Using systemic modeling and Bayesian calibration to investigate the role of the tumor microenvironment on chemoresistance

Using a novel modeling approach based on the so-called environmental stress level (ESL), we develop a mathematical model to describe systematically the collective influence of oxygen concentration and stiffness of the extracellular matrix on the response of tumor cells to a combined chemotherapeutic treatment. We perform Bayesian calibrations of the resulting model using particle filters, with in vitro experimental data for different hepatocellular carcinoma cell lines. The calibration results support the validity of our mathematical model. Furthermore, they shed light on individual as well as synergistic effects of hypoxia and tissue stiffness on tumor cell dynamics under chemotherapy.Comment: Contains supplementary materia

Measurement and mathematical modeling of thermally induced injury and heat shock protein expression kinetics in normal and cancerous prostate cells.

Abstract Purpose: Hyperthermia can induce heat shock protein (HSP) expression in tumours, which will cause enhanced tumour viability and increased resistance to additional thermal, chemotherapy, and radiation treatments. The study objective was to determine the relationship of hyperthermia protocols with HSP expression kinetics and cell death and develop corresponding computational predictive models of normal and cancerous prostate cell response. Methods: HSP expression kinetics and cell viability were measured in PC3 prostate cancer and RWPE-1 normal prostate cells subjected to hyperthermia protocols of 44 to 60 C for 1 to 30 min. Hsp27, Hsp60, and Hsp70 expression kinetics were determined by western blotting and visualised with immunofluorescence and confocal microscopy. Based on measured HSP expression data, a mathematical model was developed for predicting thermally induced HSP expression. Cell viability was measured with propidium iodide staining and flow cytometry to quantify the injury parameters necessary for predicting cell death following hyperthermia. Results: Significant Hsp27 and Hsp70 levels were induced in both cell types with maximum HSP expression occurring at 16 h post-heating, and diminishing substantially after 72 h. PC3 cells were slightly more sensitive to thermal stress than RWPE-1 cells. Arrhenius analysis of injury data suggested a transition between injury mechanisms at 54 C. HSP expression and injury models were effective at predicting cellular response to hyperthermia. Conclusion: Measurement of thermally induced HSP expression kinetics and cell viability associated with hyperthermia enabled development of thermal dosimetry guidelines and predictive models for HSP expression and cell injury as a function of thermal stress to investigate and design more effective hyperthermia therapies

High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction

<p>Abstract</p> <p>Background</p> <p>Therapeutic irreversible electroporation (IRE) is an emerging technology for the non-thermal ablation of tumors. The technique involves delivering a series of unipolar electric pulses to permanently destabilize the plasma membrane of cancer cells through an increase in transmembrane potential, which leads to the development of a tissue lesion. Clinically, IRE requires the administration of paralytic agents to prevent muscle contractions during treatment that are associated with the delivery of electric pulses. This study shows that by applying high-frequency, bipolar bursts, muscle contractions can be eliminated during IRE without compromising the non-thermal mechanism of cell death.</p> <p>Methods</p> <p>A combination of analytical, numerical, and experimental techniques were performed to investigate high-frequency irreversible electroporation (H-FIRE). A theoretical model for determining transmembrane potential in response to arbitrary electric fields was used to identify optimal burst frequencies and amplitudes for <it>in vivo </it>treatments. A finite element model for predicting thermal damage based on the electric field distribution was used to design non-thermal protocols for <it>in vivo </it>experiments. H-FIRE was applied to the brain of rats, and muscle contractions were quantified via accelerometers placed at the cervicothoracic junction. MRI and histological evaluation was performed post-operatively to assess ablation.</p> <p>Results</p> <p>No visual or tactile evidence of muscle contraction was seen during H-FIRE at 250 kHz or 500 kHz, while all IRE protocols resulted in detectable muscle contractions at the cervicothoracic junction. H-FIRE produced ablative lesions in brain tissue that were characteristic in cellular morphology of non-thermal IRE treatments. Specifically, there was complete uniformity of tissue death within targeted areas, and a sharp transition zone was present between lesioned and normal brain.</p> <p>Conclusions</p> <p>H-FIRE is a feasible technique for non-thermal tissue ablation that eliminates muscle contractions seen in IRE treatments performed with unipolar electric pulses. Therefore, it has the potential to be performed clinically without the administration of paralytic agents.</p

Design of hyperthermia protocols for inducing cardiac protection and tumor destruction by controlling heat shock protein expression

Heat shock proteins (HSP) are critical components of a complex defense mechanism essential for preserving cell survival under adverse environmental conditions. The presence of sub-lethal stressful stimuli, such as hyperthermia can induce HSP expression, thereby protecting cells from otherwise lethal insults. Thermally induced HSP expression in the heart can provide cardiac protection against ischemia reperfusion injury associated with cardiac surgery. However, thermally induced HSP expression during hyperthermia prostate cancer therapies can enhance tumor cell viability and resistance to subsequent chemotherapy and radiation treatments. Characterization of the thermally induced HSP kinetics is crucial for designing hyperthermia therapies that produce the desired HSP expression pattern most appropriate for the intended therapy outcome. This research focused on characterization of the thermally induced HSP kinetics in both cardiac cells and prostate cells and tissues to permit dosimetry guideline development and optimization models for controlling HSP expression induced during laser therapy. Although the initial design of thermal preconditioning protocols for inducing cardiac protection were explored, the majority of the dissertation will focus on cellular and tissue analysis methods and computational modeling strategies utilized in the development of a novel therapy planning tool for prostate cancer laser therapy. This work has focused on characterizing the thermally induced HSP27 and 70 expression kinetics for the prostate at the cellular and tissue level. Through the use of Magnetic Resonance Temperature Imaging which provided the spatiotemporal temperature distribution data and confocal microscopy, the HSP27 and 70 distributions were accurately determined throughout laser irradiated prostate tumors. The measured HSP expression data was employed to create the first HSP predictive computational model. A highly accurate, adaptive, finite element model was developed which is capable of predicting and optimizing the temperature, HSP expression, and damage distributions associated with laser heating in prostate tissue and tumors. Application of the treatment planning model in the design of prostate cancer thermal therapies can enable optimization of the treatment outcome by controlling the tissue response to therapy based on accurate prediction of the HSP expression and damage distributions.Biomedical Engineerin

Optical properties of breast tumor phantoms containing carbon nanotubes and nanohorns

The degree by which optical properties of tumors are altered following introduction of carbon nanotubes (CNTs) of varying concentration and type is poorly understood, making it difficult to predict the impact of CNT inclusion on the photothermal response to laser therapies. Optical properties were measured of phantoms representative of breast tumor tissue incorporated with multiwalled carbon nanotubes (MWNTs), single-walled carbon nanotubes (SWNTs), and single-walled carbon nanohorns (SWNHs) of varying concentration (0.01–0.1 mg/ml). Tissue phantoms were made from sodium alginate (3 g/ml) incorporated with polystyrene microbeads (3 μm diam and 1 mg/ml) and talc-France powder (40 mg/ml). Absorption (μa) and reduced scattering (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′) coefficients of phantoms containing CNTs were determined by the inverse adding-doubling algorithm for the wavelength range of 400–1300 nm. Optical properties of phantoms without CNTs were in the range of μa = 1.04–0.06 mm−1 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′ = 0.05–0.07 mm−1 at a wavelength of 900 nm, which corresponds with published data for human breast tumor tissue. Incorporating MWNTs, SWNTs, and SWNHs in phantoms with a concentration of 0.1 mg/ml increased (μa) by 20- to 30-fold, 5- to 6-fold, and 9- to 14-fold, respectively, for the wavelength range of 800–1100 nm with minimal change in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′ (1.2- to 1.3-fold). Introduction of CNTs into tissue phantoms increased absorption, providing a means to enhance photothermal therapy

Multilayer In Vitro Human Skin Tissue Platforms for Quantitative Burn Injury Investigation

This study presents a multilayer in vitro human skin platform to quantitatively relate predicted spatial time–temperature history with measured tissue injury response. This information is needed to elucidate high-temperature, short-duration burn injury kinetics and enables determination of relevant input parameters for computational models to facilitate treatment planning. Multilayer in vitro skin platforms were constructed using human dermal keratinocytes and fibroblasts embedded in collagen I hydrogels. After three seconds of contact with a 50–100 °C burn tip, ablation, cell death, apoptosis, and HSP70 expression were spatially measured using immunofluorescence confocal microscopy. Finite element modeling was performed using the measured thermal characteristics of skin platforms to determine the temperature distribution within platforms over time. The process coefficients for the Arrhenius thermal injury model describing tissue ablation and cell death were determined such that the predictions calculated from the time–temperature histories fit the experimental burn results. The activation energy for thermal collagen ablation and cell death was found to be significantly lower for short-duration, high-temperature burns than those found for long-duration, low-temperature burns. Analysis of results suggests that different injury mechanisms dominate at higher temperatures, necessitating burn research in the temperature ranges of interest and demonstrating the practicality of the proposed skin platform for this purpose