Model selection for assessing the effects of doxorubicin on triple-negative breast cancer cell lines.

Doxorubicin is a chemotherapy widely used to treat several types of cancer, including triple-negative breast cancer. In this work, we use a Bayesian framework to rigorously assess the ability of ten different mathematical models to describe the dynamics of four TNBC cell lines (SUM-149PT, MDA-MB-231, MDA-MB-453, and MDA-MB-468) in response to treatment with doxorubicin at concentrations ranging from 10 to 2500 nM. Each cell line was plated and serially imaged via fluorescence microscopy for 30 days following 6, 12, or 24 h of in vitro drug exposure. We use the resulting data sets to estimate the parameters of the ten pharmacodynamic models using a Bayesian approach, which accounts for uncertainties in the models, parameters, and observational data. The ten candidate models describe the growth patterns and degree of response to doxorubicin for each cell line by incorporating exponential or logistic tumor growth, and distinct forms of cell death. Cell line and treatment specific model parameters are then estimated from the experimental data for each model. We analyze all competing models using the Bayesian Information Criterion (BIC), and the selection of the best model is made according to the model probabilities (BIC weights). We show that the best model among the candidate set of models depends on the TNBC cell line and the treatment scenario, though, in most cases, there is great uncertainty in choosing the best model. However, we show that the probability of being the best model can be increased by combining treatment data with the same total drug exposure. Our analysis points to the importance of considering multiple models, built on different biological assumptions, to capture the observed variations in tumor growth and treatment response.

Modeling Patient-Specific CAR-T Cell Dynamics: Multiphasic Kinetics via Phenotypic Differentiation.

Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients present multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and patient-specific characteristics. We present a mathematical model that describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamical behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered a potential marker to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.

SINDy-SA framework: enhancing nonlinear system identification with sensitivity analysis.

Machine learning methods have revolutionized studies in several areas of knowledge, helping to understand and extract information from experimental data. Recently, these data-driven methods have also been used to discover structures of mathematical models. The sparse identification of nonlinear dynamics (SINDy) method has been proposed with the aim of identifying nonlinear dynamical systems, assuming that the equations have only a few important terms that govern the dynamics. By defining a library of possible terms, the SINDy approach solves a sparse regression problem by eliminating terms whose coefficients are smaller than a threshold. However, the choice of this threshold is decisive for the correct identification of the model structure. In this work, we build on the SINDy method by integrating it with a global sensitivity analysis (SA) technique that allows to hierarchize terms according to their importance in relation to the desired quantity of interest, thus circumventing the need to define the SINDy threshold. The proposed SINDy-SA framework also includes the formulation of different experimental settings, recalibration of each identified model, and the use of model selection techniques to select the best and most parsimonious model. We investigate the use of the proposed SINDy-SA framework in a variety of applications. We also compare the results against the original SINDy method. The results demonstrate that the SINDy-SA framework is a promising methodology to accurately identify interpretable data-driven models. Supplementary Information: The online version contains supplementary material available at 10.1007/s11071-022-07755-2.

Framework for enhancing the estimation of model parameters for data with a high level of uncertainty.

Reliable data are essential to obtain adequate simulations for forecasting the dynamics of epidemics. In this context, several political, economic, and social factors may cause inconsistencies in the reported data, which reflect the capacity for realistic simulations and predictions. In the case of COVID-19, for example, such uncertainties are mainly motivated by large-scale underreporting of cases due to reduced testing capacity in some locations. In order to mitigate the effects of noise in the data used to estimate parameters of models, we propose strategies capable of improving the ability to predict the spread of the diseases. Using a compartmental model in a COVID-19 study case, we show that the regularization of data by means of Gaussian process regression can reduce the variability of successive forecasts, improving predictive ability. We also present the advantages of adopting parameters of compartmental models that vary over time, in detriment to the usual approach with constant values.

CARTmath-A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers.

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient's T lymphocytes are genetically manipulated to recognize tumor-specific antigens, increasing tumor elimination efficiency. In recent years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate in patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable for use as mathematical models. In this work, we develop a three-population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities are considered uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reducing and optimizing the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such an in silico laboratory is an easy-to-run open-source simulator, built on a Shiny R-based platform called CARTmath. It contains the results of this manuscript as examples and documentation. The developed model together with the CARTmath platform have potential use in assessing different CAR-T cell immunotherapy protocols and its associated efficacy, becoming an accessory for in silico trials.

Hematoma de bainha dos retos / Hematoma of the rectus abdominis sheaths

Os autores relatam sua experiência com 4 casos de hematoma de bainha dos retos, analisando o diagóstico e a conduta terapêutica