scholarly journals Invasion of homogeneous and polyploid populations in nutrient-limiting environments

2020 ◽  
Author(s):  
Gregory J. Kimmel ◽  
Mark Dane ◽  
Laura Heiser ◽  
Philipp M. Altrock ◽  
Noemi Andor
Keyword(s):  
Cell Phenotype ◽  
Homogeneous Population ◽  
Nutrient Limitations ◽  
Perturbation Data ◽  
Multistep Process ◽  
Clinical Consequences ◽  
High Ploidy ◽  
Cell Subpopulations ◽  
Two Populations ◽  
Chemotactic Ability

AbstractBreast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Progression is accompanied by a switch to an invasive cell phenotype. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. We integrate mathematical modeling with microenvironmental perturbation-data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations. Hereby, subpopulations are defined by their energy efficiency and chemotactic ability. We estimate the invasion-distance traveled by a homogeneous population. For heterogeneous populations, our results suggest that an imbalance between nutrient efficacy and chemotactic superiority accelerates invasion. Such imbalance will spatially segregate the two populations and only one type will dominate at the invasion front. Only if these two phenotypes are balanced do the two subpopulations compete for the same space, which decelerates invasion. We investigate ploidy as a candidate biomarker of this phenotypic heterogeneity to discern circumstances when inhibiting chemotaxis amplifies internal competition and decelerates tumor progression, from circumstances that render clinical consequences of chemotactic inhibition unfavorable.SignificanceA better understanding of the nature of the double-edged sword of high ploidy is a prerequisite to personalize combination-therapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.

Motoneuronal development in the embryonic zebrafish

Development ◽  
1991 ◽  
Vol 113 (Supplement_2) ◽  
pp. 141-147 ◽  
Author(s):  
Judith S. Eisen
Keyword(s):  
Growth Cones ◽  
Multistep Process ◽  
Specific Muscle ◽  
Two Populations

To learn how neurons find their appropriate targets, we have studied two populations of motoneurons in the embryonic zebrafish: primary motoneurons, individually identified cells whose growth cones pioneer the first nerve pathways in the muscle, and secondary motoneurons, cells which develop later and whose growth cones apparently extend along the axons of the primary motoneurons. Transplantation studies of single, identified primary motoneurons suggest that commitment of these cells to innervate their cell-specific muscle territories may be a multistep process in which they are first committed to be motoneurons and are later committed to extend axons along specific pathways. Ablation studies suggest that interactions among the primary motoneurons are unlikely to be necessary for proper pathfinding or commitment. However, interactions with the primary motoneurons may be important for proper development of the secondary motoneurons.

scholarly journals The arterial microenvironment: the where and why of atherosclerosis

2016 ◽  
Vol 473 (10) ◽  
pp. 1281-1295 ◽  
Author(s):  
Arif Yurdagul ◽  
Alexandra C. Finney ◽  
Matthew D. Woolard ◽  
A. Wayne Orr
Keyword(s):  
Atherosclerotic Plaque ◽  
Inflammatory Cell ◽  
Plaque Formation ◽  
Cell Phenotype ◽  
Atherosclerotic Plaque Formation ◽  
Clinical Consequences

Changes in the local microenvironment regulate multiple aspects of vascular and inflammatory cell phenotype, determining the location, composition and clinical consequences of atherosclerotic plaque formation.

Differential expression of the human mucin genes MUC1 to MUC5 in relation to growth and differentiation of different mucus-secreting HT-29 cell subpopulations

1993 ◽  
Vol 106 (3) ◽  
pp. 771-783 ◽  
Author(s):  
T. Lesuffleur ◽  
N. Porchet ◽  
J.P. Aubert ◽  
D. Swallow ◽  
J.R. Gum ◽  
...  
Keyword(s):  
Steady State ◽  
Apical Surface ◽  
Parental Population ◽  
Mucin Expression ◽  
Mucin Genes ◽  
Muc Genes ◽  
Cell Subpopulations ◽  
Two Populations ◽  
Ht 29 ◽  
Muc1 Glycoprotein

Mucin expression was analysed, in relation to cell growth, in parental HT-29 cells and in two populations of mucus-secreting HT-29 cells selected by adaptation to methotrexate (HT29-MTX) or 5-fluorouracil (HT29-FU). These two populations express mature mucins that differ in their immunoreactivity to antibodies against gastric (HT29-MTX) or colonic mucins (HT29-FU). In the parental population, at late confluency, only very few cells produce mucins or the MUC1 glycoprotein, this being consistent with the low level of expression of the mRNAs corresponding to the MUC1 to MUC5C mucin genes. In the HT29-MTX and HT29-FU populations, the appearance of mucus droplets, as shown by histochemistry and immunofluorescence, starts a few days after confluency, progressively involving a greater proportion of cells and reaching a steady state at late confluency. The MUC1 glycoprotein appears earlier, already being detectable in preconfluent cells. Its distribution is restricted to the apical surface of the cells and is distinct from that of the mucus droplets. In both populations the growth-related levels of MUC1 mRNA are concordant with the apparent levels of expression of the MUC1 glycoprotein. The levels of MUC2, MUC3, MUC4 and MUC5C mRNAs differ from one population to another and, within each population, according to the stage of the culture. The highest levels of MUC2 and MUC4 mRNAs are found in the HT29-FU cells, whereas the highest levels of MUC3 and MUC5C are found in the HT29-MTX cells, suggesting that the differences observed in the mature mucins expressed by either population may be related to which MUC genes are expressed. In both populations significant or even high levels of MUC mRNAs are already present in early cultures, i.e. at a stage when the mature mucins are not yet detectable, suggesting that mucin maturation is a later event.

scholarly journals MicroRNAs: a complex regulatory network drives the acquisition of malignant cell phenotype

2010 ◽  
Vol 17 (1) ◽  
pp. F51-F75 ◽  
Author(s):  
Libero Santarpia ◽  
Milena Nicoloso ◽  
George A Calin
Keyword(s):  
Cancer Biology ◽  
Malignant Cell ◽  
Cell Phenotype ◽  
Endocrine Tumors ◽  
Functional Capabilities ◽  
Self Sufficiency ◽  
Multistep Process ◽  
The Common ◽  
Insight Into

Several lines of evidence indicate that tumorigenesis is a complex multistep process, and that most, if not all, cancers acquire the same set of functional capabilities during development and progression, albeit through various mechanistic strategies. Increasing data show an important role of microRNAs (miRNAs or miRs) in regulating various aspects of cancer biology. This review describes the role of microRNAs during the multiple steps that drive the progressive transformation of normal cells into highly malignant derivatives, outlining the role of microRNAs in regulating the common hallmarks of tumorigenesis: self-sufficiency in growth signals, insensitivity to antigrowth signals, abnormal apoptosis, limitless replicative potential, induction and sustained angiogenesis, and tissue invasion and metastasis. Recent evidence suggests an important role of microRNAs in the regulation of the expression of most genes regulating and coordinating a wide variety of processes in endocrine glands. We will highlight microRNAs of potential relevance to endocrine tumors and hormone-dependent cancers. Through this overview of how microRNAs regulate multiple targets and entire pathways, we will provide insight into the potential to develop new molecular microRNA-targeted therapies for endocrine tumors.

scholarly journals THU0031 ABATACEPT ALTERS THE FREQUENCY OF IMMUNOREGULATORY AND EFFECTOR T CELL SUBPOPULATIONS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 229.2-229
Author(s):  
B. Dreo ◽  
B. Prietl ◽  
S. Kofler ◽  
H. Sourij ◽  
A. Lackner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
T Cell Subsets ◽  
Cell Phenotype ◽  
Effector T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

Background:Under physiological conditions, T regulatory cells (Tregs) are responsible for the downregulation of the immune response. In autoimmune diseases, such as rheumatoid arthritis (RA), auto-inflammation is driven by an imbalance of activation and downregulation of immunological pathways. Thus, treatment plans for autoimmune diseases often involve the enhancement of immunoregulatory pathways by administering inhibitors of costimulation, i.e. CTLA-4-Ig (abatacept, ABA). ABA binds specifically to CD80 and CD86 on antigen presenting cells (APC). Consequently, T cell activation via the CD28 receptor is blocked. Previous studies have demonstrated surprising effects of abatacept on Tregs, specifically decreased frequency of these cells but enhancement in their function1. Whether these alterations can only be found in patients with ABA treatment, or whether they are also present in patients receiving other anti-inflammatory drugs is currently unknown.Objectives:The aim of our research was to delineate the impact of ABA on the different subsets of effector and regulatory T cells in RA and compare these findings with patients receiving tocilizumab (TCZ) or rituximab (RTX).Methods:Peripheral blood samples from 56 RA patients (median ± SE; age: 60.5 ± 1.3 years, female ratio: 0.7, disease duration: 17.9 ± 2.1 years; respectively) were drawn over a sampling period of 2 years. Freshly isolated PBMCs of RA patients were stained with fluorochrome-labelled antibodies and T cell subsets were identified by flow cytometric means. CD3+CD4+T cells were further classified using different T cell markers (CD25, CD127, CD39, CD95). All cytometric measurements were performed using a standardized BD LSR-Fortessa platform. RA patients were compared according to their treatment with ABA, TCZ or RTX.Results:Eighteen out of 56 RA patients (32%) received ABA, 25 patients (45%) received TCZ and 13 patients (23%) were under CD20+ cell depletion therapy with RTX. RA patients receiving ABA displayed a significant decrease in CD3+CD4+CD25+CD127dimTregs (3.7% ± 0.4) compared to patients with TCZ (5.4% ± 0.4, p = 0.041) and patients under RTX treatment (7.52% ± 0.93, p = 0.026). CD39+Tregs were significantly higher in RA patients treated with TCZ (49.5% + 3.2, p = 0.000) or RTX (50.5% ± 5.3, p = 0.026) compared to patients receiving ABA (24.5% ± 3.1). In addition, the frequency of CD95+Tregs was significantly reduced in ABA patients compared to RTX patients (59.6% ± 3.1 vs.76.7% ± 3.6, p = 0.014; respectively). Interestingly, T cells displaying an effector T cell phenotype (CD3+CD4+CD25+/-CD127+) were increased in ABA treated patients compared to RTX treated patients (59.6% ± 3.1 and 76.7% ± 3.6, p = 0.002). Since none of our patients were a non-responder or had high disease activity, we could not analyse whether these changes are associated with treatment outcome.Conclusion:Our data demonstrate that blockage of T cell stimulation via ABA leads to characteristic alterations in different regulatory and effector T cells not seen in patients treated with TCZ or RTX. Further studies must clarify whether the analysis of regulatory and effector T cell subpopulations before treatment initiation can be used as biomarker for treatment response.References:[1]Álvarez-Quiroga C, Abud-Mendoza C, Doníz-Padilla L, et al. CTLA-4-Ig therapy diminishes the frequency but enhances the function of treg cells in patients with rheumatoid arthritis.J Clin Immunol. 2011;31(4):588-595.doi:10.1007/s10875-011-9527-5Acknowledgments:Work done in “CBmed” was funded by the Austrian Federal Government within the COMET K1 Centre Program, Land Steiermark and Land Wien.Disclosure of Interests:None declared

scholarly journals COMP-01. MODELING THE EVOLUTION OF PLOIDY IN A RESOURCE RESTRICTED ENVIRONMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi61-vi61
Author(s):  
Noemi Andor ◽  
Jill Barnholtz-Sloan ◽  
Hanlee Ji
Keyword(s):  
Energy Demand ◽  
Cell Cycle Progression ◽  
Leading Edge ◽  
Giant Cells ◽  
High Energy ◽  
Integrin Signaling ◽  
Cell Phenotype ◽  
Lower Grade ◽  
Sequencing Data ◽  
High Ploidy

Abstract Progression of lower-grade gliomas (LGG) to glioblastoma (GBM) is accompanied by a phenotypic switch to an invasive cell phenotype. Converging evidence from colorectal-, breast-, and lung-cancers, suggests a strong enrichment of high ploidy cells among metastatic lesions as compared to the primary. Even in normal development: trophoblast giant cells are responsible for invading the placenta during embryogenesis and these cells often have tens of copies of the genome. We formulate a mechanistic Grow-or-go model that postulates higher energy demands of high-ploidy cells as driver of invasive behavior. The unit we are modeling is a cell, that comes with a certain ploidy, proliferation-, and death-rate. Variations in ploidy emerge as a result of chromosome missegregations. For each cell we calculate the probability of cell-division as a function of energy availability in the neighborhood vs. ploidy-dependent energy demand of the cell. Underlying this comparison is the dual role of integrin signaling: integrin-mediated signals allow cells to progress from G1 to S-phase. At the same time integrins mediate cell migration. The model was implemented as a cellular automaton and 2,500 simulations were ran at variable energies and missegregation rates. In low-energy environments high-ploidy clones were enriched at the leading edge of the tumor. This was not the case in high-energy environments. We applied the model to analyze previously published exome sequencing data from 14 multi-spatial and longitudinal LGG biopsies. Using the size and ploidy of co-existing clones as summary statistics for Approximate Bayesian Computation, we infer relative chromosome missegregation rates in primary LGG. A higher missegregation rate was predictive of faster progression of LGG to GBM (multivariate Cox: HR = 7.96, P = 0.041). Future validation experiments will evaluate the potential of the model to explain differences in the prognostic power of integrin signaling and cell cycle progression between males and females.

Contemporary gene flow and weak genetic structuring in Rococo toad (Rhinella schneideri) populations in habitats fragmented by agricultural activities

2011 ◽  
Vol 32 (3) ◽  
pp. 399-411 ◽  
Author(s):  
Artur Silva ◽  
Evonnildo C. Gonçalves ◽  
Eliana Morielle-Versute ◽  
Maurício P. Arruda ◽  
Maria Paula C. Schneider
Keyword(s):  
Gene Flow ◽  
Isolation By Distance ◽  
Agricultural Practices ◽  
Genetic Structuring ◽  
Genetic Stock ◽  
Homogeneous Population ◽  
The North ◽  
Contemporary Gene Flow ◽  
Rhinella Schneideri ◽  
Two Populations

AbstractThe reduced vagility and philopatric behaviour of most amphibians make them especially vulnerable to the effects of habitat fragmentation, in particular the loss of genetic variation. However, almost no data are available on the effects of agricultural practices on populations of Neotropical amphibians. Here, the genetic diversity of Rococo toad (Rhinella schneideri) populations in the highly disturbed landscape of the north-western region of the Brazilian state of São Paulo was analysed using microsatellite markers. Two areas were sampled – one dominated by open pastures (four populations) and the other by sugar cane plantations (two populations) – in an attempt to evaluate the possible influence of the type of anthropogenic matrix on genetic variability and gene flow (dispersion). The populations presented a relatively uniform genetic stock, with low levels of inbreeding (Fis) and high levels of admixture between localities (Fst, Rst, STRUCTURE) indicating no genetic subdivision. The results indicated relatively high levels of recent migration among sites (m) and no isolation by distance. The analyses also found that historical and contemporary rates of migration among populations were broadly similar. Overall, then, neither type of matrix appeared to have an effect on the connectivity of the Rococo toad populations. This suggests that the species has a considerable capacity for dispersal, allowing it to maintain a relatively homogeneous population, even under intense human pressure.

scholarly journals Auditory Thalamus Neurons During Sleep: Changes in Frequency Selectivity, Threshold, and Receptive Field Size

2000 ◽  
Vol 84 (2) ◽  
pp. 934-952 ◽  
Author(s):  
Jean-Marc Edeline ◽  
Yves Manunta ◽  
Elizabeth Hennevin
Keyword(s):  
Cortical Neurons ◽  
Frequency Selectivity ◽  
The Other ◽  
Field Size ◽  
Homogeneous Population ◽  
Auditory Thalamus ◽  
Rate Level ◽  
Level Function ◽  
Informative Content ◽  
Two Populations

The present study describes how the frequency receptive fields (RF) of auditory thalamus neurons are modified when the state of vigilance of an unanesthetized animal naturally fluctuates among wakefulness (W), slow-wave sleep (SWS), and paradoxical sleep (PS). Systematic quantification of several RF parameters—including strength of the evoked responses, response latency, acoustic threshold, shape of rate-level function, frequency selectivity, and RF size—was performed while undrugged, restrained guinea pigs presented spontaneous alternances of W, SWS, and PS. Data are from 102 cells recorded during W and SWS and from 53 cells recorded during W, SWS, and PS. During SWS, thalamic cells behaved as an homogeneous population: as compared with W, most of them (97/102 cells) exhibited decreased evoked spike rates. The frequency selectivity was enhanced and the RF size was reduced. In contrast during PS, two populations of cells were identified: one (32/53 cells) showed the same pattern of changes as during SWS, whereas the other (21/53 cells) expressed values of evoked spike rates and RF properties that did not significantly differ from those in W. These two populations were equally distributed in the different anatomical divisions of the auditory thalamus. Last, during both SWS and PS, the responses latency was longer and the acoustic threshold was higher than in W but the proportion of monotonic versus nonmonotonic rate-level functions was unchanged. During both SWS and PS, no relationship was found between the changes in burst percentage and the changes of the RF properties. These results point out the dual aspect of sensory processing during sleep. On the one hand, they show that the auditory messages sent by thalamic cells to cortical neurons are reduced both in terms of firing rate at a given frequency and in terms of frequency range. On the other hand, the fact that the frequency selectivity and the rate-level function are preserved suggests that the messages sent to cortical cells are not deprived of informative content, and that the analysis of complex acoustic sounds should remain possible. This can explain why, although attenuated, reactivity to biologically relevant stimuli is possible during sleep.

Otenzepad shows two populations of binding sites in human gastric smooth muscle

1995 ◽  
Vol 73 (1) ◽  
pp. 124-129 ◽  
Author(s):  
I. Bellido ◽  
A. Gómez ◽  
F. Sánchez de la Cuesta ◽  
J. L. Fernández
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptor ◽  
Binding Sites ◽  
Rank Order ◽  
Receptor Subtypes ◽  
Muscarinic Receptor Subtypes ◽  
Homogeneous Population ◽  
Gastric Smooth Muscle ◽  
Cholinergic Agonists And Antagonists ◽  
Two Populations

Cholinergic agonists and antagonists frequently used for gastrointestinal motility disorders often produce adverse effects. A possible explanation for this is the presence of similar muscarinic receptor subtypes on smooth muscle from different gastrointestinal organs. The aim of this study was to characterize muscarinic receptor subtypes in human gastric smooth muscle with receptor binding methods. N-[3H]Methylscopolamine ([3H]NMS) saturation experiments showed a homogeneous population of noninteracting binding sites (KD = 0.76 ± 0.07 nM, Bmax = 46.94 ± 3.69 fmol/mg of tissue protein, nH = 0.99 ± 0.01). The rank order of inhibition of [3H]NMS binding by nonlabelled compounds was atropine [Formula: see text] otenzepad [Formula: see text] pirenzepine. Atropine and pirenzepine bound to a homogeneous population of binding sites. The inhibition of [3H]NMS binding by otenzepad showed two populations of receptors (nH < 1, p < 0.01), whose apparent Ki1 of 298 ± 40 nM and apparent Ki2 of 3.463 ± 0.62 mM were similar to those reported for the M2 and M3 muscarinic receptor subtypes. The M2 subtype was the more abundant of the two, representing 79.12 ± 5.48% of the total population. We conclude that two muscarinic receptor subpopulations similar to the M2 and M3 subtypes are present in human gastric smooth muscle and that the M2-like receptor is the more abundant of the two.Key words: human stomach, muscarinic receptor subtypes, smooth muscle.

scholarly journals P0297CHANGES OF CD4CD28NULL AND CD8CD28NULL T CELLS IN CHRONIC KIDNEY DISEASE AND THE IMPACT OF DIFFERENT DIALYSIS MODALITIES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Erasmia Sampani ◽  
MARIA STANGOU ◽  
Dimitra Vasileia Daikidou ◽  
Vasiliki Nikolaidou ◽  
Despoina Asouchidou ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
Cell Immunity ◽  
Clinical Consequences ◽  
Cell Subpopulations ◽  
And Gender ◽  
T Cell Subpopulations ◽  
The Impact

Abstract Background and Aims Chronic Kidney Disease (CKD) affects both the innate and adaptive immunity, although clinical consequences, and the effect of different renal replacement methods on those alterations remain unclear. The purpose of this prospective observational study was to investigate the alterations of T cell immunity in CKD patients, as well as the effect of different dialysis methods on T lymphocyte subtypes. Method T cell subpopulations namely CD3+CD4+, CD3+CD8+, CD4+CD28- and CD8CD28- cells, were isolated from whole blood samples using flow cytometry in 40 CKD patients at predialysis state (ESRD-T0). The immunological profile was repeated six months later after initiation of renal replacement therapy (hemodialysis (HD) or peritoneal dialysis (CAPD)). Fifteen age and gender matched healthy individuals served as controls. Results Both CD4+ and CD8+ T cells were significantly reduced in ERSD-T0 patients compared to controls, 604(105-3551) vs. 943(584-1867) μ/L, p=0.001, and 352(103-1561) vs. 422.4(263-1453) μ/L, p=0.05. The percentage of both CD4+CD28null and CD8+CD28null cells, 6.4(0.3-30) % vs. 2.7(0.1-7.8) %, p=0.04 and 58.2(12.8-85.4) % vs. 39(7.8-57.1) %, p=0.01 was increased in ERSD-T0 patients comparing to controls. Furthermore the percentage of CD4+CD28null cells correlated with CRP (r=0.4, p=0.04) and serum albumin levels (r=-0.5, p=0.007), while, significant differences were noticed between patients with and without cardiovascular disease, regarding both, CD4+CD28null and CD8+CD28null cells, 8.6(1-30) % vs. 2.1(0.1-19.8) %, p=0.04 and 62.5(12.8-85.4) vs. 45.5(5.7-73.7), p=0.02, respectively. Changes in the population of CD4+CD28null after 6 months on dialysis showed significant differences between HD and CAPD methods, 110.11(-27.1 to 311.4)% vs. -28.1(-100 to 30)%, respectively, p=0.003, as were in CD8+CD28null cells, 55.23(-29.06 to 197.93)% vs. -8.34(-54.99 to 66.72)%, respectively, p=0.05. Conclusion CKD seem to affect specific T cell subtypes, at a pre-dialysis stage, and levels correlate with chronic inflammatory markers and the presence of CVD. These disturbances are further enhanced in HD, while they are alleviated in CAPD.

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