Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a type of non-Hodgkin's lymphoma in which the malignant cells produce many macroglobulin proteins. It originates from B cells and develops in the bone marrow, where Wm cells combine to produce distinct types of blood cells, resulting in reduced volumes of red blood cells, white blood cells, and platelets, making it harder for the body to fight diseases. Chemoimmunotherapy is being used for the clinical management of WM, but new targeted agents, the BTK inhibitor ibrutinib and the proteasome inhibitor bortezomib, have shown significant improvements in patients with relapsed/refractory WM. However, given its effectiveness, drug resistance and relapse are normal, and there is little research on the pathways responsible for drug effects on the tumor. METHODS: In this study, Pharmacokinetics-pharmacodynamic simulations were done to assess the effect of the proteasome inhibitor bortezomib on the tumor. For this purpose, the Pharmacokinetics-pharmacodynamic model was developed. The model parameters were determined and calculated using the Ordinary Differential Equation solver toolbox and the least-squares function. Pharmacokinetic profiles and pharmacodynamic analysis were performed to determine the change in tumor weight associated with the use of proteasome inhibitors. RESULTS: Bortezomib and ixazomib have been found to reduce tumor weight briefly, but once the dose is reduced, the tumor begins to grow again. Carfilzomib and oprozomib had better results, and rituximab reduced tumor weight more effectively. CONCLUSION: Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM.

Robust p53 recovery using chattering free sliding mode control and a gain-scheduled modified Utkin observer.

p53 protein plays an essential role in protecting the genomic integrity of mammalian cells. A drastic decrease in the amount of p53 protein has been observed in cancerous cells. By using Nutlin-based small molecule drugs, the concentration of p53 can be restored to the desired level. This paper presents the drug-dosage design for p53 pathway, based on a control-oriented nonlinear model. A chattering free sliding mode control (CFSMC) strategy is employed to track the desired trajectory of p53 concentration for both of its dynamic behaviors, i.e., sustained and oscillatory responses. A gain-scheduled modified Utkin observer (GSMUO) is designed for robust state reconstruction and disturbance estimation. The simulation results show that CFSMC and GSMUO exhibit desired robustness and performance properties in the presence of parametric variations, an input disturbance and measurement noise. Moreover, a comprehensive simulation study, along with a detailed quantitative analysis is performed to compare CFSMC-GSMUO with four different techniques: a sliding mode control (SMC) with an equivalent control based sliding mode observer (SMO) and GSMUO, respectively, and a dynamic sliding mode control (DSMC) with SMO and GSMUO, respectively. The analysis demonstrates that the tracking error and utilization of the control energy is the least in the case of CFSMC-GSMUO as compared to its counterparts.

A Novel Roll and Pitch Estimation Approach for a Ground Vehicle Stability Improvement Using a Low Cost IMU.

Onboard attitude estimation for a ground vehicle is persuaded by its application in active anti-roll bar design. Conventionally, the attitude estimation problem for a ground vehicle is a complex one, and computationally, its solution is very intensive. Lateral load transfer is an important parameter which should be taken in account for all roll stability control systems. This parameter is directly related to vehicle roll angle, which can be measured using devices such as dual antenna global positioning system (GPS) which is a costly technique, and this led to the current work in which we developed a simple and robust attitude estimation technique that is tested on a ground vehicle for roll mitigation. In the first phase Luenberger and Sliding mode observer is implemented using simplest roll dynamics model to measure the roll angle of a vehicle and the validation of results is carried using commercial software, CarSim® (CarSim, Ann Arbor, MI, USA). In the second phase of research, complementary and Kalman filters have been designed for attitude estimation. In the third phase, a low-cost inertial measurement unit (IMU) is mounted on a vehicle, and both the complementary filter (CF) and Kalman filter (KF) are applied independently to measure the data for both smooth and uneven terrains at four different frequencies. We compared the simulated and real-time results of roll and pitch angles obtained using the complementary and Kalman filters. Using the proposed method, the achieved root mean square error (RMSE) is less than 0.73 degree for pitch and 0.68 degree for roll, with a sample time of 2 ms. Thus, a warning signal can be generated to mitigate roll over. Hence, we claim that our proposed method can provide a low-cost solution to the roll-over problem for a road vehicle.

Marine Natural Products and Drug Resistance in Latent Tuberculosis.

Pyrazinamide (PZA) is the only drug for the elimination of latent Mycobacterium tuberculosis (MTB) isolates. However, due to the increased number of PZA-resistance, the chances of the success of global TB elimination seems to be more prolonged. Recently, marine natural products (MNPs) as an anti-TB agent have received much attention, where some compounds extracted from marine sponge, Haliclona sp. exhibited strong activity under aerobic and hypoxic conditions. In this study, we screened articles from 1994 to 2019 related to marine natural products (MNPs) active against latent MTB isolates. The literature was also mined for the major regulators to map them in the form of a pathway under the dormant stage. Five compounds were found to be more suitable that may be applied as an alternative to PZA for the better management of resistance under latent stage. However, the mechanism of actions behind these compounds is largely unknown. Here, we also applied synthetic biology to analyze the major regulatory pathway under latent TB that might be used for the screening of selective inhibitors among marine natural products (MNPs). We identified key regulators of MTB under latent TB through extensive literature mining and mapped them in the form of regulatory pathway, where SigH is negatively regulated by RshA. PknB, RshA, SigH, and RNA polymerase (RNA-pol) are the major regulators involved in MTB survival under latent stage. Further studies are needed to screen MNPs active against the main regulators of dormant MTB isolates. To reduce the PZA resistance burden, understanding the regulatory pathways may help in selective targets of MNPs from marine natural sources.

Sliding mode controller-observer pair for p53 pathway.

A significant loss of p53 protein, an anti-tumour agent, is observed in early cancerous cells. Induction of small molecules based drug is by far the most prominent technique to revive and maintain wild-type p53 to the desired level. In this study, a sliding mode control (SMC) based robust non-linear technique is presented for the drug design of a control-oriented p53 model. The control input generated by conventional SMC is discontinuous; however, depending on the physical nature of the system, drug infusion needs to be continuous. Therefore, to obtain a smooth control signal, a dynamic SMC (DSMC) is designed. Moreover, the boundedness of the zero-dynamics is also proved. To make the model-based control design possible, the unknown states of the system are estimated using an equivalent control based, reduced-order sliding mode observer. The robustness of the proposed technique is assessed by introducing input disturbance and parametric uncertainty in the system. The effectiveness of the proposed control scheme is witnessed by performing in-silico trials, revealing that the sustained level of p53 can be achieved by controlled drug administration. Moreover, a comparative quantitative analysis shows that both controllers yield similar performance. However, DSMC consumes less control energy.

Robust stabilization of underactuated nonlinear systems: A fast terminal sliding mode approach.

This paper presents a fast terminal sliding mode based control design strategy for a class of uncertain underactuated nonlinear systems. Strategically, this development encompasses those electro-mechanical underactuated systems which can be transformed into the so-called regular form. The novelty of the proposed technique lies in the hierarchical development of a fast terminal sliding attractor design for the considered class. Having established sliding mode along the designed manifold, the close loop dynamics become finite time stable which, consequently, result in high precision. In addition, the adverse effects of the chattering phenomenon are reduced via strong reachability condition and the robustness of the system against uncertainties is confirmed theoretically. A simulation as well as experimental study of an inverted pendulum is presented to demonstrate the applicability of the proposed technique.

A novel anti-windup framework for cascade control systems: an application to underactuated mechanical systems.

This paper describes the anti-windup compensator (AWC) design methodologies for stable and unstable cascade plants with cascade controllers facing actuator saturation. Two novel full-order decoupling AWC architectures, based on equivalence of the overall closed-loop system, are developed to deal with windup effects. The decoupled architectures have been developed, to formulate the AWC synthesis problem, by assuring equivalence of the coupled and the decoupled architectures, instead of using an analogy, for cascade control systems. A comparison of both AWC architectures from application point of view is provided to consolidate their utilities. Mainly, one of the architecture is better in terms of computational complexity for implementation, while the other is suitable for unstable cascade systems. On the basis of the architectures for cascade systems facing stability and performance degradation problems in the event of actuator saturation, the global AWC design methodologies utilizing linear matrix inequalities (LMIs) are developed. These LMIs are synthesized by application of the Lyapunov theory, the global sector condition and the ℒ2 gain reduction of the uncertain decoupled nonlinear component of the decoupled architecture. Further, an LMI-based local AWC design methodology is derived by utilizing a local sector condition by means of a quadratic Lyapunov function to resolve the windup problem for unstable cascade plants under saturation. To demonstrate effectiveness of the proposed AWC schemes, an underactuated mechanical system, the ball-and-beam system, is considered, and details of the simulation and practical implementation results are described.