A Multi-Scale Computational Approach to Understanding Cancer Metabolism

Lucia, Ángelo; DiMaggio, Peter A.

doi:10.1007/978-3-030-05249-2_13

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…Nash Equilibrium modeling. The modeling approach used in this manuscript is based on the Nash equilibrium (NE) framework for determining unknown fluxes throughout a given network recently developed by Lucia and coworkers 25,26,27 and is quite unlike FBA, MFA, or kinetic modeling. The NE approach is a first principles approach that uses chemical equilibrium and mass balance and is based on the following three ideas: 1) Enzymes are players in a multi-player game.…”

Section: Methodsmentioning

confidence: 99%

“…3) The goal of the metabolic network is to find the best overall solution given the natural competition for nutrients among enzymes. A detailed description of the mathematical framework associated with the Nash Equilibrium approach is given in Lucia and DiMaggio 27 , the first part of which is a tutorial describing the mathematical formulation, governing equations, and algorithmic aspects such as charge balancing, linear independence of constraints, enzyme-substrate reactions, etc. Here we present the basic formulation as well as a Nash Equilibrium pseudo-algorithm in order to give the reader a better overall understanding of the sequence of computations used in the general case.…”

Section: Methodsmentioning

confidence: 99%

“…In this work, we propose a novel approach for modeling and numerical simulation of liver metabolism during static cold storage that leverages the Nash Equilibrium (NE) methodology recently developed by Lucia and coworkers 25,26,27 and enables modeling the dynamics with a very limited set of thermodynamic parameters that are readily accessible in literature. A general overview of the NE methodology is presented, followed by a description of the generalized metabolic network model developed for NE modeling of perfusion, in turn followed by numerical results for Nash Equilibrium (NE) simulations of liver metabolism for SCS.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Energy Depletion in Rat Livers Using Nash Equilibrium Metabolic Pathway Analysis

Lucia

Ferrarese

Uygun

2021

Preprint

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The current gold standard of Static Cold Storage (SCS), which is static cold storage on ice (about +4°C) in a specialized media such as the University of Wisconsin solution (UW), limits storage to few hours for vascular and metabolically active tissues such as the liver and the heart. The liver is arguably the pinnacle of metabolism in human body and therefore metabolic pathway analysis immediately becomes very relevant. In this article, a Nash Equilibrium (NE) approach, which is a first principles approach, is used to model and simulate the static cold storage of a proposed model of liver cells. Simulations of energy depletion in the liver in static cold storage measured by ATP content and energy charge are presented along with comparisons to experimental data. In addition, conversion of Nash Equilibrium iterations to time are described along with an uncertainty analysis for the parameters in the model. Results in this work show that the Nash Equilibrium approach provides a good match to experimental data for energy depletion and that the uncertainty in model parameters is very small with percent variances less than 0.1%.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modeling Energy Depletion in Rat Livers Using Nash Equilibrium Metabolic Pathway Analysis

Lucia

Ferrarese

Uygun

2021

Preprint

Self Cite

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“…The modeling approach used in this manuscript is based on the Nash equilibrium (NE) framework for determining unknown fluxes throughout a given network recently developed by Lucia and coworkers (Lucia and DiMaggio, 2019). The application of NE to liver metabolism is discussed in detail in and will be briefly summarized here: 1) Enzymes are players in a multi-player game.…”

Section: Nash Equilibrium Modelingmentioning

confidence: 99%

“…Others have suggested the use of antioxidants (Salaris et al, 1991;Hines et al, 2013) to combat oxidative stress. The objective of this article is to test if the recently developed Nash Equilibrium (NE) modeling approach (Lucia and DiMaggio, 2019) to metabolic network analysis can be used to study oxidative stress and provide quantitative information for antioxidant supplementation in liver machine perfusion. This article is organized as follows.…”

Section: Introductionmentioning

confidence: 99%

Metabolic perturbation studies using a Nash Equilibrium model of liver machine perfusion: modeling oxidative stress and effect of glutathione supplementation

Lucia,

Uygun

2024

Front. Syst. Biol.

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The current clinical standard of Static Cold Storage (SCS) which involves preservation on ice (about +4°C) in a hypoxic state limits storage to a few hours for metabolically active tissues such as the liver and the heart. This period of hypoxia during can generate superoxide and other free radicals from purine metabolism, a well-established component of ischemia/reperfusion injury (IRI). Machine perfusion is at the cutting edge of organ preservation, which provides a functional, oxygenated preservation modality that can avoid/attenuate IRI. In clinical application, perfusion usually follows a period of SCS. This presentation of oxygen following hypoxia can lead to superoxide and hydrogen peroxide generation, but machine perfusion also allows manipulation of the temperature profiles and supply of antioxidant treatments, which could be used to minimize such issues. However, metabolomic data is difficult to gather, and there are currently no mathematical models present to allow rational design of experiments or guide clinical practice. In this article, the effects of a gradual warming temperature policy and glutathione supplementation to minimize oxidative stress are studied. An optimal gradual warming temperature policy for mid-thermic machine perfusion of a liver metabolic model is determined using a combination of Nash Equilibrium and Monte Carlo optimization. Using this optimal gradual warming temperature policy, minimum GSH requirements to maintain hydrogen peroxide concentrations in the normal region are calculated using a different Monte Carlo optimization methodology. In addition, the dynamic behavior of key metabolites and cofactors are determined. Results show that the minimum GSH requirement increases and that the ratio of GSH/GSSG decreases with increasing hydrogen peroxide concentration. In addition, at high concentrations of hydrogen peroxide it is shown that cytochrome C undergoes dysfunction leading to a decrease in useful oxygen consumption and ATP synthesis from the electron transport chain and an overall reduction in the energy charge for the liver cells.

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Optimal Temperature Protocols for Liver Machine Perfusion Using a Monte Carlo Method

Lucia

Uygun

2022

IFAC-PapersOnLine

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A Multi-Scale Computational Approach to Understanding Cancer Metabolism

Cited by 4 publications

References 16 publications

Modeling Energy Depletion in Rat Livers Using Nash Equilibrium Metabolic Pathway Analysis

Modeling Energy Depletion in Rat Livers Using Nash Equilibrium Metabolic Pathway Analysis

Metabolic perturbation studies using a Nash Equilibrium model of liver machine perfusion: modeling oxidative stress and effect of glutathione supplementation

Optimal Temperature Protocols for Liver Machine Perfusion Using a Monte Carlo Method

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