scholarly journals Invasion fronts and adaptive dynamics in a model for the growth of cell populations with heterogeneous mobility

2021 ◽  
pp. 1-18
Author(s):  
T. LORENZI ◽  
B. PERTHAME ◽  
X. RUAN
Keyword(s):  
Population Density ◽  
Density Function ◽  
Cell Population ◽  
Adaptive Dynamics ◽  
Reaction Diffusion Equation ◽  
Cell Populations ◽  
Maximum Point ◽  
Front Edge ◽  
Cell Mobility ◽  
Local Cell

We consider a model for the dynamics of growing cell populations with heterogeneous mobility and proliferation rate. The cell phenotypic state is described by a continuous structuring variable and the evolution of the local cell population density function (i.e. the cell phenotypic distribution at each spatial position) is governed by a non-local advection–reaction–diffusion equation. We report on the results of numerical simulations showing that, in the case where the cell mobility is bounded, compactly supported travelling fronts emerge. More mobile phenotypic variants occupy the front edge, whereas more proliferative phenotypic variants are selected at the back of the front. In order to explain such numerical results, we carry out formal asymptotic analysis of the model equation using a Hamilton–Jacobi approach. In summary, we show that the locally dominant phenotypic trait (i.e. the maximum point of the local cell population density function along the phenotypic dimension) satisfies a generalised Burgers’ equation with source term, we construct travelling-front solutions of such transport equation and characterise the corresponding minimal speed. Moreover, we show that, when the cell mobility is unbounded, front edge acceleration and formation of stretching fronts may occur. We briefly discuss the implications of our results in the context of glioma growth.

scholarly journals Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy

2020 ◽  
Vol 15 ◽  
pp. 14 ◽  
Author(s):  
Rebecca E.A. Stace ◽  
Thomas Stiehl ◽  
Mark A.J. Chaplain ◽  
Anna Marciniak-Czochra ◽  
Tommaso Lorenzi
Keyword(s):  
Cancer Cell ◽  
Cell Population ◽  
Evolutionary Dynamics ◽  
Analytical Description ◽  
Chemotherapeutic Agents ◽  
Cell Populations ◽  
Theoretical Ground ◽  
Individual Based Model ◽  
Nonlocal Parabolic Equation ◽  
Epigenetic Drug

We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structured by the expression level of a gene that controls cell proliferation and chemoresistance. In order to obtain an analytical description of evolutionary dynamics, we formally derive a deterministic continuum counterpart of this discrete model, which is given by a nonlocal parabolic equation for the cell population density function. Integrating computational simulations of the individual-based model with analysis of the corresponding continuum model, we perform a complete exploration of the model parameter space. We show that harsher environmental conditions and higher probabilities of spontaneous epimutation can lead to more effective chemotherapy, and we demonstrate the existence of an inverse relationship between the efficacy of the epigenetic drug and the probability of spontaneous epimutation. Taken together, the outcomes of the model provide theoretical ground for the development of anticancer protocols that use lower concentrations of chemotherapeutic agents in combination with epigenetic drugs capable of promoting the re-expression of epigenetically regulated genes.

Inactivation of Surface-adherent Listeria monocytogenes Hypochlorite and Heat

1991 ◽  
Vol 54 (1) ◽  
pp. 4-6 ◽  
Author(s):  
SHIN-HO LEE ◽  
JOSEPH F. FRANK
Keyword(s):  
Stainless Steel ◽  
Listeria Monocytogenes ◽  
Cell Population ◽  
Incubation Time ◽  
Cell Populations ◽  
Adherent Cell ◽  
Adherent Cells ◽  
D Cells

Inactivation by hypochlorite of Listeria monocytogenes cells adherent to stainless steel was determined. Adherent cell populations were prepared by incubating stainless steel slides with a 24 h culture of L. monocytogenes for 4 h at 21°C. Adherent microcolonies were prepared by growing L. monocytogenes on stainless steel slides submerged in a 1:15 dilution of tryptic soy broth at 21°C. The slides were then rinsed and transferred to fresh sterile broth every 2 d with a total incubation time of 8 d. Although the 4 h and 8 d adherent populations were at similar levels, 8 d adherent cells were over 100 times more resistant than the 4 h adherent cell population when exposed to 200 ppm hypochlorite for 30 s. When stainless steel slides containing adherent cells were heated at 72°C both adherent cell populations were inactivated after 1 min. Detectable numbers of L. monocytogenes remained on stainless steel slides after treatment at 65°C for 3 min when adherent 8 d cells were tested but not when adherent 4 h cells were used.

scholarly journals CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets

F1000Research ◽  
2019 ◽  
Vol 6 ◽  
pp. 748 ◽  
Author(s):  
Malgorzata Nowicka ◽  
Carsten Krieg ◽  
Helena L. Crowell ◽  
Lukas M. Weber ◽  
Felix J. Hartmann ◽  
...  
Keyword(s):  
Cell Population ◽  
High Throughput ◽  
Mixed Models ◽  
Exploratory Data Analysis ◽  
Linear Mixed Models ◽  
High Dimensional ◽  
Cell Populations ◽  
Dimensional Scaling ◽  
Exploratory Data

High-dimensional mass and flow cytometry (HDCyto) experiments have become a method of choice for high-throughput interrogation and characterization of cell populations. Here, we present an updated R-based pipeline for differential analyses of HDCyto data, largely based on Bioconductor packages. We computationally define cell populations using FlowSOM clustering, and facilitate an optional but reproducible strategy for manual merging of algorithm-generated clusters. Our workflow offers different analysis paths, including association of cell type abundance with a phenotype or changes in signalling markers within specific subpopulations, or differential analyses of aggregated signals. Importantly, the differential analyses we show are based on regression frameworks where the HDCyto data is the response; thus, we are able to model arbitrary experimental designs, such as those with batch effects, paired designs and so on. In particular, we apply generalized linear mixed models or linear mixed models to analyses of cell population abundance or cell-population-specific analyses of signaling markers, allowing overdispersion in cell count or aggregated signals across samples to be appropriately modeled. To support the formal statistical analyses, we encourage exploratory data analysis at every step, including quality control (e.g., multi-dimensional scaling plots), reporting of clustering results (dimensionality reduction, heatmaps with dendrograms) and differential analyses (e.g., plots of aggregated signals).

FORMATION OF CELL COLONIES IN X-IRRADIATED REGENERATING LIVERS OF RATS

1965 ◽  
Vol 43 (6) ◽  
pp. 817-828 ◽  
Author(s):  
M. Maini Webber ◽  
H. F. Stich
Keyword(s):  
Partial Hepatectomy ◽  
Cell Population ◽  
Selection Pressure ◽  
Precancerous Lesion ◽  
Abnormal Chromosome ◽  
Cell Populations ◽  
Chemical Carcinogen ◽  
Normal Cells ◽  
Heterogeneous Cell Population ◽  
High Incidence

A high incidence of mitotic irregularities was observed when X-irradiated livers were induced to regenerate after a partial hepatectomy. Mitotic irregularities resulted in the formation of a heterogeneous cell population. As regeneration proceeded, the liver was found to be composed of two different cell populations: (i) one consisting of polyploid and aneuploid cells and incapable of giving rise to many descendants, and (ii) another consisting of apparently normal cells and capable of extensive proliferation which resulted in the formation of cell colonies. The regeneration of liver is mainly attributed to the cell colonies. No tumors appeared in the liver. These results demonstrate that a heterogeneous cell population of a "precancerous lesion" does not necessarily lead to the formation of a neoplasm. A selection pressure can be considered as necessary to favor the multiplication of cells with abnormal chromosome complements over that of cells with normal complements, as is seen in the livers of rats fed a chemical carcinogen. However, in the case of X-irradiated livers, normal cells seem to be favored.

scholarly journals Effect of cell population density on G2 arrest in Tetrahymena.

1975 ◽  
Vol 67 (3) ◽  
pp. 518-522 ◽  
Author(s):  
I L Cameron ◽  
N C Bols
Keyword(s):  
Cell Cycle ◽  
Population Density ◽  
Cell Population ◽  
Tritiated Thymidine ◽  
Tetrahymena Pyriformis ◽  
High Cell ◽  
Ciliated Protozoan ◽  
G2 Phase ◽  
Cell Densities ◽  
Two Peaks

The ciliated protozoan, Tetrahymena pyriformis strain GL-C, has been used to study the effect of cell population density during starvation on the synchrony obtained after refeeding and on the number of cells arrested in G2 phase of the cell cycle. At high cell densities two peaks of division indices were observed after refeeding while only one was observed at low cell densities. Cell division began earlier in cultures starved at high cell densities. Most importantly, the proportion of cells in G2 was considerably higher in populations starved at high cell densities. When tritiated thymidine was present during the refeeding period, radioautographs of cell samples at different times showed that the first cells to exhibit division furrows contained unlabeled nuclei. The first peak in the division index after refeeding was observed only at higher cell densities and is attributed to the cells arrested in G2. These results suggest that Tetrahymena is an excellent organism to study the concept of resting stages in the cell cycle and their control.

192 IDENTIFICATION AND CHARACTERIZATION OF Oct4-EGFP EXPRESSING CELLS IN TRANSGENIC PIG TESTIS

2014 ◽  
Vol 26 (1) ◽  
pp. 210
Author(s):  
M. Nowak-Imialek ◽  
N. Lachmann ◽  
D. Herrmann ◽  
F. Jacob ◽  
H. Niemann
Keyword(s):  
Stem Cells ◽  
Cell Population ◽  
Germ Cells ◽  
Germ Line ◽  
Cell Mass ◽  
Testicular Tissue ◽  
Egfp Expression ◽  
Cell Populations ◽  
Marker Genes ◽  
Transgenic Pigs

We have produced germ line transgenic pigs carrying the entire 18-kb genomic sequence of the murine Oct4 gene fused to the enhanced green fluorescent protein (EGFP) cDNA (OG2 construct; Nowak-Imialek et al., 2011 Stem Cells Dev.). Expression of the EGFP reporter construct is confined to germ line cells, the inner cell mass, and trophectoderm of blastocysts, and testicular germ cells, including putative spermatogonial stem cells (SSC). SSC are unique among stem cells because they can both self-renew and differentiate into spermatozoa. In-depth knowledge on porcine SSC has been hampered by the inability to isolate these cells from the complex cell population of the testis. In the Oct4-EGFP transgenic mouse, SSC are the only adult stem cells that express Oct4. Fluorescence microscopy of testicular tissue isolated from transgenic piglets revealed minimum numbers of EGFP-positive cells, whereas testicular tissue isolated from adult transgenic boars contained a high amount of EGFP fluorescent cells. Northern blot analysis confirmed stronger EGFP expression in the testis of adult transgenic pigs than in the testis from transgenic piglets. Time course and the signal intensity of EGFP expression in Oct4-EGFP testis paralleled mRNA expression of the endogenous Oct4 gene. Here, we used adult Oct4-EGFP transgenic pigs as a model for fluorescence-activated cell sorting (FACS)-based isolation of EGFP-expressing cells from testes. To obtain a single-cell suspension, the testes were enzymatically dissociated using two digestion steps. Thereafter, FACS based on EGFP expression was successfully used to purify specific testicular cell populations. Two cell populations, i.e. EGFP+ (14%) and EGFP– (45%) could be isolated. Subsequently, qualitative PCR analyses were performed on EGFP+, EGFP–, and unsorted cell populations using marker genes specific for pluripotency and undifferentiated germ cells (OCT4, FGFR3, UTF1, PGP9.5, GFRα1, CD90, SALL4), differentiating germ cells (c-KIT), meiosis (BOLL), spermatids (PRM2), and somatic cells (VIM, LHCGR). All of the genes, including OCT4, UTF1, FGFR3, PGP9.5, CD90, SALL4, and GFRα1 were expressed at least 3-fold and up to 12-fold greater in the EGFP-positive population. Vimentin, which is mainly expressed in Sertoli cells and LHCGR, which is mainly expressed in Leydig cells, were expressed in unsorted and EGFP– cell populations and at very low level in EGFP+ cells. Moreover, expression of the c-KIT and PRM2 markers were detected also in EGFP+ cell population, indicating that these cells contain also differentiating spermatogonia. To explore the characteristics of the Oct4-EGFP expressing cells in greater detail, localization in the porcine testis sections and analysis of co-expression with germ cell markers using immunohistochemistry is currently underway.

Emergence of Dominant T-Cell Populations in Patients with CLL after Allogeneic Transplantation: Mediators for Gvl Effects?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3503-3503
Author(s):  
Matthias Ritgen ◽  
Monika Brueggemann ◽  
Sebastian Boettcher ◽  
Thorsten Raff ◽  
Christiane Pott ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Population ◽  
Cell Populations ◽  
Gamma Delta ◽  
T Cell Clones ◽  
Disease Response ◽  
Cell Clones ◽  
Kinetics Of

Abstract Allogeneic stem cell transplantation (SCT) is the only known curative treatment for high-risk CLL. We have recently shown that minimal residual disease (MRD) monitoring can identify patients with graft versus leukemia (GvL)-induced disease response to either reduction of immunosuppression (IS) or to administration of donor lymphocyte infusions (DLI), suggesting that those patients are potentially cured by an ongoing immunologic antileukemic effect induced by donor immune cells (Leukemia 22:1377). It is uncertain, however, which cell population maintains this process; although T as well as NK-cell mediated effects are discussed. The present study addressed the question whether disease response upon immunomodulation after SCT is associated with the occurrence of dominant T cell clones. Methods: 32 patients allografted for high-risk CLL who had MRD follow-up by clone-specific PCR or MRD-flow available were included in this investigation. We used the BIOMED T-cell receptor multiplex PCRs (TCR-PCR) to search for T cell clones which might be involved in the documented GVL effects. TCR rearrangements were sequenced and analyzed using the IMGT database. Results: 16 of 32 patients showed MRD response after IS reduction or DLI. GVL-induced MRD clearance was associated with onset of chronic GVHD in almost all instances. Twenty-four different dominant TCR rearrangements could be identified in 15/32 patients by BIMOD TCR-PCR. Most of the T cell populations show rearranged gamma/delta TCRs suggesting that regulatory gamma/delta T cells might be involved in this process. TCR sequences employed were TRGV9 (13), TRGV2 (2) and TRGV1, TRGV4, TRGV8, TRGV10, TRGV11, TRBV5, TRBV6, TRBV12, TRBV15. In 4 patients with a potential productive TCR rearrangement (TRGV4+TRDV1, TRBV6, TRGV2, TRGV11+TRGV9) we were able to design a TCR-specific real-time PCR for quantitative follow-up of this clonal T cell population. This data was compared to flow cytometric monitoring of T-cell subpopulations and MRD kinetics post SCT. In those 4 patients we could demonstrate an inverse correlation of the kinetics of MRD and the kinetics of clonal T cell expansions. T cell clones emerging during this phase remained on a stable level throughout the whole follow-up in patients showing durable MRD negativity. Conclusion: In CLL, MRD clearance after SCT is correlated to the emergence of dominant T cell clones, suggesting that GVL activity is based on allo- or CLL-specific T cell expansion. Further studies are needed to clarify the role of these T cell clones for GVL and GVHD development.

KIR Ligation During Ex Vivo Expansion Allows Molding Of The KIR Repertoire

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2288-2288
Author(s):  
Dean A. Lee ◽  
Vladimir V Senyukov ◽  
Jerome R Trembley
Keyword(s):  
Nk Cells ◽  
Cell Population ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Hla Ligand ◽  
Cell Subpopulations ◽  
Hla Haplotypes

Abstract NK Cell subpopulations express tremendous diversity through polymorphisms, haplotypes, differential expression, and licensing of the Killer Immunoglobulin-like Receptors (KIR). KIR diversity affects both the predisposition to cancer, and the response to therapies such as hematopoietic stem cell transplantation. Clinical trials that take advantage of the anti-cancer properties of NK cells have been limited to choosing donors on the basis of KIR genotypes and/or HLA haplotypes. Moreover, adoptive immunotherapy approaches have been limited by low NK cell doses. The latter hurdle has been recently mitigated by methods for expanding clinical grade NK cells ex vivo. These approaches for growing large numbers of cells now enable investigation into selecting more potent NK cell subsets for increased therapeutic efficacy. We hypothesized that the desired KIR repertoire could be molded through inhibition of undesirable KIR populations by crosslinking with relevant anti-KIR antibodies during expansion with our previously described method, which produces a mean 30,000-fold expansion of NK cells in 3 weeks. First, we determined that maximum inhibition was obtained when anti-KIR antibodies were applied to previously activated NK cells, crosslinked with secondary antibody, and then restimulated for proliferation. Robust reduction of targeted KIR-positive populations could be achieved for each inhibitory KIR (Fig. 1). When pre-activated with anti-KIR2DL1 for one stimulation cycle, NK cells expressing this KIR were decreased by a median of 70.4% ± 19.3%. Similarly, KIR2DL2/3+ NK cells could be reduced by 56% ± 17.5%, and KIR3DL1+ NK cells could be reduced by 53.5% ± 16.3%. When anti-KIR antibodies were combined, similar suppression of multiple-KIR subpopulations was observed. Other NK cell receptors were not significantly affected during targeted KIR inhibition. We then assessed the resulting NK cell populations for degranulation responses to targets with selected HLA as KIR ligands. Inhibition of KIR-expressing subpopulations during expansion resulted in NK cell populations with enhanced degranulation against tumor cells expressing the HLA ligand of the targeted KIR. Importantly, the cytotoxicity of the bulk NK cell population against HLA-negative targets remained. These results indicate that KIR crosslinking during NK cell propagation enables significant reduction in the targeted KIR subpopulations, resulting in an NK cell population with a selective decrease in KIR inhibition. By utilizing antibody-controlled expansion for molding of the KIR repertoire according to patient HLA type, a personalized NK cell product may be produced with enhanced potency, improving NK cell immunotherapy. Disclosures: No relevant conflicts of interest to declare.

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