scholarly journals A hybrid three-scale model of tumor growth

2017 ◽  
Vol 28 (01) ◽  
pp. 61-93 ◽  
Author(s):  
H. L. Rocha ◽  
R. C. Almeida ◽  
E. A. B. F. Lima ◽  
A. C. M. Resende ◽  
J. T. Oden ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Differential Equations ◽  
Tumor Growth ◽  
Nonlinear Differential Equations ◽  
Reaction Diffusion Equations ◽  
Scale Model ◽  
Wide Range ◽  
Induced Stresses ◽  
The Impact

Cancer results from a complex interplay of different biological, chemical, and physical phenomena that span a wide range of time and length scales. Computational modeling may help to unfold the role of multiple evolving factors that exist and interact in the tumor microenvironment. Understanding these complex multiscale interactions is a crucial step toward predicting cancer growth and in developing effective therapies. We integrate different modeling approaches in a multiscale, avascular, hybrid tumor growth model encompassing tissue, cell, and sub-cell scales. At the tissue level, we consider the dispersion of nutrients and growth factors in the tumor microenvironment, which are modeled through reaction–diffusion equations. At the cell level, we use an agent-based model (ABM) to describe normal and tumor cell dynamics, with normal cells kept in homeostasis and cancer cells differentiated into quiescent, proliferative, migratory, apoptotic, hypoxic, and necrotic states. Cell movement is driven by the balance of a variety of forces according to Newton’s second law, including those related to growth-induced stresses. Phenotypic transitions are defined by specific rule of behaviors that depend on microenvironment stimuli. We integrate in each cell/agent a branch of the epidermal growth factor receptor (EGFR) pathway. This pathway is modeled by a system of coupled nonlinear differential equations involving the mass laws of 20 molecules. The rates of change in the concentration of some key molecules trigger proliferation or migration advantage response. The bridge between cell and tissue scales is built through the reaction and source terms of the partial differential equations. Our hybrid model is built in a modular way, enabling the investigation of the role of different mechanisms at multiple scales on tumor progression. This strategy allows representing both the collective behavior due to cell assembly as well as microscopic intracellular phenomena described by signal transduction pathways. Here, we investigate the impact of some mechanisms associated with sustained proliferation on cancer progression. Speci- fically, we focus on the intracellular proliferation/migration-advantage-response driven by the EGFR pathway and on proliferation inhibition due to accumulation of growth-induced stresses. Simulations demonstrate that the model can adequately describe some complex mechanisms of tumor dynamics, including growth arrest in avascular tumors. Both the sub-cell model and growth-induced stresses give rise to heterogeneity in the tumor expansion and a rich variety of tumor behaviors.

History and Morality

2020 ◽  
Author(s):  
Donald Bloxham
Keyword(s):  
Foreign Country ◽  
Moral Thought ◽  
Majority Opinion ◽  
The Past ◽  
Wide Range ◽  
Moral Judgements ◽  
Value Judgements ◽  
The Impact

Against majority opinion within his profession, Donald Bloxham argues that it is legitimate, often unavoidable, and frequently important for historians to make value judgements about the past. History and Morality draws on a wide range of historical examples, and its author’s insights as a practising historian. Examining concepts like impartiality, neutrality, contextualization, and the use and abuse of the idea of the past as a foreign country, Bloxham’s book investigates how the discipline has got to the point where what is preached can be so inconsistent with what is practised. It illuminates how far tacit moral judgements infuse works of history, and how strange those histories would look if the judgements were removed. Bloxham argues that rather than trying to eradicate all judgemental elements from their work historians need to think more consistently about how, and with what justification, they make the judgements that they do. The importance of all this lies not just in the responsibilities that historians bear towards the past—responsibilities to take historical actors on those actors’ own terms and to portray the impact of those actors’ deeds—but also in the role of history as a source of identity, pride, and shame in the present. The account of moral thought in History and Morality has ramifications far beyond the activities of vocational historians.

scholarly journals 695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Loise Francisco-Anderson ◽  
Loise Francisco-Anderson ◽  
Mary Abdou ◽  
Michael Goldberg ◽  
Erin Troy ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Extracellular Vesicle ◽  
The Body ◽  
Checkpoint Inhibition ◽  
Small Intestinal ◽  
The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

scholarly journals Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma

2021 ◽  
Vol 22 (7) ◽  
pp. 3578
Author(s):  
Federico Armando ◽  
Adnan Fayyad ◽  
Stefanie Arms ◽  
Yvonne Barthel ◽  
Dirk Schaudien ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Virus Infection ◽  
Tumor Growth ◽  
Canine Distemper Virus ◽  
Xenograft Model ◽  
Histiocytic Sarcoma ◽  
Oncolytic Viruses ◽  
Canine Distemper ◽  
Murine Xenograft Model ◽  
The Impact

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.

scholarly journals Scale dependence of cirrus heterogeneity effects. Part II: MODIS NIR and SWIR channels

2018 ◽  
Vol 18 (16) ◽  
pp. 12105-12121 ◽  
Author(s):  
Thomas Fauchez ◽  
Steven Platnick ◽  
Tamás Várnai ◽  
Kerry Meyer ◽  
Céline Cornet ◽  
...  
Keyword(s):  
Radiative Transfer ◽  
Spatial Resolution ◽  
Thermal Infrared ◽  
Radiative Effects ◽  
Ice Clouds ◽  
Plane Parallel ◽  
Wide Range ◽  
The Impact ◽  
Side Illumination

Abstract. In a context of global climate change, the understanding of the radiative role of clouds is crucial. On average, ice clouds such as cirrus have a significant positive radiative effect, but under some conditions the effect may be negative. However, many uncertainties remain regarding the role of ice clouds on Earth's radiative budget and in a changing climate. Global satellite observations are particularly well suited to monitoring clouds, retrieving their characteristics and inferring their radiative impact. To retrieve ice cloud properties (optical thickness and ice crystal effective size), current operational algorithms assume that each pixel of the observed scene is plane-parallel and homogeneous, and that there is no radiative connection between neighboring pixels. Yet these retrieval assumptions are far from accurate, as real radiative transfer is 3-D. This leads to the plane-parallel and homogeneous bias (PPHB) plus the independent pixel approximation bias (IPAB), which impacts both the estimation of top-of-the-atmosphere (TOA) radiation and the retrievals. An important factor that determines the impact of these assumptions is the sensor spatial resolution. High-spatial-resolution pixels can better represent cloud variability (low PPHB), but the radiative path through the cloud can involve many pixels (high IPAB). In contrast, low-spatial-resolution pixels poorly represent the cloud variability (high PPHB), but the radiation is better contained within the pixel field of view (low IPAB). In addition, the solar and viewing geometry (as well as cloud optical properties) can modulate the magnitude of the PPHB and IPAB. In this, Part II of our study, we simulate TOA 0.86 and 2.13 µm solar reflectances over a cirrus uncinus scene produced by the 3DCLOUD model. Then, 3-D radiative transfer simulations are performed with the 3DMCPOL code at spatial resolutions ranging from 50 m to 10 km, for 12 viewing geometries and nine solar geometries. It is found that, for simulated nadir observations taken at resolution higher than 2.5 km, horizontal radiation transport (HRT) dominates biases between 3-D and 1-D reflectance calculations, but these biases are mitigated by the side illumination and shadowing effects for off-zenith solar geometries. At resolutions coarser than 2.5 km, PPHB dominates. For off-nadir observations at resolutions higher than 2.5 km, the effect that we call THEAB (tilted and homogeneous extinction approximation bias) due to the oblique line of sight passing through many cloud columns contributes to a large increase of the reflectances, but 3-D radiative effects such as shadowing and side illumination for oblique Sun are also important. At resolutions coarser than 2.5 km, the PPHB is again the dominant effect. The magnitude and resolution dependence of PPHB and IPAB is very different for visible, near-infrared and shortwave infrared channels compared with the thermal infrared channels discussed in Part I of this study. The contrast of 3-D radiative effects between solar and thermal infrared channels may be a significant issue for retrieval techniques that simultaneously use radiative measurements across a wide range of solar reflectance and infrared wavelengths.

scholarly journals On Global Dynamics in Duffing Equation with Quasiperiodic Perturbation

2020 ◽  
Vol 22 (2) ◽  
pp. 164-176
Author(s):  
Timofey N. Dragunov ◽  
Kirill E. Morozov ◽  
Albert D. Morozov
Keyword(s):  
Differential Equations ◽  
Dimensional Space ◽  
Nonlinear Differential Equations ◽  
Uniform Mesh ◽  
Global Dynamics ◽  
Nonlinear Operator Equations ◽  
Wide Range ◽  
Perturbations Of Initial Data ◽  
Analysis Of Stability ◽  
Stated Problem

An iterative method for solution of Cauchy problem for one-dimensional nonlinear hyperbolic differential equation is proposed in this paper. The method is based on continuous method for solution of nonlinear operator equations. The keystone idea of the method consists in transition from the original problem to a nonlinear integral equation and its successive solution via construction of an auxiliary system of nonlinear differential equations that can be solved with the help of different numerical methods. The result is presented as a mesh function that consists of approximate values of the solution of stated problem and is constructed on a uniform mesh in a bounded domain of two-dimensional space. The advantages of the method are its simplicity and also its universality in the sense that the method can be applied for solving problems with a wide range of nonlinearities. Finally it should be mentioned that one of the important advantages of the proposed method is its stability to perturbations of initial data that is substantiated by methods for analysis of stability of solutions of systems of ordinary differential equations. Solving several model problems shows effectiveness of the proposed method.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

scholarly journals Homotopy Perturbation Method

2017 ◽  
pp. 24-61
Keyword(s):  
Heat Transfer ◽  
Differential Equations ◽  
Perturbation Method ◽  
Exact Solutions ◽  
Homotopy Perturbation Method ◽  
Numerical Solutions ◽  
Nonlinear Differential Equations ◽  
Homotopy Perturbation ◽  
Wide Range ◽  
Transfer Problems

The homotopy perturbation method (HPM) is employed to compute an approximation to the solution of the system of nonlinear differential equations governing on the problem. It has been attempted to show the capabilities and wide-range applications of the homotopy perturbation method in comparison with the previous ones in solving heat transfer problems. The obtained solutions, in comparison with the exact solutions admit a remarkable accuracy. A clear conclusion can be drawn from the numerical results that the HPM provides highly accurate numerical solutions for nonlinear differential equations.

Business Ethics is Socio-Political, or Not at All

2015 ◽  
pp. 251-281
Author(s):  
Ana-Maria Pascal
Keyword(s):  
Business Ethics ◽  
Theoretical Background ◽  
Kantian Ethics ◽  
Political Responsibility ◽  
Wide Range ◽  
Mining Project ◽  
Public Ethics ◽  
High Degree ◽  
The Impact

This chapter explores the moral aspects of commercial deals that allegedly democratic governments enter into with foreign investors. These are discussed against a twofold theoretical background – where the philosophical ideal of public ethics based on truth and transparency meets business ethics theories. The Kantian ethics of duty proves to be the key link between these, as particularly relevant for cases where the impact on a wide range of stakeholders is considerable. The main case under consideration is the controversial USD $2 billion Romanian mining project at Rosia Montana, which highlights the need for accountability mentioned above and lends itself well to a multi-fold business ethics analysis. The role of the civil society in effectively stopping the project is a good illustration of the stakeholder theory. The chapter concludes with the thesis that a high degree of socio-political responsibility may be best achieved when trying to combine principle-based and utilitarian thinking.

scholarly journals Second hits exacerbate alcohol-related organ damage: an update

2020 ◽  
Vol 56 (1) ◽  
pp. 8-16
Author(s):  
Natalia A Osna ◽  
Murali Ganesan ◽  
Devanshi Seth ◽  
Todd A Wyatt ◽  
Srivatsan Kidambi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Alcohol Exposure ◽  
Organ Damage ◽  
Lifestyle Factor ◽  
Matrix Stiffness ◽  
Reactive Aldehydes ◽  
Wide Range ◽  
Excessive Alcohol ◽  
The Impact

Abstract Chronic and excessive alcohol abuse cause direct and indirect detrimental effects on a wide range of body organs and systems and accounts for ~4% of deaths worldwide. Many factors influence the harmful effects of alcohol. This concise review presents newer insights into the role of select second hits in influencing the progression of alcohol-induced organ damage by synergistically acting to generate a more dramatic downstream biological defect. This review specifically addresses on how a lifestyle factor of high fat intake exacerbates alcoholic liver injury and its progression. This review also provides the mechanistic insights into how increasing matrix stiffness during liver injury promotes alcohol-induced fibrogenesis. It also discusses how hepatotropic viral (HCV, HBV) infections as well as HIV (which is traditionally not known to be hepatotropic), are potentiated by alcohol exposure to promote hepatotoxicity and fibrosis progression. Finally, this review highlights the impact of reactive aldehydes generated during alcohol and cigarette smoke coexposure impair innate antimicrobial defense and increased susceptibility to infections. This review was inspired by the symposium held at the 17th Congress of the European Society for Biomedical research on Alcoholism in Lille, France entitled ‘Second hits in alcohol-related organ damage’.

scholarly journals Who stands to benefit? Wellbeing, belonging and challenges to equity in engagement in extra-curricular activities at university

2020 ◽  
pp. 146978742090820 ◽  
Author(s):  
Naomi Winstone ◽  
Kieran Balloo ◽  
Karen Gravett ◽  
Daniel Jacobs ◽  
Harry Keen
Keyword(s):  
Sense Of Belonging ◽  
Individual Characteristics ◽  
Student Identity ◽  
Mediating Role ◽  
Wide Range ◽  
Extra Curricular Activities ◽  
The University ◽  
The Impact ◽  
Perceived Outcomes

Students’ engagement in extra-curricular activities can play a significant role in their development of a student identity, as well as leading to a greater sense of belonging and wellbeing. However, individual characteristics such as sociability may influence the likelihood of students engaging in extra-curricular activities. We collected mixed mode data from two online surveys to explore students’ perceptions of the impact of engagement in extra-curricular activities on their experience at university, as well as the mediating role of engagement in extra-curricular activities in the relationships between extraversion and wellbeing and sense of belonging to the University. Our data demonstrate that extraversion is positively associated with both belonging and wellbeing, and that engagement in extra-curricular activities also mediates these relationships. Our qualitative data uncover further nuances in engagement with extra-curricular activities; while many perceived outcomes are positive, some students express regret at opportunities missed, and find it challenging to balance extra-curricular activities and their studies. Taken together, these findings indicate that not all students stand to benefit equally from engagement in extra-curricular activities. Providing a range of opportunities that are accessible to a wide range of students may promote equity in participation in extra-curricular activities.

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