which DNA stiffness is overcome within cells.

Evolutionary dynamics of two related malignant plasma cell lines.

Cancer is the consequence of sequential acquisition of mutations within somatic cells. Mutations alter the relative reproductive fitness of cells, enabling the population to evolve in time as a consequence of selection. Cancer therapy itself can select for or against specific subclones.

Optimization of virotherapy for cancer.

Several viruses preferentially infect and replicate in cancer cells by usurping pathways that are defective in the tumor cell population. Such viruses have a potential as oncolytic agents. The aim of tumor virotherapy is that after injection of the replicating virus, it propagates in the tumor cell population with amplification.

Distinct role of PLCbeta3 in VEGF-mediated directional migration and vascular sprouting.

Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis.

Alveolar recruitment and arterial desflurane concentration during bariatric surgery.

Background: We investigated whether reversal of intraoperative atelectasis with the lung recruitment maneuver (RM) affects desflurane arterial concentrations during bariatric surgery.

Methods: After anesthetic induction and maintenance with propofol, patients were randomized to receive alveolar RM at intervals (RM group) or not (controls). Desflurane 6% was initiated, and rate of increase of alveolar desflurane concentration (ratio of end-expiratory to inspiratory concentrations, F(A)/F(I)) and desflurane blood concentrations were measured in both groups.

Kinetic analysis of interaction of BRCA1 tandem breast cancer c-terminal domains with phosphorylated peptides reveals two binding conformations.

Tandem breast cancer C-terminal (BRCT) domains, present in many DNA repair and cell cycle checkpoint signaling proteins, are phosphoprotein binding modules. The best-characterized tandem BRCT domains to date are from the protein BRCA1 (BRCA1-BRCT), an E3 ubiquitin ligase that has been linked to breast and ovarian cancer. While X-ray crystallography and NMR spectroscopy studies have uncovered the structural determinants of specificity of BRCA1-BRCT for phosphorylated peptides, a detailed kinetic and thermodynamic characterization of the interaction is also required to understand how structure and dynamics are connected and therefore better probe the mechanism of phosphopeptide recognition by BRCT domains.

Mathematical analysis of models for reaction kinetics in intracellular environments.

Two models that have been proposed in the literature for description of kinetics in intracellular environments characterized by macromolecular crowding and inhomogeneities, are mathematically analyzed and discussed. The models are first derived by using phenomenological arguments that lead to generalizations of the law of mass action. The prediction of these models in the case of bimolecular binding reaction is then analyzed.

Modeling of cancer virotherapy with recombinant measles viruses.

The Edmonston vaccine strain of measles virus has potent and selective activity against a wide range of tumors. Tumor cells infected by this virus or genetically modified strains express viral proteins that allow them to fuse with neighboring cells to form syncytia that ultimately die. Moreover, infected cells may produce new virus particles that proceed to infect additional tumor cells.

A microenvironment based model of antimitotic therapy of Gompertzian tumor growth.

A model of tumor growth, based on two-compartment cell population dynamics, and an overall Gompertzian growth has been previously developed. The main feature of the model is an inter-compartmental transfer function that describes the net exchange between proliferating (P) and quiescent (Q) cells and yields Gompertzian growth for tumor cell population N = P + Q. Model parameters provide for cell reproduction and cell death.

Branching morphology of the rat hepatic portal vein tree: a micro-CT study.

In contrast to the lung and the myocardium, the liver is a relatively homogeneous organ with fewer anatomic constraints on vascular branching. Hence, we hypothesize that the hepatic vasculature could more closely follow optimization of branching geometry than is the case in other organs. The geometrical and fractal properties of the rat hepatic portal vein tree were investigated, with the aid of three-dimensional micro-computed tomography data.

Mathematical modeling of cancer radiovirotherapy.

Cancer virotherapy represents a dynamical system that requires mathematical modeling for complete understanding of the outcomes. The combination of virotherapy with radiation (radiovirotherapy) has been recently shown to successfully eliminate tumors when virotherapy alone failed. However, it introduces a new level of complexity.

Modeling positive regulatory feedbacks in cell-cell interactions.

Our current understanding of molecular mechanisms of cellular regulation still does not support quantitative predictions of the overall growth kinetics of normal or malignant tissues. However, discernment of the role of growth-factor mediated cell-cell communication in tissue kinetics is possible by the use of simple mathematical models. Here we discuss the design and use of mathematical models in quantifying the contribution of autocrine and paracrine (i.

Dynamic iodide trapping by tumor cells expressing the thyroidal sodium iodide symporter.

The thyroidal sodium iodide symporter (NIS) in combination with various radioactive isotopes has shown promise as a therapeutic gene in various tumor models. Therapy depends on adequate retention of the isotope in the tumor. We hypothesized that in the absence of iodide organification, isotope trapping is a dynamic process either due to slow efflux or re-uptake of the isotope by cells expressing NIS.

Changes in structure and stability of calbindin-D(28K) upon calcium binding.

Calbindin-D(28K) is a biologically important protein required for normal neural function and for the transport of calcium in epithelial cells of the intestine and kidney. We have used fluorescence and circular dichroism (CD) spectroscopy to characterize the effects of calcium binding on the structure and stability of calbindin. Ca(2+) titration monitored by fluorescence spectroscopy reveals the presence of two classes of calcium-binding sites with association constants approximately 10(7.