Antimonotonicity, Crisis, and Route to Chaos in a Tumor Growth Model

2021 ◽  
pp. 583-596
Author(s):  
Dionysios Sourailidis ◽  
Christos Volos ◽  
Lazaros Moysis ◽  
Ioannis Stouboulos
Keyword(s):  
Tumor Growth ◽  
Phase Portrait ◽  
Nonlinear Theory ◽  
Chaos Theory ◽  
Immune Cells ◽  
Period Doubling ◽  
New Model ◽  
Tumor Growth Model ◽  
Route To Chaos ◽  
First Time

In this chapter, a new model of a tumor growth is dynamically investigated. The model is presented in a form of a system of three ordinary differential equations, which describe the avascular, vascular, and metastasis tumor growth, respectively. For the investigation of system's dynamics and especially of the population of the immune cells in system's behavior, some of the most well-known tools from nonlinear theory, such as the phase portrait, the Poincaré map, the bifurcation diagram the Kaplan-Yorke dimension, and the Lyapunov exponents have been used. Interesting phenomena related with chaos theory, such as a period-doubling route to chaos, crisis phenomena, and antimonotonicity, have been revealed for the first time in this model.

A Dream that has Come True: Chaos from a Nonlinear Circuit with a Real Memristor

2020 ◽  
Vol 30 (13) ◽  
pp. 2030036
Author(s):  
Christos K. Volos ◽  
Viet-Thanh Pham ◽  
Hector E. Nistazakis ◽  
Ioannis N. Stouboulos
Keyword(s):  
Chaos Theory ◽  
Period Doubling ◽  
Nonlinear Circuits ◽  
Nonlinear Element ◽  
Chaotic Attractors ◽  
Nonlinear Circuit ◽  
Coexisting Attractors ◽  
Circuit Element ◽  
Route To Chaos ◽  
First Time

In the last decade, researchers, who work in the field of nonlinear circuits, have the “dream” to use a real memristor, which is the only nonlinear fundamental circuit element, in a new or other reported nonlinear circuit in literature, in order to experimentally investigate chaos. With this intention, for the first time, a well-known nonlinear circuit, in which its nonlinear element has been replaced with a commercially available memristor (KNOWM memristor), is presented in this work. Interesting phenomena concerning chaos theory, such as period-doubling route to chaos, coexisting attractors, one-scroll and double-scroll chaotic attractors are experimentally observed.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals 601 Development of improved small molecule STING agonists suitable for systemic administration

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A636-A636
Author(s):  
Maciej Rogacki ◽  
Stefan Chmielewski ◽  
Magdalena Zawadzka ◽  
Jolanta Mazurek ◽  
Katarzyna Wnuk-Lipińska ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Systemic Administration ◽  
Cytokine Release ◽  
Major Player ◽  
Human Immune ◽  
New Generation ◽  
Dose Dependent ◽  
Complete Tumor

BackgroundStimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells.MethodsBinding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring.ResultsRyvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells.ConclusionsNew generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.

scholarly journals Mouse IgG3 binding to macrophage-like cells is prevented by deglycosylation of the antibody or by Accutase treatment of the cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alicja Karabasz ◽  
Monika Bzowska ◽  
Joanna Bereta ◽  
Maria Czarnek ◽  
Maja Sochalska ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Complex Network ◽  
Immune Cells ◽  
Specific Receptor ◽  
Fcγ Receptors ◽  
Specific Receptors ◽  
First Time

AbstractThe binding of mouse IgG3 to Fcγ receptors (FcγR) and the existence of a mouse IgG3-specific receptor have been discussed for 40 years. Recently, integrin beta-1 (ITGB1) was proposed to be a part of an IgG3 receptor involved in the phagocytosis of IgG3-coated pathogens. We investigated the interaction of mouse IgG3 with macrophage-like J774A.1 and P388D1 cells. The existence of an IgG3-specific receptor was verified using flow cytometry and a rosetting assay, in which erythrocytes clustered around the macrophage-like cells coated with an erythrocyte-specific IgG3. Our findings confirmed that receptors binding antigen-free IgG3 are present on J774A.1 and P388D1 cells. We demonstrated for the first time that the removal of N-glycans from IgG3 completely abolished its binding to the cells. Moreover, we discovered that the cells treated with Accutase did not bind IgG3, indicating that IgG3-specific receptors are substrates of this enzyme. The results of antibody-mediated blocking of putative IgG3 receptors suggested that apart from previously proposed ITGB1, FcγRII, FcγRIII, also additional, still unknown, receptor is involved in IgG3 binding. These findings indicate that there is a complex network of glycan-dependent interactions between mouse IgG3 and the surface of effector immune cells.

scholarly journals A stable scheme for a nonlinear, multiphase tumor growth model with an elastic membrane

2014 ◽  
Vol 30 (7) ◽  
pp. 726-754 ◽  
Author(s):  
Ying Chen ◽  
Steven M. Wise ◽  
Vivek B. Shenoy ◽  
John S. Lowengrub
Keyword(s):  
Tumor Growth ◽  
Growth Model ◽  
Elastic Membrane ◽  
Tumor Growth Model ◽  
Stable Scheme

scholarly journals Robust domain of attraction estimation for a tumor growth model

2021 ◽  
Vol 410 ◽  
pp. 126482
Author(s):  
Kaouther Moussa ◽  
Mirko Fiacchini ◽  
Mazen Alamir
Keyword(s):  
Tumor Growth ◽  
Growth Model ◽  
Domain Of Attraction ◽  
Tumor Growth Model

scholarly journals Personalized Radiotherapy Planning Based on a Computational Tumor Growth Model

2017 ◽  
Vol 36 (3) ◽  
pp. 815-825 ◽  
Author(s):  
Matthieu Le ◽  
Herve Delingette ◽  
Jayashree Kalpathy-Cramer ◽  
Elizabeth R. Gerstner ◽  
Tracy Batchelor ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Model ◽  
Radiotherapy Planning ◽  
Tumor Growth Model

SYSTEM IDENTIFICATION IN TUMOR GROWTH MODELING USING SEMI-EMPIRICAL EIGENFUNCTIONS

2012 ◽  
Vol 22 (06) ◽  
pp. 1250003 ◽  
Author(s):  
THIERRY COLIN ◽  
ANGELO IOLLO ◽  
DAMIANO LOMBARDI ◽  
OLIVIER SAUT
Keyword(s):  
System Identification ◽  
Tumor Growth ◽  
Solution Space ◽  
Cellular Division ◽  
Volume Increase ◽  
Tumor Growth Model ◽  
Species Population ◽  
Tumor Growth Modeling ◽  
Low Dimensional ◽  
Semi Empirical

A tumor growth model based on a parametric system of partial differential equations is considered. The system corresponds to a phenomenological description of a multi-species population evolution. A velocity field taking into account the volume increase due to cellular division is introduced and the mechanical closure is provided by a Darcy-type law. The complexity of the biological phenomenon is taken into account through a set of parameters included in the model that need to be calibrated. To this end, a system identification method based on a low-dimensional representation of the solution space is introduced. We solve several idealized identification cases corresponding to typical situations where the information is scarce in time and in terms of observable fields. Finally, applications to actual clinical data are presented.

Transitions Through Period Doubling Route to Chaos

1991 ◽  
Author(s):  
R. M. Evan-lwanowski ◽  
Chu-Ho Lu
Keyword(s):  
Period Doubling ◽  
Mirror Image ◽  
Flip Flop ◽  
Physical Systems ◽  
Starting Conditions ◽  
Spatial System ◽  
Stationary Bifurcation ◽  
Extreme Sensitivity ◽  
Route To Chaos ◽  
Parameter Values

Abstract The Duffing driven, damped, “softening” oscillator has been analyzed for transition through period doubling route to chaos. The forcing frequency and amplitude have been varied in time (constant sweep). The stationary 2T, 4T… chaos regions have been determined and used as the starting conditions for nonstationary regimes, consisting of the transition along the Ω(t)=Ω0±α2t,f=const., Ω-line, and along the E-line: Ω(t)=Ω0±α2t;f(t)=f0∓α2t. The results are new, revealing, puzzling and complex. The nonstationary penetration phenomena (delay, memory) has been observed for a single and two-control nonstationary parameters. The rate of penetrations tends to zero with increasing sweeps, delaying thus the nonstationary chaos relative to the stationary chaos by a constant value. A bifurcation discontinuity has been uncovered at the stationary 2T bifurcation: the 2T bifurcation discontinuity drops from the upper branches of (a, Ω) or (a, f) curves to their lower branches. The bifurcation drops occur at the different control parameter values from the response x(t) discontinuities. The stationary bifurcation discontinuities are annihilated in the nonstationary bifurcation cascade to chaos — they reside entirely on the upper or lower nonstationary branches. A puzzling drop (jump) of the chaotic bifurcation bands has been observed for reversed sweeps. Extreme sensitivity of the nonstationary bifurcations to the starting conditions manifests itself in the flip-flop (mirror image) phenomena. The knowledge of the bifurcations allows for accurate reconstruction of the spatial system itself. The results obtained may model mathematically a number of engineering and physical systems.

Detailed Stress Analysis of a Spherical Acrylic Submersible by 3-D Finite Element Modeling

1999 ◽  
Author(s):  
Partha S. Das
Keyword(s):  
Finite Element ◽  
Numerical Modeling ◽  
Dissimilar Materials ◽  
Analysis Model ◽  
Element Analysis ◽  
Finite Element Analysis Model ◽  
New Model ◽  
Ocean Exploration ◽  
Near Future ◽  
First Time

Abstract Harbor Branch Oceanographic Institution (HBOI) designed, built and has operated two JOHNSON-SEA-LINK (JSL) manned submersibles for the past 25 years. The JSL submersibles each incorporate a 66–68 in. (1.6764–1.7272 m) OD, 4–5.25 in. (0.1016–0.13335 m) thick acrylic two-man sphere as a Pressure Vessel for Human Occupancy (PVHO). This type of spherical acrylic sphere or submersible was first introduced in around 1970 and is known as Naval Experimental Manned Observatory (NEMO) submersibles. As the demand increases for ocean exploration to 3000 ft. (914.4 m) depth to collect samples, to study the ocean surfaces, the problem of developing cracks at the interface of these manned acrylic submersibles following few hundred dives have become a common phenomena. This has drawn considerable attentions for reinvestigation of the spherical acrylic submersible in order to overcome this crack generation problem at the interface. Therefore, a new full-scale 3-D nonlinear FEA (Finite Element Analysis) model, similar to the spherical acrylic submersible that HBOI uses for ocean exploration, has been developed for the first time in order to simulate the structural behavior at the interface and throughout the sphere, for better understanding of the mechanical behavior. Variation of the stiffness between dissimilar materials at the interface, lower nylon gasket thickness, over designed aluminum hatch are seemed to be few of the causes for higher stresses within acrylic sphere at the nylon gasket/acrylic interface. Following the basic understanding of the stresses and relative displacements at the interface and within different parts of the submersible, various models have been developed on the basis of different shapes and thickness of nylon gaskets, openings of the acrylic sphere, hatch geometry and its materials, specifically to study their effect on the overall performance of the acrylic submersible. Finally, the new model for acrylic submersible has been developed by redesigning the top aluminum hatch and hatch ring, the sphere openings at both top and bottom, as well as the nylon gasket inserts. Altogether this new design indicates a significant improvement over the existing spherical acrylic submersible by reducing the stresses at the top gasket/acrylic interface considerably. Redesigning of the bottom penetrator plate, at present, is underway. In this paper, results from numerical modeling only are reported in details. Correlation between experimental-numerical modeling results for the new model will be reported in the near future.

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