Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation.

Cancer with all its more than 200 variants continues to be a major health problem around the world with nearly 10 million deaths recorded in 2020, and leukemia accounted for more than 300,000 cases according to the Global Cancer Observatory. Although new treatment strategies are currently being developed in several ongoing clinical trials, the high complexity of cancer evolution and its survival mechanisms remain as an open problem that needs to be addressed to further enhanced the application of therapies. In this work, we aim to explore cancer growth, particularly chronic lymphocytic leukemia, under the combined application of CAR-T cells and chlorambucil as a nonlinear dynamical system in the form of first-order Ordinary Differential Equations. Therefore, by means of nonlinear theories, sufficient conditions are established for the eradication of leukemia cells, as well as necessary conditions for the long-term persistence of both CAR-T and cancer cells. Persistence conditions are important in treatment protocol design as these provide a threshold below which the dose will not be enough to produce a cytotoxic effect in the tumour population. In silico experimentations allowed us to design therapy administration protocols to ensure the complete eradication of leukemia cells in the system under study when considering only the infusion of CAR-T cells and for the combined application of chemoimmunotherapy. All results are illustrated through numerical simulations. Further, equations to estimate cytotoxicity of chlorambucil and CAR-T cells to leukemia cancer cells were formulated and thoroughly discussed with a 95% confidence interval for the parameters involved in each formula.

Personalized Immunotherapy Treatment Strategies for a Dynamical System of Chronic Myelogenous Leukemia.

This paper is devoted to exploring personalized applications of cellular immunotherapy as a control strategy for the treatment of chronic myelogenous leukemia described by a dynamical system of three first-order ordinary differential equations. The latter was achieved by applying both the Localization of Compact Invariant Sets and Lyapunov's stability theory. Combination of these two approaches allows us to establish sufficient conditions on the immunotherapy treatment parameter to ensure the complete eradication of the leukemia cancer cells. These conditions are given in terms of the system parameters and by performing several in silico experimentations, we formulated a protocol for the therapy application that completely eradicates the leukemia cancer cells population for different initial tumour concentrations. The formulated protocol does not dangerously increase the effector T cells population. Further, complete eradication is considered when solutions go below a finite critical value below which cancer cells cannot longer persist; i.e., one cancer cell. Numerical simulations are consistent with our analytical results.

Tumor Clearance Analysis on a Cancer Chemo-Immunotherapy Mathematical Model.

Mathematical models may allow us to improve our knowledge on tumor evolution and to better comprehend the dynamics between cancer, the immune system and the application of treatments such as chemotherapy and immunotherapy in both short and long term. In this paper, we solve the tumor clearance problem for a six-dimensional mathematical model that describes tumor evolution under immune response and chemo-immunotherapy treatments. First, by means of the localization of compact invariant sets method, we determine lower and upper bounds for all cells populations considered by the model and we use these results to establish sufficient conditions for the existence of a bounded positively invariant domain in the nonnegative orthant by applying LaSalle's invariance principle. Then, by exploiting a candidate Lyapunov function we determine sufficient conditions on the chemotherapy treatment to ensure tumor clearance. Further, we investigate the local stability of the tumor-free equilibrium point and compute conditions for asymptotic stability and tumor persistence. All conditions are given by inequalities in terms of the system parameters, and we perform numerical simulations with different values on the chemotherapy treatment to illustrate our results. Finally, we discuss the biological implications of our work.

Sensorless H∞ speed-tracking synthesis for surface-mount permanent magnet synchronous motor.

In this paper, a sensorless speed tracking control is proposed for a surface-mount permanent magnet synchronous motor by using a nonlinear H∞-controller via stator currents measurements for feedback. An output feedback nonlinear H∞-controller was designed such that the undisturbed system is uniformly asymptotically stable around the desired speed reference, while also the effects of external vanishing and non-vanishing disturbances, noise, and input backlash were attenuated locally. The rotor position was calculated from the causal dynamic output feedback compensator and from the desired speed reference. The existence of the proper solutions of the perturbed differential Riccati equations ensures stabilizability and detectability of the control system. The efficiency of the proposed sensorless controller was supported by numerical simulations.

Regularity and Matching Pursuit feature extraction for the detection of epileptic seizures.

BACKGROUND: The neurological disorder known as epilepsy is characterized by involuntary recurrent seizures that diminish a patient's quality of life. Automatic seizure detection can help improve a patient's interaction with her/his environment, and while many approaches have been proposed the problem is still not trivially solved. METHODS: In this work, we present a novel methodology for feature extraction on EEG signals that allows us to perform a highly accurate classification of epileptic states. Specifically, Hölderian regularity and the Matching Pursuit algorithm are used as the main feature extraction techniques, and are combined with basic statistical features to construct the final feature sets. These sets are then delivered to a Random Forests classification algorithm to differentiate between epileptic and non-epileptic readings. RESULTS: Several versions of the basic problem are tested and statistically validated producing perfect accuracy in most problems and 97.6% accuracy on the most difficult case. COMPARISON WITH EXISTING METHODS: A comparison with recent literature, using a well known database, reveals that our proposal achieves state-of-the-art performance. CONCLUSIONS: The experimental results show that epileptic states can be accurately detected by combining features extracted through regularity analysis, the Matching Pursuit algorithm and simple time-domain statistical analysis. Therefore, the proposed method should be considered as a promising approach for automatic EEG analysis.

Identification of epilepsy stages from ECoG using genetic programming classifiers.

OBJECTIVE: Epilepsy is a common neurological disorder, for which a great deal of research has been devoted to analyze and characterize brain activity during seizures. While this can be done by a human expert, automatic methods still lag behind. This paper analyzes neural activity captured with Electrocorticogram (ECoG), recorded through intracranial implants from Kindling model test subjects. The goal is to automatically identify the main seizure stages: Pre-Ictal, Ictal and Post-Ictal. While visually differentiating each stage can be done by an expert if the complete time-series is available, the goal here is to automatically identify the corresponding stage of short signal segments. METHODS AND MATERIALS: The proposal is to pose the above task as a supervised classification problem and derive a mapping function that classifies each signal segment. Given the complexity of the signal patterns, it is difficult to a priori choose any particular classifier. Therefore, Genetic Programming (GP), a population based meta-heuristic for automatic program induction, is used to automatically search for the mapping functions. Two GP-based classifiers are used and extensively evaluated. The signals from epileptic seizures are obtained using the Kindling model of elicited epilepsy in rodent test subjects, for which a seizure was elicited and recorded on four separate days. RESULTS: Results show that signal segments from a single seizure can be used to derive accurate classifiers that generalize when tested on different signals from the same subject; i.e., GP can automatically produce accurate mapping functions for intra-subject classification. A large number of experiments are performed with the GP classifiers achieving good performance based on standard performance metrics. Moreover, a proof-of-concept real-world prototype is presented, where a GP classifier is transferred and hard-coded on an embedded system using a digital-to-analogue converter and a field programmable gate array, achieving a low average classification error of 14.55%, sensitivity values between 0.65 and 0.97, and specificity values between 0.86 and 0.94. CONCLUSIONS: The proposed approach achieves good results for stage identification, particularly when compared with previous works that focus on this task. The results show that the problem of intra-class classification can be solved with a low error, and high sensitivity and specificity. Moreover, the limitations of the approach are identified and good operating configurations can be proposed based on the results.