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Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure

Abstract (Expand)

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common … inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

Authors: Saskia Haupt, Alexander Zeilmann, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Date Published: 1st May 2021

Publication Type: Journal

From spontaneous to strategic natural window ventilation: Improving indoor air quality in Swiss schools

Abstract

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Authors: Claudia C. Vassella, Jeremy Koch, Alexander Henzi, Alexander Jordan, Roger Waeber, Reto Iannaccone, Roland Charrière

Date Published: 1st May 2021

Publication Type: Journal

Scoring interval forecasts: Equal-tailed, shortest, and modal interval

Abstract

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Authors: Jonas R. Brehmer, Tilmann Gneiting

Date Published: 1st May 2021

Publication Type: Journal

Post-processing numerical weather prediction ensembles for probabilistic solar irradiance forecasting

Abstract

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Authors: Benedikt Schulz, Mehrez El Ayari, Sebastian Lerch, Sándor Baran

Date Published: 1st May 2021

Publication Type: Journal

Double detonations of sub-M Ch CO white dwarfs: variations in Type Ia supernovae due to different core and He shell masses

Abstract

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Authors: Sabrina Gronow, Christine E. Collins, Stuart A. Sim, Friedrich K. Röpke

Date Published: 1st May 2021

Publication Type: Journal

Borel and Volume Classes for Dense Representations of Discrete Groups

Abstract

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Author: James Farre

Date Published: 19th Apr 2021

Publication Type: Journal

The Law of Attraction: Relating Computed Energetics of Physisorption with Performance of Graphene-Based Sensors for Nitroaromatic Contaminants

Abstract (Expand)

The ability to detect persistent nitroaromatic contaminants, e.g. DNT and TNT, with high sensitivity and selectivity is central to environmental science and medicinal diagnostics. Graphene-based materials … rise to this challenge, offering supreme performance, biocompatibility, and low toxicity at a reasonable cost. In the first step of the electrochemical sensing process, these substrates establish non-covalent interactions with the analytes, which we show to be indicative of their respective detection limits. Employing a combination of semiempirical tight binding quantum chemistry, meta- dynamics, density functional theory, and symmetry-adapted perturbation theory in conjunction with curated data from experimental literature, we investigate the physisorption of DNT and TNT on a series of functionalised graphene derivatives. In agreement with experimental observations, systems with greater planarity and positively charged substrates afford stronger non-covalent interactions than their highly oxidised distorted counterparts. Despite the highly polar nature of the investigated species, their non-covalent interactions are largely driven by dispersion forces. To harness these design principles, we considered a series of boron and nitrogen (co)doped two-dimensional materials. One of these systems featuring a chain of B–N–C units was found to adsorb nitroaromatic molecules stronger than the pristine graphene itself. These findings form the basis for the design principles of sensing materials and illustrate the utility of relatively low cost in silico procedures for testing the viability of designed graphene-based sensors for a plethora of analytes.

Authors: Anna Piras, Ganna Gryn'ova

Date Published: 5th Apr 2021

Publication Type: Unpublished

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