scholarly journals Genealogies in Growing Solid Tumors

2018 ◽  
Author(s):  
Duke U. Rick Durrett
Keyword(s):  
Evolutionary Dynamics ◽  
Big Bang ◽  
Two Dimensions ◽  
Three Dimensions ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Alternative Theory ◽  
The Past ◽  
Fitness Advantage ◽  
Expanding Population

AbstractOver the past two decades, the theory of tumor evolution has largely focused on the selective sweeps model. According to this theory, tumors evolve by a succession of clonal expansions that are initiated by driver mutations that have a fitness advantage over the resident types. A 2015 study of colon cancer [44] has suggested an alternative theory of tumor evolution, the so-called Big Bang model, in which all of the necessary driver mutations are acquired before expansion began, and the evolutionary dynamics within the expanding population are predominantly neutral. In this paper, we will describe a simple mathematical model inspired by work of Hallatschek and Nelson [25] that makes quantitative predictions about spatial patterns of genetic variability. While this model has some success in matching observed patterns in two dimensions, it fails miserably in three dimensions. Despite this failure, we think the model analyzed here will be a useful first step in building an accurate model.

scholarly journals Genotype patterns in growing solid tumors

2018 ◽  
Author(s):  
Mridu Nanda ◽  
Rick Durrett ◽  
U Harvard ◽  
U Duke
Keyword(s):  
Evolutionary Dynamics ◽  
Big Bang ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Alternative Theory ◽  
Cancer Data ◽  
The Past ◽  
Big Bang Model ◽  
Expanding Population ◽  
Colon Cancer Data

AbstractOver the past decade, the theory of tumor evolution has largely focused on the selective sweeps model. According to this theory, tumors evolve by a succession of clonal expansions that are initiated by driver mutations. In a 2015 analysis of colon cancer data, Sottoriva et al [34] proposed an alternative theory of tumor evolution, the so-called Big Bang model, in which one or more driver mutations are acquired by the founder gland, and the evolutionary dynamics within the expanding population are predominantly neutral. In this paper we will describe a simple mathematical model that reproduces qualitative features of the observed paatterns of genetic variability and makes quantitative predictions.

scholarly journals Revisiting the tumorigenesis timeline with a data-driven generative model

2019 ◽  
Vol 117 (2) ◽  
pp. 857-864 ◽  
Author(s):  
Kamel Lahouel ◽  
Laurent Younes ◽  
Ludmila Danilova ◽  
Francis M. Giardiello ◽  
Ralph H. Hruban ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
Mechanistic Explanation ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Early Event ◽  
Driver Gene ◽  
Driver Genes ◽  
Fitness Advantage ◽  
Sequencing Studies ◽  
Cancer Types

Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.

scholarly journals A tug-of-war between driver and passenger mutations in cancer and other adaptive processes

2014 ◽  
Author(s):  
Christopher Dennis McFarland ◽  
Leonid A Mirny ◽  
Kirill S Korolev
Keyword(s):  
Mutation Rate ◽  
Cancer Progression ◽  
Evolutionary Dynamics ◽  
Cancer Genomics ◽  
Treatment Strategies ◽  
Driver Mutations ◽  
Fitness Advantage ◽  
Adaptive Processes ◽  
Passenger Mutations ◽  
Stochastic Population Model

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few ‘driver’ mutations occur alongside thousands of random ‘passenger’ mutations––a natural consequence of cancer's elevated mutation rate. Some passengers can be deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression that is described by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers meltdown. We find support for the model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to rationalize successes and failures of different treatment strategies. We find that a tumor’s load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by both current and future therapies.

scholarly journals Normal tissue architecture determines the evolutionary course of cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jeffrey West ◽  
Ryan O. Schenck ◽  
Chandler Gatenbee ◽  
Mark Robertson-Tessi ◽  
Alexander R. A. Anderson
Keyword(s):  
Evolutionary Dynamics ◽  
Neutral Evolution ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Tissue Architecture ◽  
Spatial Constraints ◽  
Fitness Effects ◽  
Two Factors ◽  
Mixing Rates ◽  
Precancerous Stage

AbstractCancer growth can be described as a caricature of the renewal process of the tissue of origin, where the tissue architecture has a strong influence on the evolutionary dynamics within the tumor. Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time. This approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Time-varying competition leads to an emergent transition from Darwinian premalignant growth to subsequent invasive neutral tumor growth. Initial spatial constraints determine the emergent mode of evolution (Darwinian to neutral) without a change in cell-specific mutation rate or fitness effects. Driver acquisition during the Darwinian precancerous stage may be modulated en route to neutral evolution by the combination of two factors: spatial constraints and limited cellular mixing. These two factors occur naturally in ductal carcinomas, where the branching topology of the ductal network dictates spatial constraints and mixing rates.

scholarly journals Tumour heterogeneity and evolutionary dynamics in colorectal cancer

Oncogenesis ◽  
2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Dedrick Kok Hong Chan ◽  
Simon James Alexander Buczacki
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Evolutionary Dynamics ◽  
Big Bang ◽  
Complex Model ◽  
Neutral Evolution ◽  
Driver Mutations ◽  
Current Evidence ◽  
Tumour Heterogeneity ◽  
Driver Genes

AbstractColorectal cancer (CRC) has a global burden of disease. Our current understanding of CRC has progressed from initial discoveries which focused on the stepwise accumulation of key driver mutations, as encapsulated in the Vogelstein model, to one in which marked heterogeneity leads to a complex interplay between clonal populations. Current evidence suggests that an initial explosion, or “Big Bang”, of genetic diversity is followed by a period of neutral dynamics. A thorough understanding of this interplay between clonal populations during neutral evolution gives insights into the roles in which driver genes may participate in the progress from normal colonic epithelium to adenoma and carcinoma. Recent advances have focused not only on genetics, transcriptomics, and proteomics but have also investigated the ecological and evolutionary processes which transform normal cells into cancer. This review first describes the role which driver mutations play in the Vogelstein model and subsequently demonstrates the evidence which supports a more complex model. This article also aims to underscore the significance of tumour heterogeneity and diverse clonal populations in cancer progression.

The Sea Fight Tomorrow

2018 ◽  
Author(s):  
Donald C. Williams
Keyword(s):  
Three Dimensions ◽  
The Past ◽  
The World ◽  
The Future ◽  
Metaphysics Of Time ◽  
Manifold Theory ◽  
Dimensions Of Space

This chapter is the first of this book to deal specifically with the metaphysics of time. This chapter defends the pure manifold theory of time. On this view, time is just another dimension of extent like the three dimensions of space, the past, present, and future are equally real, and the world is at bottom tenseless. What is true is eternally true. For example, it is now true that there will be a sea fight tomorrow or that there will not be a sea fight tomorrow. It is argued that the pure manifold theory does not entail fatalism and that contingent statements about the future do not imply that only the past and present exist.

scholarly journals Data on Orientation to Happiness in Higher Education Institutions from Mexico and El Salvador

Data ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. 27
Author(s):  
Domingo Villavicencio-Aguilar ◽  
Edgardo René Chacón-Andrade ◽  
Maria Fernanda Durón-Ramos
Keyword(s):  
Higher Education ◽  
El Salvador ◽  
Latin American ◽  
Higher Education Institutions ◽  
Two Dimensions ◽  
Three Dimensions ◽  
Stepwise Multiple Regression ◽  
Teacher Student ◽  
And Gender ◽  
Student’S T

Happiness-oriented people are vital in every society; this is a construct formed by three different types of happiness: pleasure, meaning, and engagement, and it is considered as an indicator of mental health. This study aims to provide data on the levels of orientation to happiness in higher-education teachers and students. The present paper contains data about the perception of this positive aspect in two Latin American countries, Mexico and El Salvador. Structure instruments to measure the orientation to happiness were administrated to 397 teachers and 260 students. This data descriptor presents descriptive statistics (mean, standard deviation), internal consistency (Cronbach’s alpha), and differences (Student’s t-test) presented by country, population (teacher/student), and gender of their orientation to happiness and its three dimensions: meaning, pleasure, and engagement. Stepwise-multiple-regression-analysis results are also presented. Results indicated that participants from both countries reported medium–high levels of meaning and engagement happiness; teachers reported higher levels than those of students in these two dimensions. Happiness resulting from pleasure activities was the least reported in general. Males and females presented very similar levels of orientation to happiness. Only the population (teacher/student) showed a predictive relationship with orientation to happiness; however, the model explained a small portion of variance in this variable, which indicated that other factors are more critical when promoting orientation to happiness in higher-education institutions.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals Free partition functions and an averaged holographic duality

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Nima Afkhami-Jeddi ◽  
Henry Cohn ◽  
Thomas Hartman ◽  
Amirhossein Tajdini
Keyword(s):  
Partition Function ◽  
Spectral Gap ◽  
Central Charge ◽  
Three Dimensional ◽  
Two Dimensions ◽  
Three Dimensions ◽  
Partition Functions ◽  
General Constraints ◽  
Dimensional Gravity ◽  
Holographic Duality

Abstract We study the torus partition functions of free bosonic CFTs in two dimensions. Integrating over Narain moduli defines an ensemble-averaged free CFT. We calculate the averaged partition function and show that it can be reinterpreted as a sum over topologies in three dimensions. This result leads us to conjecture that an averaged free CFT in two dimensions is holographically dual to an exotic theory of three-dimensional gravity with U(1)c×U(1)c symmetry and a composite boundary graviton. Additionally, for small central charge c, we obtain general constraints on the spectral gap of free CFTs using the spinning modular bootstrap, construct examples of Narain compactifications with a large gap, and find an analytic bootstrap functional corresponding to a single self-dual boson.

Turbulent three-dimensional dielectric electrohydrodynamic convection between two plates

2012 ◽  
Vol 696 ◽  
pp. 228-262 ◽  
Author(s):  
A. Kourmatzis ◽  
J. S. Shrimpton
Keyword(s):  
Spatial Data ◽  
Three Dimensional ◽  
Reynolds Numbers ◽  
Two Dimensions ◽  
Three Dimensions ◽  
Energy Budgets ◽  
Turbulent Regime ◽  
Scalar Flux ◽  
Wide Range ◽  
Scalar Variance

AbstractThe fundamental mechanisms responsible for the creation of electrohydrodynamically driven roll structures in free electroconvection between two plates are analysed with reference to traditional Rayleigh–Bénard convection (RBC). Previously available knowledge limited to two dimensions is extended to three-dimensions, and a wide range of electric Reynolds numbers is analysed, extending into a fully inherently three-dimensional turbulent regime. Results reveal that structures appearing in three-dimensional electrohydrodynamics (EHD) are similar to those observed for RBC, and while two-dimensional EHD results bear some similarities with the three-dimensional results there are distinct differences. Analysis of two-point correlations and integral length scales show that full three-dimensional electroconvection is more chaotic than in two dimensions and this is also noted by qualitatively observing the roll structures that arise for both low (${\mathit{Re}}_{E} = 1$) and high electric Reynolds numbers (up to ${\mathit{Re}}_{E} = 120$). Furthermore, calculations of mean profiles and second-order moments along with energy budgets and spectra have examined the validity of neglecting the fluctuating electric field ${ E}_{i}^{\ensuremath{\prime} } $ in the Reynolds-averaged EHD equations and provide insight into the generation and transport mechanisms of turbulent EHD. Spectral and spatial data clearly indicate how fluctuating energy is transferred from electrical to hydrodynamic forms, on moving through the domain away from the charging electrode. It is shown that ${ E}_{i}^{\ensuremath{\prime} } $ is not negligible close to the walls and terms acting as sources and sinks in the turbulent kinetic energy, turbulent scalar flux and turbulent scalar variance equations are examined. Profiles of hydrodynamic terms in the budgets resemble those in the literature for RBC; however there are terms specific to EHD that are significant, indicating that the transfer of energy in EHD is also attributed to further electrodynamic terms and a strong coupling exists between the charge flux and variance, due to the ionic drift term.

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