Theoretical Biology and Medical Modelling最新文献

Background: Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.

Methods: A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.

Results: The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.

Conclusion: Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.

Background: Cardiac tamponade is a condition whereby fluid accumulation in the pericardial sac surrounding the heart causes elevation and equilibration of pericardial and cardiac chamber pressures, reduced cardiac output, changes in hemodynamics, partial chamber collapse, pulsus paradoxus, and arterio-venous acid-base disparity. Our large-scale model of the human cardiovascular-respiratory system (H-CRS) is employed to study mechanisms underlying cardiac tamponade and pulsus paradoxus. The model integrates hemodynamics, whole-body gas exchange, and autonomic nervous system control to simulate pressure, volume, and blood flow.

Methods: We integrate a new pericardial model into our previously developed H-CRS model based on a fit to patient pressure data. Virtual experiments are designed to simulate pericardial effusion and study mechanisms of pulsus paradoxus, focusing particularly on the role of the interventricular septum. Model differential equations programmed in C are solved using a 5th-order Runge-Kutta numerical integration scheme. MATLAB is employed for waveform analysis.

Results: The H-CRS model simulates hemodynamic and respiratory changes associated with tamponade clinically. Our model predicts effects of effusion-generated pericardial constraint on chamber and septal mechanics, such as altered right atrial filling, delayed leftward septal motion, and prolonged left ventricular pre-ejection period, causing atrioventricular interaction and ventricular desynchronization. We demonstrate pericardial constraint to markedly accentuate normal ventricular interactions associated with respiratory effort, which we show to be the distinct mechanisms of pulsus paradoxus, namely, series and parallel ventricular interaction. Series ventricular interaction represents respiratory variation in right ventricular stroke volume carried over to the left ventricle via the pulmonary vasculature, whereas parallel interaction (via the septum and pericardium) is a result of competition for fixed filling space. We find that simulating active septal contraction is important in modeling ventricular interaction. The model predicts increased arterio-venous CO2 due to hypoperfusion, and we explore implications of respiratory pattern in tamponade.

Conclusion: Our modeling study of cardiac tamponade dissects the roles played by septal motion, atrioventricular and right-left ventricular interactions, pulmonary blood pooling, and the depth of respiration. The study fully describes the physiological basis of pulsus paradoxus. Our detailed analysis provides biophysically-based insights helpful for future experimental and clinical study of cardiac tamponade and related pericardial diseases.

Background: The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate.

Methods: A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues.

Results: This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model.

Conclusion: Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters.

Background: In hemodialysis patients, the most common cause of vascular access failure is neointimal hyperplasia of vascular smooth muscle cells at the venous anastomosis of arteriovenous fistulas and grafts. The release of growth factors due to surgical injury, oxidative stress and turbulent flow has been suggested as a possible mechanism for neointimal hyperplasia.

Results: In this work, we construct a mathematical model which analyzes the role that growth factors might play in the stenosis at the venous anastomosis. The model consists of a system of partial differential equations describing the influence of oxidative stress and turbulent flow on growth factors, the interaction among growth factors, smooth muscle cells, and extracellular matrix, and the subsequent effect on the stenosis at the venous anastomosis, which, in turn, affects the level of oxidative stress and degree of turbulent flow. Computer simulations suggest that our model can be used to predict access stenosis as a function of the initial concentration of the growth factors inside the intimal-luminal space.

Conclusion: The proposed model describes the formation of venous neointimal hyperplasia, based on pathogenic mechanisms. The results suggest that interventions aimed at specific growth factors may be successful in prolonging the life of the vascular access, while reducing the costs of vascular access maintenance. The model may also provide indication of when invasive access surveillance to repair stenosis should be undertaken.

Background: Abel and Trevors have delineated three aspects of sequence complexity, Random Sequence Complexity (RSC), Ordered Sequence Complexity (OSC) and Functional Sequence Complexity (FSC) observed in biosequences such as proteins. In this paper, we provide a method to measure functional sequence complexity.

Methods and results: We have extended Shannon uncertainty by incorporating the data variable with a functionality variable. The resulting measured unit, which we call Functional bit (Fit), is calculated from the sequence data jointly with the defined functionality variable. To demonstrate the relevance to functional bioinformatics, a method to measure functional sequence complexity was developed and applied to 35 protein families. Considerations were made in determining how the measure can be used to correlate functionality when relating to the whole molecule and sub-molecule. In the experiment, we show that when the proposed measure is applied to the aligned protein sequences of ubiquitin, 6 of the 7 highest value sites correlate with the binding domain.

Conclusion: For future extensions, measures of functional bioinformatics may provide a means to evaluate potential evolving pathways from effects such as mutations, as well as analyzing the internal structural and functional relationships within the 3-D structure of proteins.

Background: Although propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression.

Methods: Theoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model.

Results: Compared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%.

Conclusion: The integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.

Background: Portal hypertension is a clinical syndrome that manifests as ascites, portosystemic encephalopathy and variceal hemorrhage, and these alterations often lead to death.

Hypothesis: Splanchnic and/or systemic responses to portal hypertension could have pathophysiological mechanisms similar to those involved in the post-traumatic inflammatory response.The splanchnic and systemic impairments produced throughout the evolution of experimental prehepatic portal hypertension could be considered to have an inflammatory origin. In portal vein ligated rats, portal hypertensive enteropathy, hepatic steatosis and portal hypertensive encephalopathy show phenotypes during their development that can be considered inflammatory, such as: ischemia-reperfusion (vasodilatory response), infiltration by inflammatory cells (mast cells) and bacteria (intestinal translocation of endotoxins and bacteria) and lastly, angiogenesis. Similar inflammatory phenotypes, worsened by chronic liver disease (with anti-oxidant and anti-enzymatic ability reduction) characterize the evolution of portal hypertension and its complications (hepatorenal syndrome, ascites and esophageal variceal hemorrhage) in humans.

Conclusion: Low-grade inflammation, related to prehepatic portal hypertension, switches to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease.

Background: The Proteomic Code is a set of rules by which information in genetic material is transferred into the physico-chemical properties of amino acids. It determines how individual amino acids interact with each other during folding and in specific protein-protein interactions. The Proteomic Code is part of the redundant Genetic Code.

Review: The 25-year-old history of this concept is reviewed from the first independent suggestions by Biro and Mekler, through the works of Blalock, Root-Bernstein, Siemion, Miller and others, followed by the discovery of a Common Periodic Table of Codons and Nucleic Acids in 2003 and culminating in the recent conceptualization of partial complementary coding of interacting amino acids as well as the theory of the nucleic acid-assisted protein folding.

Methods and conclusions: A novel cloning method for the design and production of specific, high-affinity-reacting proteins (SHARP) is presented. This method is based on the concept of proteomic codes and is suitable for large-scale, industrial production of specifically interacting peptides.

Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology?

Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign" intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates early in life to form a multi-layer intimal hyperplasia and then continues to self-renew in a controlled manner throughout life, relatively rarely compromising the blood supply to the heart, causing complications requiring intervention only in a small fraction of the population, while all humans are carriers of benign hyperplasia. Unfortunately, this fundamental fact has not been widely appreciated in arteriosclerosis research and medical education, which continue to operate on the assumption that the normal arterial intima is always an "ideal" single-layer endothelium. As a result, the disease is perceived and studied as a new pathological event caused by new mechanisms. The discovery that normal coronary arteries are morphologically indistinguishable from deadly coronary arteriosclerosis continues to elicit surprise.

Conclusion: Two questions should inform the priorities of our research: (1) what controls switch the single cell-layer intimal phenotype into normal hyperplasia? (2) how is normal (benign) hyperplasia maintained? We would be hard-pressed to gain practical insights without scrutinizing our premises.