scholarly journals Mechanical influences on in silico tumor evolution

2021 ◽  
Author(s):  
Jakob Rosenbauer ◽  
Marco Berghoff ◽  
James A. Glazier ◽  
Alexander Schug
Keyword(s):  
Mechanical Properties ◽  
Evolutionary Process ◽  
Cell Types ◽  
Nutrient Supply ◽  
Therapeutic Interventions ◽  
Tumor Evolution ◽  
Evolutionary Trajectory ◽  
Fitness Advantage ◽  
Trade Offs ◽  
Evolutionary Speed

AbstractExperimental insight and conceptual understanding of tumor growth are steadily growing and leading to new therapeutic interventions. Experiments and clinical studies are able to link single-cell properties to macroscopic tumor attributes. The development of cellular subpopulations in heterogeneous tumors can be understood as an evolutionary system with different cell types competing over both space and nutrients. However, to predict the growth trajectory and development of a tumor, fitness and trade-offs of cell properties in the context of the surroundings are required and often inaccessible. The optimum of the evolutionary trajectory provides a target for intervention, but can mostly not be identified. We propose that the optimal value of cellular properties is influenced by the tumor surrounding. Computational multiscale-modeling of tissue enables the observation of the trajectory of each cell while modeling the tumor surrounding. We model a 3D spheroid tumor and the fitness of individual cells and the evolutionary behavior of the tumor are quantified and linked to global parameters. Cell–cell adhesion and cell motility are two important mechanical properties for cell development and used as free parameters. Mechanical properties alone are able to drive the tumor towards low adhesion.We implement a dynamically changing nutrient surrounding representing the fluctuating blood-supply through blood vessel collapse and angiogenesis. We find that the evolutionary speed depends on the frequency of the fluctuations. We identify a frequency domain in which the evolutionary speed is significantly increased over a tumor with constant nutrient supply. The findings suggest that mechanically-induced fluctuations can accelerate tumor evolution.Author summaryLimited space and nutrients together with competing cell types drive an evolutionary process inside tumors. This process selects for the fittest cell types and optimizes the growing behavior for its local surroundings. An expanding tumor exerts mechanical forces on its cells and its surroundings, leading to a fluctuating nutrient supply through collapsing blood vessels. Here, we observe the influence of a dynamically changing surrounding on the evolutionary behavior of heterogeneous tumors in a high-resolution computational model. We find that the evolutionary speed depends on the frequency of the fluctuations and a fitness advantage of low-adhesion cells.

scholarly journals Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Nathaniel S. Woodling ◽  
Arjunan Rajasingam ◽  
Lucy J. Minkley ◽  
Alberto Rizzo ◽  
Linda Partridge
Keyword(s):  
Glial Cell ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Developmental Timing ◽  
Cell Type ◽  
Specific Effects ◽  
Trade Offs ◽  
Distinct Cell ◽  
Pi3k Signalling ◽  
Cell Type Specific

Abstract Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

scholarly journals Distinguishing linear and branched evolution given single-cell DNA sequencing data of tumors

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Leah L. Weber ◽  
Mohammed El-Kebir
Keyword(s):  
Dna Sequencing ◽  
Single Cell ◽  
Evolutionary Process ◽  
Treatment Decision ◽  
Real Data ◽  
Current Data ◽  
Fast Method ◽  
Sequencing Data ◽  
Evolutionary Trajectory ◽  
Cancer Types

Abstract Background Cancer arises from an evolutionary process where somatic mutations give rise to clonal expansions. Reconstructing this evolutionary process is useful for treatment decision-making as well as understanding evolutionary patterns across patients and cancer types. In particular, classifying a tumor’s evolutionary process as either linear or branched and understanding what cancer types and which patients have each of these trajectories could provide useful insights for both clinicians and researchers. While comprehensive cancer phylogeny inference from single-cell DNA sequencing data is challenging due to limitations with current sequencing technology and the complexity of the resulting problem, current data might provide sufficient signal to accurately classify a tumor’s evolutionary history as either linear or branched. Results We introduce the Linear Perfect Phylogeny Flipping (LPPF) problem as a means of testing two alternative hypotheses for the pattern of evolution, which we prove to be NP-hard. We develop Phyolin, which uses constraint programming to solve the LPPF problem. Through both in silico experiments and real data application, we demonstrate the performance of our method, outperforming a competing machine learning approach. Conclusion Phyolin is an accurate, easy to use and fast method for classifying an evolutionary trajectory as linear or branched given a tumor’s single-cell DNA sequencing data.

scholarly journals A Review on Tailoring Stiffness in Compliant Systems, via Removing Material: Cellular Materials and Topology Optimization

2021 ◽  
Vol 11 (8) ◽  
pp. 3538
Author(s):  
Mauricio Arredondo-Soto ◽  
Enrique Cuan-Urquizo ◽  
Alfonso Gómez-Espinosa
Keyword(s):  
Mechanical Properties ◽  
Topology Optimization ◽  
Evolutionary Process ◽  
Cellular Materials ◽  
Related Literature ◽  
And Topology ◽  
Fundamental Process ◽  
Compliant Systems ◽  
Basic Concepts

Cellular Materials and Topology Optimization use a structured distribution of material to achieve specific mechanical properties. The controlled distribution of material often leads to several advantages including the customization of the resulting mechanical properties; this can be achieved following these two approaches. In this work, a review of these two as approaches used with compliance purposes applied at flexure level is presented. The related literature is assessed with the aim of clarifying how they can be used in tailoring stiffness of flexure elements. Basic concepts needed to understand the fundamental process of each approach are presented. Further, tailoring stiffness is described as an evolutionary process used in compliance applications. Additionally, works that used these approaches to tailor stiffness of flexure elements are described and categorized. Finally, concluding remarks and recommendations to further extend the study of these two approaches in tailoring the stiffness of flexure elements are discussed.

scholarly journals Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2798
Author(s):  
Maria Alba Sorolla ◽  
Anabel Sorolla ◽  
Eva Parisi ◽  
Antonieta Salud ◽  
José M. Porcel
Keyword(s):  
Pleural Fluid ◽  
Liquid Biopsy ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Pleural Effusions ◽  
Malignant Pleural Effusions ◽  
Micro Rnas ◽  
Low Sensitivity

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

scholarly journals Cell mechanical properties of human breast carcinoma cells depend on temperature

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christian Aermes ◽  
Alexander Hayn ◽  
Tony Fischer ◽  
Claudia Tanja Mierke
Keyword(s):  
Mechanical Properties ◽  
Power Law ◽  
Cell Mechanics ◽  
Cell Types ◽  
Creep Response ◽  
Temperature Range ◽  
Myosin Filaments ◽  
Cell Mechanical Properties ◽  
Increasing Temperature ◽  
Mcf 7

AbstractThe knowledge of cell mechanics is required to understand cellular processes and functions, such as the movement of cells, and the development of tissue engineering in cancer therapy. Cell mechanical properties depend on a variety of factors, such as cellular environments, and may also rely on external factors, such as the ambient temperature. The impact of temperature on cell mechanics is not clearly understood. To explore the effect of temperature on cell mechanics, we employed magnetic tweezers to apply a force of 1 nN to 4.5 µm superparamagnetic beads. The beads were coated with fibronectin and coupled to human epithelial breast cancer cells, in particular MCF-7 and MDA-MB-231 cells. Cells were measured in a temperature range between 25 and 45 °C. The creep response of both cell types followed a weak power law. At all temperatures, the MDA-MB-231 cells were pronouncedly softer compared to the MCF-7 cells, whereas their fluidity was increased. However, with increasing temperature, the cells became significantly softer and more fluid. Since mechanical properties are manifested in the cell’s cytoskeletal structure and the paramagnetic beads are coupled through cell surface receptors linked to cytoskeletal structures, such as actin and myosin filaments as well as microtubules, the cells were probed with pharmacological drugs impacting the actin filament polymerization, such as Latrunculin A, the myosin filaments, such as Blebbistatin, and the microtubules, such as Demecolcine, during the magnetic tweezer measurements in the specific temperature range. Irrespective of pharmacological interventions, the creep response of cells followed a weak power law at all temperatures. Inhibition of the actin polymerization resulted in increased softness in both cell types and decreased fluidity exclusively in MDA-MB-231 cells. Blebbistatin had an effect on the compliance of MDA-MB-231 cells at lower temperatures, which was minor on the compliance MCF-7 cells. Microtubule inhibition affected the fluidity of MCF-7 cells but did not have a significant effect on the compliance of MCF-7 and MDA-MB-231 cells. In summary, with increasing temperature, the cells became significant softer with specific differences between the investigated drugs and cell lines.

In-Plane Stiffness and Yield Strength of Periodic Metal Honeycombs

2004 ◽  
Vol 126 (2) ◽  
pp. 137-156 ◽  
Author(s):  
A.-J. Wang ◽  
D. L. McDowell
Keyword(s):  
Mechanical Properties ◽  
Yield Strength ◽  
Relative Density ◽  
Cell Types ◽  
Elastic Stiffness ◽  
Honeycomb Structures ◽  
Initial Yield ◽  
Cell Structures ◽  
Plane Anisotropy ◽  
Different Cell Types

In-plane mechanical properties of periodic honeycomb structures with seven different cell types are investigated in this paper. Emphasis is placed on honeycombs with relative density between 0.1 and 0.3, such that initial yield is associated with short column compression or bending, occurring prior to elastic buckling. Effective elastic stiffness and initial yield strength of these metal honeycombs under in-plane compression, shear, and diagonal compression (for cell structures that manifest in-plane anisotropy) are reported as functions of relative density. Comparison among different honeycomb structures demonstrates that the diamond cells, hexagonal periodic supercells composed of six equilateral triangles and the Kagome cells have superior in-plane mechanical properties among the set considered.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

scholarly journals The concept of revelation in terms of the evolution of consciousness

2016 ◽  
Vol 72 (4) ◽  
Author(s):  
Klaus Nürnberger
Keyword(s):  
Evolutionary Process ◽  
Religious Tradition ◽  
Well Being ◽  
Big Bang ◽  
Evolutionary Trajectory ◽  
Evolution Of Consciousness ◽  
Realist Approach ◽  
Creative Power ◽  
Challenges And Opportunities ◽  
Social Environmental

Following Paul’s injunction in 1 Corinthians 9:19–23 we have to ‘become scientists’ to a scientifically informed audience. While theology cannot agree with the naturalist denial of transcendence, it can adopt the experiential-realist approach typical for the sciences in its description of the Christian faith as an immanent part of cosmic evolution, albeit at a higher level of emergence. The article begins with my understanding of evolutionary theory (big bang cosmology, entropy, emergence, neural networks as infrastructure of consciousness, evolution and differentiation, sequences of past, present and future, contingency etc.) It then describes God consciousness as the intuition, perception or conceptualisation of the transcendent Source and Destiny of experienced reality and locates God consciousness in the evolutionary process. Biblical God consciousness displays two distinct characteristics: God’s creative power is experienced in reality, while God’s benevolent intentionality is proclaimed on the basis of a religious tradition. The evolutionary trajectory of biblical God consciousness, culminating in the Christ-event, is sketched and the God consciousness of Jesus is deduced from its religious embeddedness, its social-environmental relationships and its religious impact. Implications of an experiential-realist approach are (1) a dynamic, rather than ontological Christology and (2) the cosmic significance of the sacrifice of God in Christ. On this basis revelation is described first in experiential-realist and then in theological terms. The tension between the experience of God’s creative power and the proclamation of God’s benevolence leads to a dynamic, rather than ontological rendering of the Trinity. Finally, traditional eschatological assumptions are reconceptualised as God’s dynamic vision of comprehensive well-being operating like a horizon that moves on as we approach it and displays ever new vistas, challenges and opportunities.

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