Adaptive non‐linear control for cancer therapy through a Fokker–Planck observer

In recent years, many efforts have been made to present optimal strategies for cancer therapy through the mathematical modelling of tumour‐cell population dynamics and optimal control theory. In many cases, therapy effect is included in the drift term of the stochastic Gompertz model. By fitting the model with empirical data, the parameters of therapy function are estimated. The reported research works have not presented any algorithm to determine the optimal parameters of therapy function. In this study, a logarithmic therapy function is entered in the drift term of the Gompertz model. Using the proposed control algorithm, the therapy function parameters are predicted and adaptively adjusted. To control the growth of tumour‐cell population, its moments must be manipulated. This study employs the probability density function (PDF) control approach because of its ability to control all the process moments. A Fokker–Planck‐based non‐linear stochastic observer will be used to determine the PDF of the process. A cost function based on the difference between a predefined desired PDF and PDF of tumour‐cell population is defined. Using the proposed algorithm, the therapy function parameters are adjusted in such a manner that the cost function is minimised. The existence of an optimal therapy function is also proved. The numerical results are finally given to demonstrate the effectiveness of the proposed method.Inspec keywords: physiological models, cancer, patient treatment, probability, stochastic processes, tumours, Fokker‐Planck equation, statistical analysis, cellular biophysicsOther keywords: adaptive nonlinear control, cancer therapy, Fokker‐Planck observer, tumour cell growth behavior, mathematical modelling, tumour‐cell population dynamics, optimal control theory, stochastic Gompertz model, empirical data, statistical methods, logarithmic function, probability density function, nonlinear stochastic observer     

Optimal control methods for drug delivery in cancerous tumour by anti‐angiogenic therapy and chemotherapy

There are numerous mathematical models simulating the behaviour of cancer by considering variety of states in different treatment strategies, such as chemotherapy. Among the models, one is developed which is able to consider the blood vessel‐production (angiogenesis) in the vicinity of the tumour and the effect of anti‐angiogenic therapy. In the mentioned‐model, normal cells, cancer cells, endothelial cells, chemotherapy and anti‐angiogenic agents are taking into account as state variables, and the rate of injection of the last two are considered as control inputs. Since controlling the cancerous tumour growth is a challenging matter for patient''s life, the time schedule design of drug injection is very significant. Two optimal control strategies, an open‐loop (calculus of variations) and a closed‐loop (state‐dependent Riccati equation), are applied on the system in order to find an optimal time scheduling for each drug injection. By defining a proper cost function, an optimal control signal is designed for each one. Both obtained control inputs have reasonable answers, and the system is controlled eventually, but by comparing them, it is concluded that both methods have their own benefits which will be discussed in details in the conclusion section.     

Green synthesis of silver nanoparticles using Rubia tinctorum extract and evaluation the anti‐cancer properties in vitro

Cancer is one of the leading causes of human death. Nanotechnology could offer new and optimised anticancer agents in order to fight cancer. It was shown that metal nanoparticles, in particular silver nanoparticles (AgNPs) were effective in cancer therapy. In this study, AgNPs were synthesised using Rubia tinctorum L. extract (Ru‐AgNPs). Then, cytotoxicity effects of the Ru‐AgNPs against MDA‐MB‐231 carcinoma cell line and human dermal fibroblast as normal cell line were performed. Furthermore, anti‐apoptotic effects of Ru‐AgNPs on these cancer and normal cell lines were compared using acridine orange/propidium iodide staining, flow cytometry analysis and real‐time qPCR in apoptosis gene markers. Results of UV‐vis spectroscopy showed that Ru‐AgNPs have a peak at 430 nm, which indicated synthesis of AgNPs. Ru‐AgNPs had spherical shape and average size of 12 nm. Ru‐AgNPs have cytotoxicity on MDA‐MB‐231 cells and decrease cancerous cell viability (IC50 = 4 µg/ml/48 h). Ru‐AgNPs could induce apoptosis in MDA‐MB‐231 cells through upregulation of Bax and downregulation of Bcl‐2 gene expression. The results opened up new avenues to develop Rubia based metal complexes as an anticancer agent.Inspec keywords: cellular biophysics, genetics, cancer, toxicology, nanoparticles, nanofabrication, nanomedicine, silver, biomedical materials, ultraviolet spectra, visible spectraOther keywords: Ru‐AgNPs, MDA‐MB‐231 carcinoma cell line, normal cell line, cancerous cell viability, in vitro anticancer properties, green synthesis, silver nanoparticles, Rubia tinctorum L. extract, cytotoxicity effects, human dermal fibroblast HFF, antiapoptotic effects, acridine orange‐propidium iodide staining, flow cytometry analysis, real‐time qPCR, apoptosis gene markers, UV‐visible spectroscopy, spherical shape, Bcl‐2 gene expression, Ag     

Control of depth of anaesthesia using fractional‐order adaptive high‐gain controller

This study presents a fractional‐order adaptive high‐gain controller for control of depth of anaesthesia. To determine the depth of anaesthesia, the bispectral index (BIS) is utilised. To attain the desired BIS, the propofol infusion rate (as the control signal) should be appropriately adjusted. The effect of the propofol on the human body is modelled with the pharmacokinetic–pharmacodynamic (PK/PD) model. Physical properties of the patient such as gender, age, height and a like determine the parameters of the PK/PD model. This necessitates us to employ an appropriate adaptive controller. To attain this goal, a fractional‐order adaptive high‐gain controller is constructed to solve the tracking problem for minimum phase systems with relative degree two (such as the PK/PD model). This leads to a time‐varying gain adjusting according to a fractional‐order adaptation mechanism. Simulation results performed on various patients (considering the external disturbance and the measurement noise) show the effectiveness of the proposed method.Inspec keywords: medical control systems, gain control, adaptive control, closed loop systems, time‐varying systemsOther keywords: fractional‐order adaptive high‐gain controller, control signal, pharmacokinetic–pharmacodynamic model, fractional‐order adaptation mechanism, anaesthesia depth control, bispectral index, PK‐PD model, propofol infusion rate, tracking problem, minimum phase systems, time‐varying gain, BIS     

Pseudo‐spectral method for controlling the drug dosage in cancer

A mixed chemotherapy–immunotherapy treatment protocol is developed for cancer treatment. Chemotherapy pushes the trajectory of the system towards the desired equilibrium point, and then immunotherapy alters the dynamics of the system by affecting the parameters of the system. A co‐existing cancerous equilibrium point is considered as the desired equilibrium point instead of the tumour‐free equilibrium. Chemotherapy protocol is derived using the pseudo‐spectral (PS) controller due to its high convergence rate and simple implementation structure. Thus, one of the contributions of this study is simplifying the design procedure and reducing the controller computational load in comparison with Lyapunov‐based controllers. In this method, an infinite‐horizon optimal control problem is proposed for a non‐linear cancer model. Then, the infinite‐horizon optimal control of cancer is transformed into a non‐linear programming problem. The efficient Legendre PS scheme is suggested to solve the proposed problem. Then, the dynamics of the system is modified by immunotherapy is another contribution. To restrict the upper limit of the chemo‐drug dose based on the age of the patients, a Mamdani fuzzy system is designed, which is not present yet. Simulation results on four different dynamics cases how the efficiency of the proposed treatment strategy.Inspec keywords: patient treatment, cancer, convergence, linear programming, optimal control, nonlinear programming, nonlinear control systems, Lyapunov methods, drugs, tumoursOther keywords: nonlinear programming problem, efficient Legendre PS scheme, chemo‐drug dose, Mamdani fuzzy system, treatment strategy, pseudospectral method, drug dosage, mixed chemotherapy–immunotherapy treatment protocol, cancer treatment, desired equilibrium point, immunotherapy alters, cancerous equilibrium point, tumour‐free equilibrium, chemotherapy protocol, pseudospectral controller, high convergence rate, simple implementation structure, controller computational load, Lyapunov‐based controllers, infinite‐horizon optimal control problem, nonlinear cancer model     

Multi‐scale approach for simulating time‐delay biochemical reaction systems

This study presents a multi‐scale approach for simulating time‐delay biochemical reaction systems when there are wide ranges of molecular numbers. The authors construct a new efficient approach based on partitioning into slow and fast subsets in conjunction with predictor–corrector methods. This multi‐scale approach is shown to be much more efficient than existing methods such as the delay stochastic simulation algorithm and the modified next reaction method. Numerical testing on several important problems in systems biology confirms the accuracy and computational efficiency of this approach.Inspec keywords: biochemistry, delays, biological techniques, predictor‐corrector methodsOther keywords: multiscale approach, time‐delay biochemical reaction systems, predictor–corrector methods, delay stochastic simulation algorithm, modified next reaction method, numerical testing, systems biology, method accuracy, computational efficiency     

Deploying swarm intelligence in medical imaging identifying metastasis,micro‐calcifications and brain image segmentation

This study proposes an umbrella deployment of swarm intelligence algorithm, such as stochastic diffusion search for medical imaging applications. After summarising the results of some previous works which shows how the algorithm assists in the identification of metastasis in bone scans and microcalcifications on mammographs, for the first time, the use of the algorithm in assessing the CT images of the aorta is demonstrated along with its performance in detecting the nasogastric tube in chest X‐ray. The swarm intelligence algorithm presented in this study is adapted to address these particular tasks and its functionality is investigated by running the swarms on sample CT images and X‐rays whose status have been determined by senior radiologists. In addition, a hybrid swarm intelligence‐learning vector quantisation (LVQ) approach is proposed in the context of magnetic resonance (MR) brain image segmentation. The particle swarm optimisation is used to train the LVQ which eliminates the iteration‐dependent nature of LVQ. The proposed methodology is used to detect the tumour regions in the abnormal MR brain images.Inspec keywords: swarm intelligence, image segmentation, brain, neurophysiology, medical image processing, biomedical MRI, computerised tomography, diagnostic radiography, bone, diseases, learning (artificial intelligence), particle swarm optimisation, iterative methods, tumours, medical disordersOther keywords: medical imaging identifying metastasis, microcalcifications, umbrella deployment, stochastic diffusion, metastasis identification, bone scans, mammographs, CT imaging, aorta, nasogastric tube, chest X‐ray, hybrid swarm intelligence‐learning vector quantisation approach, magnetic resonance brain image segmentation, particle swarm optimisation, iteration‐dependent nature, tumour regions, abnormal MR brain imaging     

Retrieving relevant time‐course experiments: a study on Arabidopsis microarrays

Understanding time‐course regulation of genes in response to a stimulus is a major concern in current systems biology. The problem is usually approached by computational methods to model the gene behaviour or its networked interactions with the others by a set of latent parameters. The model parameters can be estimated through a meta‐analysis of available data obtained from other relevant experiments. The key question here is how to find the relevant experiments which are potentially useful in analysing current data. In this study, the authors address this problem in the context of time‐course gene expression experiments from an information retrieval perspective. To this end, they introduce a computational framework that takes a time‐course experiment as a query and reports a list of relevant experiments retrieved from a given repository. These retrieved experiments can then be used to associate the environmental factors of query experiment with the findings previously reported. The model is tested using a set of time‐course Arabidopsis microarrays. The experimental results show that relevant experiments can be successfully retrieved based on content similarity.Inspec keywords: botany, lab‐on‐a‐chip, genetics, bioinformatics, information retrieval, data mining, data analysis, associative processingOther keywords: relevant time‐course experiment retrieval, time‐course Arabidopsis microarray, time‐course gene regulation, stimulus response, systems biology, computational method, gene behaviour model, gene networked interaction, latent parameter, model parameter estimation, meta‐analysis, data analysis, time‐course gene expression experiment, information retrieval, computational framework, time‐course experiment query, relevant experiment list, repository, environmental factor, query experiment, experimental content similarity     

Optimal sliding mode control of drug delivery in cancerous tumour chemotherapy considering the obesity effects

Different control strategies have been proposed for drug delivery in chemotherapy during recent years. These control algorithms are designed based on dynamic models of various orders. The order of the model depends on the number of effects considered in the model. In a recent model, the effect of obesity on the tumour progression and optimal control strategy in chemotherapy have been investigated in a fifth‐order state‐space model. However, the optimal controller is open loop and not robust to the common uncertainties of such biological system. Here, the sliding surface is obtained by the optimal trajectory and by considering uncertainties of some parameters, the robust‐sliding control law is formulated in a way to slid on the optimal surface. Then, a sliding mode controller is designed to determine the drug dose rate such that the system follows the optimal desired trajectory. The stability of the control system is proved and the simulation results indicate that three states track the trajectory and the remaining two states satisfy the constraints.Inspec keywords: drug delivery systems, drugs, tumours, cancer, optimal control, open loop systems, controllers, medical control systemsOther keywords: optimal sliding mode control, drug delivery, cancerous tumour chemotherapy, obesity effects, control algorithms, dynamic models, tumour progression, optimal control strategy, fifth‐order state‐space model, open loop, biological system, sliding surface, optimal trajectory, robust‐sliding control law, sliding mode controller, drug dose rate     

Overlapping functional modules detection in PPI network with pair‐wise constrained non‐negative matrix tri‐factorisation

A large amount of available protein–protein interaction (PPI) data has been generated by high‐throughput experimental techniques. Uncovering functional modules from PPI networks will help us better understand the underlying mechanisms of cellular functions. Numerous computational algorithms have been designed to identify functional modules automatically in the past decades. However, most community detection methods (non‐overlapping or overlapping types) are unsupervised models, which cannot incorporate the well‐known protein complexes as a priori. The authors propose a novel semi‐supervised model named pairwise constrains nonnegative matrix tri‐factorisation (PCNMTF), which takes full advantage of the well‐known protein complexes to find overlapping functional modules based on protein module indicator matrix and module correlation matrix simultaneously from PPI networks. PCNMTF determinately models and learns the mixed module memberships of each protein by considering the correlation among modules simultaneously based on the non‐negative matrix tri‐factorisation. The experiment results on both synthetic and real‐world biological networks demonstrate that PCNMTF gains more precise functional modules than that of state‐of‐the‐art methods.Inspec keywords: proteins, molecular biophysics, cellular biophysics, matrix algebraOther keywords: overlapping functional module detection, PPI network, pair‐wise constrained nonnegative matrix trifactorisation, protein–protein interaction data, cellular functions, protein complexes, real‐world biological networks, synthetic biological networks     

Exploiting intrinsic fluctuations to identify model parameters

Parameterisation of kinetic models plays a central role in computational systems biology. Besides the lack of experimental data of high enough quality, some of the biggest challenges here are identification issues. Model parameters can be structurally non‐identifiable because of functional relationships. Noise in measured data is usually considered to be a nuisance for parameter estimation. However, it turns out that intrinsic fluctuations in particle numbers can make parameters identifiable that were previously non‐identifiable. The authors present a method to identify model parameters that are structurally non‐identifiable in a deterministic framework. The method takes time course recordings of biochemical systems in steady state or transient state as input. Often a functional relationship between parameters presents itself by a one‐dimensional manifold in parameter space containing parameter sets of optimal goodness. Although the system''s behaviour cannot be distinguished on this manifold in a deterministic framework it might be distinguishable in a stochastic modelling framework. Their method exploits this by using an objective function that includes a measure for fluctuations in particle numbers. They show on three example models, immigration‐death, gene expression and Epo‐EpoReceptor interaction, that this resolves the non‐identifiability even in the case of measurement noise with known amplitude. The method is applied to partially observed recordings of biochemical systems with measurement noise. It is simple to implement and it is usually very fast to compute. This optimisation can be realised in a classical or Bayesian fashion.Inspec keywords: biochemistry, physiological models, stochastic processes, measurement errors, fluctuations, parameter estimationOther keywords: model parameter identification, deterministic framework, biochemical system, steady state, transient state, stochastic modelling framework, objective function, immigration‐death model, gene expression, Epo–EpoReceptor interaction, stochastic fluctuations, measurement noise     

Non‐fragile reliable control synthesis of the sugarcane borer

This study considers the problem of non‐fragile reliable control synthesis for mathematical model of interaction between the sugarcane borer (Diatraea saccharalis) and its egg parasitoid Trichogramma galloi. In particular, the control could be substituted by periodic releases of a small population of natural enemies and hence it is important to propose the time‐varying controller in sugarcane borer. The main aim of this study is to design a state feedback non‐fragile (time‐varying) reliable controller such that the states of the sugarcane borer system reach the equilibrium point within the desired period. A novel approach is proposed to deal with the uncertain matrices which appear in non‐fragile reliable control. Finally, simulations based on sugarcane borer systems are conducted to illustrate the advantages and effectiveness of the proposed design technique. The result reveals that the proposed non‐fragile control provides good performance in spite of periodic releases of a small population of natural enemies occurs.Inspec keywords: microorganisms, plant diseases, biology computing, state feedback, biocontrol, control system synthesisOther keywords: nonfragile reliable control synthesis, sugarcane borer, mathematical model, Diatraea saccharalis, egg parasitoid, Trichogramma galloi, periodic releases, natural enemies, state feedback nonfragile time‐varying reliable controller, equilibrium point, design technique     

Effective implicit finite‐difference method for sensitivity analysis of stiff stochastic discrete biochemical systems

Simulation of cellular processes is achieved through a range of mathematical modelling approaches. Deterministic differential equation models are a commonly used first strategy. However, because many biochemical processes are inherently probabilistic, stochastic models are often called for to capture the random fluctuations observed in these systems. In that context, the Chemical Master Equation (CME) is a widely used stochastic model of biochemical kinetics. Use of these models relies on estimates of kinetic parameters, which are often poorly constrained by experimental observations. Consequently, sensitivity analysis, which quantifies the dependence of systems dynamics on model parameters, is a valuable tool for model analysis and assessment. A number of approaches to sensitivity analysis of biochemical models have been developed. In this study, the authors present a novel method for estimation of sensitivity coefficients for CME models of biochemical reaction systems that span a wide range of time‐scales. They make use of finite‐difference approximations and adaptive implicit tau‐leaping strategies to estimate sensitivities for these stiff models, resulting in significant computational efficiencies in comparison with previously published approaches of similar accuracy, as evidenced by illustrative applications.Inspec keywords: biochemistry, sensitivity analysis, stochastic processes, cellular biophysics, probability, fluctuations, master equation, reaction kinetics, finite difference methodsOther keywords: effective implicit finite‐difference method, sensitivity analysis, stiff stochastic discrete biochemical systems, cellular processes, mathematical modelling, deterministic differential equation models, inherently probabilistic‐stochastic models, random fluctuations, Chemical Master Equation, biochemical kinetics, kinetic parameter estimation, systems dynamics, CME models, biochemical reaction systems, finite‐difference approximations, adaptive implicit tau‐leaping strategies, computational efficiencies     

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.Inspec keywords: control system synthesis, tumours, variable structure systems, observers, cancer, robust control, drugs, proteins, medical control systemsOther keywords: wild‐type p53, nonlinear technique, drug design, control‐oriented p53 model, control input, drug infusion, smooth control signal, dynamic SMC, zero‐dynamics, model‐based control design, input disturbance, controlled drug administration, sliding mode controller–observer pair, cancerous cells, antitumour agent, molecule based drug     

Efficient co‐cultivation of human fibroblast cells (HFCs) and adipose‐derived stem cells (ADSs) on gelatin/PLCL nanofiber

In this study, we investigated whether the nanofibers produced by natural‐synthetic polymers can probably promote the proliferation of co‐cultured adipose‐derived stem cells/human fibroblast cells (ADSs/HFCs) and synthesis of collagen. Nanofiber was fabricated by blending gelatin and poly (L‐lactide co‐ɛ‐caprolactone) (PLCL) polymer nanofiber (Gel/PLCL). Cell morphology and the interaction between cells and Gel/PLCL nanofiber were evaluated by FESEM and fluorescent microscopy. MTS assay and quantitative real‐time polymerase chain reaction were applied to assess the proliferation of co‐cultured ADSs/HFCs and the collagen type I and III synthesis, respectively. The concentrations of two cytokines including fibroblast growth factor‐basic and transforming growth factor‐β1 were also measured in culture medium of co‐cultured ADSs/HDCs using enzyme‐linked immunosorbent assay assay. Actually, nanofibers exhibited proper structural properties in terms of stability in cell proliferation and toxicity analysis processes. Gel/PLCL nanofiber promoted the growth and the adhesion of HFCs. Our results showed in contact co‐culture of ADSs/HFCs on the Gel/PLCL nanofiber increased cellular adhesion and proliferation synergistically compared to non‐coated plate. Also, synthesis of collagen and cytokines secretion of co‐cultured ADSs/HFCs on Gel/PLCL scaffolds is significantly higher than non‐coated plates. To conclude, the results suggest that Gel/PLCL nanofiber can imitate physiological characteristics in vivo and enhance the efficacy of co‐cultured ADSs/HFCs in wound healing process.Inspec keywords: biomedical materials, enzymes, adhesion, fluorescence, polymer fibres, tissue engineering, wounds, nanofibres, cellular biophysics, molecular biophysics, gelatin, biochemistry, nanomedicine, field emission scanning electron microscopy, nanofabricationOther keywords: cell morphology, cell proliferation, efficient cocultivation, HFCs, ADSs, gelatin‐PLCL nanofiber, natural‐synthetic polymers, cocultured adipose‐derived stem cells‐human fibroblast cells, FESEM, fluorescent microscopy, MTS assay, quantitative real‐time polymerase chain reaction, collagen type I synthesis, collagen type III synthesis, cytokines, transforming growth factor‐β1, fibroblast growth factor‐basic growth factor‐β1, culture medium, enzyme‐linked immunosorbent assay assay, structural properties, toxicity analysis, cellular adhesion, physiological characteristics in vivo, wound healing     

M‐matrix‐based stability conditions for genetic regulatory networks with time‐varying delays and noise perturbations

Stability is essential for designing and controlling any dynamic systems. Recently, the stability of genetic regulatory networks has been widely studied by employing linear matrix inequality (LMI) approach, which results in checking the existence of feasible solutions to high‐dimensional LMIs. In the previous study, the authors present several stability conditions for genetic regulatory networks with time‐varying delays, based on M ‐matrix theory and using the non‐smooth Lyapunov function, which results in determining whether a low‐dimensional matrix is a non‐singular M ‐matrix. However, the previous approach cannot be applied to analyse the stability of genetic regulatory networks with noise perturbations. Here, the authors design a smooth Lyapunov function quadratic in state variables and employ M ‐matrix theory to derive new stability conditions for genetic regulatory networks with time‐varying delays. Theoretically, these conditions are less conservative than existing ones in some genetic regulatory networks. Then the results are extended to genetic regulatory networks with time‐varying delays and noise perturbations. For genetic regulatory networks with n genes and n proteins, the derived conditions are to check if an n × n matrix is a non‐singular M ‐matrix. To further present the new theories proposed in this study, three example regulatory networks are analysed.Inspec keywords: genetics, linear matrix inequalities, Lyapunov matrix equations, molecular biophysics, noise, proteinsOther keywords: M‐matrix‐based stability condition, genetic regulatory networks, time‐varying delays, noise perturbations, linear matrix inequality approach, high‐dimensional LMI, Lyapunov function, state variables, M‐matrix theory, proteins, nonsingular M‐matrix     

Investigating receptor enzyme activity using time‐scale analysis

At early drug discovery, purified protein‐based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time‐independent inhibitor is reversible and a time‐dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model‐based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time‐independent under certain parametric conditions. Hence, the observation of time‐independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell‐based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time‐independent under certain conditions. Furthermore, model‐based steady‐state analysis reveals the complexity nature of the drug–receptor process.Inspec keywords: enzymes, molecular biophysics, drugs, biochemistry, reaction kinetics, cellular biophysicsOther keywords: receptor enzyme activity, time‐scale analysis, drug discovery, purified protein‐based assays, compound potency, dose response, reversible time‐independent inhibitor, irreversible time‐dependent inhibitor, kinetics model, target receptor degradation, drug inhibition, in vitro cell‐based assay setting, model‐based steady‐state analysis, drug‐receptor process     

System‐based strategies for p53 recovery

The authors have proposed a systems theory‐based novel drug design approach for the p53 pathway. The pathway is taken as a dynamic system represented by ordinary differential equations‐based mathematical model. Using control engineering practices, the system analysis and subsequent controller design is performed for the re‐activation of wild‐type p53. p53 revival is discussed for both modes of operation, i.e. the sustained and oscillatory. To define the problem in control system paradigm, modification in the existing mathematical model is performed to incorporate the effect of Nutlin. Attractor point analysis is carried out to select the suitable domain of attraction. A two‐loop negative feedback control strategy is devised to drag the system trajectories to the attractor point and to regulate cellular concentration of Nutlin, respectively. An integrated framework is constituted to incorporate the pharmacokinetic effects of Nutlin in the cancerous cells. Bifurcation analysis is also performed on the p53 model to see the conditions for p53 oscillation.Inspec keywords: proteins, tumours, cancer, cellular biophysics, molecular biophysics, molecular configurations, biochemistry, differential equations, closed loop systems, bifurcation, biology computingOther keywords: system‐based strategies, p53 recovery, systems theory‐based novel drug design approach, dynamic system, ordinary differential equations‐based mathematical model, control engineering practices, subsequent controller design, wild‐type p53, p53 revival, oscillatory, control system paradigm, mathematical model, Nutlin effect, attractor point analysis, domain‐of‐attraction, two‐loop negative feedback control strategy, cellular concentration, pharmacokinetic effects, cancerous cells, bifurcation analysis, p53 oscillation, anomalous cell     

Mining gene link information for survival pathway hunting

This study proposes a gene link‐based method for survival time‐related pathway hunting. In this method, the authors incorporate gene link information to estimate how a pathway is associated with cancer patient''s survival time. Specifically, a gene link‐based Cox proportional hazard model (Link‐Cox) is established, in which two linked genes are considered together to represent a link variable and the association of the link with survival time is assessed using Cox proportional hazard model. On the basis of the Link‐Cox model, the authors formulate a new statistic for measuring the association of a pathway with survival time of cancer patients, referred to as pathway survival score (PSS), by summarising survival significance over all the gene links in the pathway, and devise a permutation test to test the significance of an observed PSS. To evaluate the proposed method, the authors applied it to simulation data and two publicly available real‐world gene expression data sets. Extensive comparisons with previous methods show the effectiveness and efficiency of the proposed method for survival pathway hunting.Inspec keywords: cancer, physiological models, bioinformatics, genomicsOther keywords: permutation test, pathway survival score, gene link‐based Cox proportional hazard model, cancer patient survival time, survival time‐related pathway hunting, gene link‐based method