Biology subjects

Caviglia, G.

Publications and source records attributed to Caviglia, G..

7 recordsLinked to original sources

bioRxiv2025

From Michaelis-Menten parameters to microscopic rate constants: an inversion approach for enzyme kinetics

A basic model of enzyme kinetics is the enzyme-catalyzed reaction, in which a single enzyme E binds a substrate S to form a complex C, which subsequently releases a product P and regenerates the enzyme. According to the mass-action law, this process can be described by a system of four ordinary differential equations for the four unknown concentrations, governed by the microscopic rate constants: forward (kf), reverse (kr), and catalytic (kcat). Under suitable assumptions, the full system reduces to the classical Michaelis-Menten model, depending on two experimentally measurable parameters: the half saturation constant (Km), and the limiting rate Vmax. This paper addresses the inverse problem of recovering kf and kr from Km and Vmax (or equivalently kcat, retrievable from Vmax). The proposed method exploits a new identity satisfied by any substrate concentration s(t) in the full mass-action system, which provides the starting point for the inversion procedure. Here, a detailed presentation of an algorithm for reaching this goal is provided, along with an assessment of reconstruction accuracy and an outline of simulations and applications. Beyond enzyme kinetics, the approach supports the construction of novel chemical reaction networks, with potential applications to modeling complex biochemical pathways involved in diseases such as cancer.

bioinformatics↗

bioRxiv2023

In-silico modelling of the mitogen-activated kinase (MAPK) pathway in colorectal cancer: mutations and targeted therapy

Chemical reaction networks are powerful tools for computing the complex nature of cancers onset, progression, and therapy. The main reason for their effectiveness is in the fact that these networks can be rather naturally encoded as a dynamical system whose asymptotic solution mimics the proteins concentration profile at equilibrium. The paper relies on this mathematical approach to investigate global and local effects on the chemical reaction network of the colorectal cancer, triggered by partial and complete mutations occurring in its mitogen-activated kinase (MAPK) pathway. Further, this same approach allowed the in-silico modelling and dosage of a multi-target therapeutic intervention that utilizes MAPK as its molecular target.

systems biology↗

bioRxiv2023

SSI: A Statistical Sensitivity Index for Chemical Reaction Networks in cancer

SO_SCPLOWUMMARYC_SCPLOWAt the cellular level, cancer is triggered by mutations of the proteins involved in signalling networks made of hundreds of reacting species. The corresponding mathematical model consists of a large system of non-linear Ordinary Differential Equations for the unknown proteins concentrations depending on a consistently large number of kinetic parameters and initial concentrations. For this model, the present paper considers the problem of assessing the impact of each parameter and initial concentration on the systems output. More specifically, we introduced a statistical sensitivity index whose values can be easily computed by means of principal component analysis, and which leads to the partition of the parameters and initial concentrations sets into sensible and non-sensible families. This approach allows the identification of those kinetic parameters and initial concentrations that mostly impact the mutation-driven modification of the proteomic profile at equilibrium, and of those pathways in the network that are mostly affected by the presence of mutations in the cancer cell.

systems biology↗

bioRxiv2020

Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells.

Colorectal cancer (CRC) is one of the most deadly and commonly diagnosed tumors worldwide. Several genes are involved in its development and progression. The most frequent mutations concern APC, KRAS, SMAD4, and TP53 genes, suggesting that CRC relies on the alteration of different pathways. However, with classic molecular approaches, it is not easy to simultaneously analyze the interconnections between these pathways. For this reason, we propose a computational model based on a huge chemical reaction network to simulate the effects induced on the global signaling associated with CRC by single or multiple concurrent mutations or by drug treatment. This approach displays several advantages. The model can quantify the alteration in the concentration of the proteins connected with the examined mutation. Moreover, working on the global signaling of CRC, it is possible to disclose unexpected interactions between the involved pathways, representing new therapeutic targets. HighlightsO_LIColorectal cancer relates to defects in many different pathways within cell signaling C_LIO_LICell signaling is modeled as a chemical ration network with 10 interacting pathways C_LIO_LIGlobal effects induced by single or multiple concurrent mutations are quantified C_LIO_LIA possible extension of the model to account for a targeted drug is discussed C_LI

cancer biology↗

bioRxiv2020

Gain and Loss of Function mutations in biological chemical reaction networks: a mathematical model with application to colorectal cancer cells

This paper studies a system of Ordinary Differential Equations modeling a chemical reaction network and derives from it a simulation tool mimicking Loss of Function and Gain of Function mutations found in cancer cells. More specifically, from a theoretical perspective, our approach focuses on the determination of moiety conservation laws for the system and their relation with the corresponding stoichiometric surfaces. Then we show that Loss of Function mutations can be implemented in the model via modification of the initial conditions in the system, while Gain of Function mutations can be implemented by eliminating specific reactions. Finally, the model is utilized to examine in detail the G1-S phase of a colorectal cancer cell.

systems biology↗

bioRxiv2019

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

A very recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper was to confirm this result in vivo, using small animal models of CT26 cancer tissues. Specifically, assuming that the endoplasmic reticulum plays a specific functional role in the framework of a three-compartment model for FDG kinetics, we are able to explain positron emission tomography dynamic data in a more reliable way than by means of a standard Sokoloff two-compartment system. This result is made more solid from a computational viewpoint by means of some identifiability considerations based on a mathematical analysis of the compartmental equations.

cancer biology↗

bioRxiv2017

Parametric Imaging Of FDG-PET Data Using Physiology And Iterative Regularization: Application To The Hepatic And Renal Systems

I. AIMS I. AIMS II. METHODS III. RESULTS IV. CONCLUSIONS REFERENCES Positron Emission Tomography (PET) [1] is a nuclear medicine imaging technique capable of detecting the time dependent spatial distribution of pico-molar quantities of a labelled tracer, which is diffused into a living body. FDG-PET is a PET modality in which the radiopharmaceutical [18F]Fluoro-2-deoxy-D-glucose (FDG) is used as a tracer to observe metabolic processes related to glucose consumption. In order to overcome the limits of spatial resolution in PET and to improve the quality of information achievable from PET images, one approach is to develop parametric imaging methods able of showing the tracer metabolism at a local level. Starting from the design of compartmental models appropriate to describe the tracer kinetics in a predefined physiol ...

physiology↗