SEARCH · PubMed Health

Results for “clonal modeling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources

PubMed1998

Modelling the dynamics of LCMV infection in mice: conventional and exhaustive CTL responses.

Lymphocytic choriomeningitis virus (LCMV) infection in mice provides an example of an extraordinarily dynamic process with an extreme sensitivity of phenotype of infection to parameters of virus/host interaction. A mathematical model is developed to examine the dynamics of virus-specific cytotoxic T lymphocyte (CTL) response for LCMV infection in mice. The model, formulated by a system of nonlinear delay-differential equations, considers the interacting populations of viruses, precursor CTLs, terminally differentiated effector CTLs and total virus antigen load. Clonal elimination of virus-specific cytotoxic T cells in high-dose LCMV-Docile infection represents an example of the classical phenomenon--high zone tolerance. To describe both conventional and exhaustive CTL responses in the acute phase of LCMV-D infection two mechanisms are invoked: the high virus antigen load inhibition of T-cells proliferation via energy induction and the activation-induced cell death by apoptosis. Parameters of the model, characterizing the rates of virus and CTL production and elimination in spleen, are estimated by assimilating with the model data on the LCMV-D infection in C57BL/6 mice for low-, moderate- and high-dose infections. It is suggested that not only the clonal expansions have to be described in mathematical models as being virus regulated but also the later phases of primary immune response. Down-regulation of the primary CTL response is controlled by a network of mechanisms inducing anergy and apoptosis in activated T cells. The model is used to investigate the effect of variations in virus and CTL response parameters on LCMV infection outcome and suggest predictions for experimental studies, in particular the phenotype of LCMV-WE infection in C57BL/6 as a function of initial virus doses.

Animals↗

PubMed2002

Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay.

Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A relationship between the two tumours has been suggested in the literature. This study investigated the clonality of both the stroma and the epithelium of these fibroepithelial tumours and attempted to construct a model in which fibroadenoma can progress in both an epithelial and a stromal direction. Fibroadenomas (n=25) and phyllodes tumours (n=12) were selected for analysis. Tissue was microdissected and analysed for clonality using a polymerase chain reaction (PCR)-based assay targeted at an X-linked polymorphic marker, the human androgen receptor gene (HUMARA). Nineteen fibroadenomas and nine phyllodes tumours could be analysed. Normal-appearing epithelium, hyperplastic epithelium, and stroma removed from fibroadenomas were polyclonal. As expected, carcinoma in situ (CIS) removed from four fibroadenomas was monoclonal. Three areas of apparent stromal expansion within fibroadenoma were monoclonal, suggesting stromal progression. Mostly, the stroma of phyllodes tumours was monoclonal and the epithelium polyclonal. In two cases, however, the epithelium seemed to be monoclonal, whereas in three other cases the stromal component was polyclonal. These findings indicate that fibroadenoma can progress in an epithelial direction to CIS and in a stromal direction to phyllodes tumour.

Breast Neoplasms↗

PubMed1999

Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution.

Invasive squamous carcinoma of the uterine cervix (CC) arises from sequential progression of low-grade (L) and high-grade (H) squamous intraepithelial lesions (SILs). In clinical observations, these lesions are frequently found as synchronous multiple foci. The nature and evolutionary mechanism of these lesions are largely unknown. We have performed allelotyping of three 3p markers (at 3p14, 3p22-24, and 3p25) on 22 LSILs and 15 HSILs microdissected from patients with multiple (n = 21) or uniform (n = 6) cervical lesions. The results were analyzed together with our previous allelotyping of 57 deeply invasive CCs. Loss of heterozygosity at one of the three markers was observed in 23%, 27%, and 31 % of LSILs, HSILs, and CCs, respectively. Frequent and early allelic loss was noted (in 30% of LSILs and 50% of HSILs) at 3p14, which may harbor tumor suppressor genes involved in early stages of cervical carcinogenesis. A high frequency of microsatellite alteration (MA) was found in LSIL (41%) and HSIL (67%) but not in CC (5.3%). In particular, MA was more frequently found in low-grade lesions in association with invasive cancers (75%, 6/8) than in those associated with SILs (29%, 4/14) (P < 0.05). Together with the finding of a monoclonal origin of premalignant and malignant cervical lesions, the present results allow us to propose a model of local field effect of genomic instability that progressively affects the clonal evolution of SIL of uterine cervix.

Carcinoma in Situ↗

PubMed2005

Population genetics of complex life-cycle parasites: an illustration with trematodes.

Accurate inferences on population genetics data require a sound underlying theoretical null model. Organisms alternating sexual and asexual reproduction during their life-cycle have been largely neglected in theoretical population genetic models, thus limiting the biological interpretation of population genetics parameters measured in natural populations. In this article, we derive the expectations of those parameters for the life-cycle of monoecious trematodes, a group comprising several important human and livestock parasites that obligatorily alternate sexual and asexual reproduction during their life-cycle. We model how migration rates between hosts, sexual and asexual mutation rates, adult selfing rate and the variance in reproductive success of parasites during the clonal phase affect the amount of neutral genetic diversity of the parasite (effective population size) and its apportionment within and between definitive hosts (using F-statistics). We demonstrate, in particular, that variance in reproductive success of clones, a parameter that has been completely overlooked in previous population genetics models, is very important in shaping the distribution of the genetic variability both within and among definitive hosts. Within definitive hosts, the parameter F(IS) (a measure of the deviation from random mating) is decreased by high variance in clonal reproductive success of larvae but increased by high adult self-fertilisation rates. Both clonal multiplication and selfing have similar effects on between-host genetic differentiation (F(ST)). Migration occurring before and after asexual reproduction can have different effects on the patterns of F(IS), depending on values of the other parameters such as the mutation rate. While the model applies to any hermaphroditic organism alternating sexual and clonal reproduction (e.g. many plants), the results are specifically discussed in the light of the limited population genetic data on monoecious trematodes available to date and their previous interpretation. We hope that our model will encourage more empirical population genetics studies on monoecious trematodes and other organisms with similar life-cycles.

Animals↗

PubMed1996

Dose-response curve for anaesthetics based on the Monod-Wyman-Changeux model.

We have analysed the dose-response curve for halothane and isoflurane according to the Monod-Wyman-Changeux (MWC) model. This model describes the nature of the physiological data reported by Wakamori, Ikemoto and Akaike for inhibitory Cl currents induced by GABA or glycine in dissociated rat brain neurones and by Herrington and colleagues for Ca2+ currents in clonal pituitary cells. With some assumptions on the difference in response to anaesthetics between patients, the model is applicable in vivo, and it also describes well the human dose-response curve for isoflurane reported by Mather, Raftery and Prys-Roberts. However, the steeply sigmoidal dose-response curve in humans for halothane presented by deJong and Eger is difficult to understand with the same model, because it gives rise to unrealistic MWC variables.

Anesthetics, Inhalation↗

PubMedDate not supplied

The role of AP-1, NF-kappaB and ROS/NOS in skin carcinogenesis: the JB6 model is predictive.

Generation of reactive oxygen species (ROS) stimulates transcription by activating transcription factors activator protein 1 (AP-1) and nuclear factor kappaB (NF-KB). The mouse epidermal JB6 cells constitute a model system that has significantly contributed to the understanding of these events. Clonal variants of JB6 cells are differentially responsive to transformation induced by tumor promoters such as phorbol esters (TPA), epidermal growth factor (EGF) and tumor necrosis factor alpha (TNF-alpha), as well as oxidative stress. TPA and EGF, acting through the MAP kinase pathway, activate AP-1 and subsequently NF-kappaB proteins and downstream transcription processes that are involved in the transformation response in transformation-sensitive (P+) JB6 cells. The effect of TNF-alpha is primarily on the NF-kappaB pathway. ROS and other free radicals can activate AP-1 and NF-KB transcription coordinately. In JB6 cells, both ERK/Fra-1 and NF-kappaB activity is essential for the transformation response. Inhibition of NF-kappaB and AP-1 activity abrogates transformation in JB6 cells as well as in transgenic mice and human keratinocytes. A similar effect is seen with antioxidants, which inhibit NF-kappaB and AP-1 activity as well as transformation in JB6 cells. The JB6 model is therefore valuable for monitoring early events in oxidative stress related signaling leading to carcinogenesis, and for identifying molecular targets for cancer chemoprevention.

Animals↗

PubMed2006

Therapy-related acute myeloid leukemia 6 years after clonal detection of inv(11)(q21q23) and MLL gene rearrangement.

Results of recent studies with animal models suggest that expression of MLL fusion proteins promotes acute leukemogenesis. However, the most potent MLL fusion proteins are not sufficient for the development of acute myeloid leukemia (AML). The clinical data on the pathogenesis of this type of leukemia are limited. We analyzed the case of a patient with therapy-related AML with MLL rearrangement. The patient initially developed AML with t(8;21). Although the patient achieved complete remission with chemotherapy, an abnormal karyotype, inv(11)(q21q23), was detected. After 6-year persistence of a clone with the inversion 11 karyotype in the bone marrow, secondary AML developed. Results of fluorescence in situ hybridization analysis combined with magnet-activated cell sorting analysis showed that MLL rearrangement was detected in CD34+ and CD13+ fractions but not in a CD3+ fraction of the bone marrow. There were 2 important clinical findings. One was that MLL rearrangement was not sufficient for the development of leukemia. The other was that MLL rearrangement targets specific lineages.

Antigens, CD34↗

PubMed2000

Cellular automaton of idealized brain tumor growth dynamics.

A novel cellular automaton model of proliferative brain tumor growth has been developed. This model is able to simulate Gompertzian tumor growth over nearly three orders of magnitude in radius using only four microscopic parameters. The predicted composition and growth rates are in agreement with a test case pooled from the available medical literature. The model incorporates several new features, improving previous models, and also allows ready extension to study other important properties of tumor growth, such as clonal competition.

Algorithms↗

PubMed1988

Autoimmunity and its therapy: mathematical modelling.

A mathematical description of autotolerance and autoimmunity based on the previous model of immune response for normal antigen stimulation is given. In particular, the clonal deletion theory and non-specific stimulation of T-helper cells are included. Thus, an idea about the origin of autoimmune disease and the qualitative description of its course is presented. Possible therapies, such as immunosuppression and extracorporeal removal of autoantibodies, are also discussed.

Antigens↗

PubMedDate not supplied

Hit-and-run mechanism of HBV-mediated progression to hepatocellular carcinoma.

AIM AND BACKGROUND: Hepatitis B virus is implicated in the development of hepatocellular caracinoma. No oncogenes have been identified within the viral genome. Furthermore, it frequently fragments after integration into the hepatocyte genome. Simultaneous investigations of hepatitis B virus integration patterns and genetic changes in precancerous tissues are important to understand the role played by hepatitis B virus integration in hepatocellular caracinoma. METHOD: We used a combination approach of dual characterization of highly polymorphic loci and the change in hepatitis B virus-DNA integration pattern. Large regenerative nodules were dissected from 6 explanted hepatitis B virus infected cirrhotic livers. Nodules within each liver segment were schematically mapped and histopathologically analyzed. Genomic DNA from each nodule was analyzed for hepatitis B virus integration and the genetic stability of 12 microsatellite loci including D3S2321, D8S1022, D17S1159, D4S2281, D5S1/2, D16S675, D16S685, D16S490, D16S526, D16S673, D16S677 and D16S690. RESULTS: Data from different liver segments revealed few viral integrations and average allele loss. The most exciting results came from a segment containing a set of clonally and spatially related nodules having similar histologic features, a progressive lineage of allele loss, HBV integration and loss of integration. CONCLUSIONS: This model portrait, a scenario of genetic events that precede tumor formation where the acquisition and loss of hepatitis B virus integrations in clonally related regenerative nodules, might explain how the virus acts as a hit-and-run mutagen.

Carcinoma, Hepatocellular↗

PubMed2005

Estimating the life-span of oligodendrocytes from clonal data on their development in cell culture.

This paper presents a new method to analyze clonal data on oligodendrocyte development in cell culture. The process of oligodendrocyte generation from precursor cells is modelled as a multi-type Bellman-Harris branching process as suggested in an earlier paper [K. Boucher, A. Zorin, A.Y. Yakovlev, M. Mayer-Proschel, M. Noble, An alternative stochastic model of generation of oligodendrocytes in cell culture, J. Math. Biol. 43 (2001) 22]. This model has been extended to allow for death of oligodendrocytes as well as a dissimilar distribution of the first mitotic cycle duration as compared to the subsequent cycles of precursor cells, which lengths are assumed to be independent and identically distributed random variables. Since the time-span of oligodendrocytes is not directly observable in clonal data, plausible parametric assumptions are invoked to make estimation problems tractable. In particular, the time to cell death follows a two-parameter gamma distribution, while the lapse of time between the event of cell death and the event of cell disintegration is assumed to be exponentially distributed. A simulated pseudo maximum likelihood method for estimation of model parameters has been developed using simulation-based approximations of the expected numbers and variance-covariance matrices for different types of cells. Finite sample properties of the estimation procedure are studied by computer simulations. The proposed method is illustrated with an analysis of the clonal development of O-2A progenitor cells isolated from the rat optic nerve and the corpus callosum.

Animals↗

PubMed1997

Heterogeneity of chemosensitivity in six clonal cell lines derived from a spontaneous murine astrocytoma and its relationship to genotypic and phenotypic characteristics.

Heterogeneity in drug sensitivity must, in part, account for the relative lack of success with single agent chemotherapy for glioblastoma multiforme (GBM). In order to develop in vitro model systems to investigate this, clones derived from the VM spontaneous murine astrocytoma have been characterised with regard to drug sensitivity. Six clonal cell lines have been tested for sensitivity to a panel of cytotoxic drugs using an intermediate duration 35S-methionine uptake assay. These lines have previously been extensively characterised with regard to morphological, antigenic, kinetic, tumourigenic potential in syngeneic animals and chromosomal properties and display considerable heterogeneity. The present study indicates that heterogeneity extends to sensitivity to all classes of cytotoxic drugs. The greatest difference in sensitivity between the clones was seen in response to cell cycle-specific drugs like the Vinca alkaloids (14-fold and 20-fold for vincristine (VCR) and vindesine (VIND) respectively), while the nitrosoureas, CCNU and BCNU displayed a smaller fold difference in sensitivity (4.3 and 3.6-fold difference respectively). All the clones were considerably more resistant to the adriamycin (ADM), cis-platinum (C-PLAT) and the Vinca alkaloids than the parental cell line although the difference in sensitivity between the clones and parental cell line were less marked for the nitrosoureas and procarbazine (PCB). It has also been possible to examine the relationship between drug sensitivity and the phenotypic and genotypic properties of these clonal cell lines. There is a relationship between chromosome number and sensitivity of a wide variety of cytotoxic drugs including the nitrosoureas, Vinca alkaloids, PCB, C-PLAT, BLEO but not ADR or 5-FU. Clones with small numbers of chromosomes were more resistant than clones with gross polyploidy. Similarly, sensitivity to Vinca alkaloids and ADM, but not other classes of drugs, was greatest in cells with numerous cytoplasmic processes and which did not express large amounts of cell surface fibronectin. Preliminary experiments have been conducted on reconstituting clonal mixtures of cells with different sensitivity to Vinca alkaloids and results from these studies indicate that the drug resistance phenotype is dominant, with clonal mixtures of sensitive and resistant cell adopting the sensitivity of the more resistant partner. These cell lines should prove to be useful models for examining the cell biological basis of drug resistance in glioma and may lead to the identification and exploitation of novel cellular targets in new therapies for GBM.

Animals↗

PubMed1997

Cell size control and a cell-intrinsic maturation program in proliferating oligodendrocyte precursor cells.

We have used clonal analysis and time-lapse video recording to study the proliferative behavior of purified oligodendrocyte precursor cells isolated from the perinatal rat optic nerve growing in serum-free cultures. First, we show that the cell cycle time of precursor cells decreases with increasing concentrations of PDGF, the main mitogen for these cells, suggesting that PDGF levels may regulate the cell cycle time during development. Second, we show that precursor cells isolated from embryonic day 18 (E18) nerves differ from precursor cells isolated from postnatal day 7 (P7) or P14 nerves in a number of ways: they have a simpler morphology, and they divide faster and longer before they stop dividing and differentiate into postmitotic oligodendrocytes. Third, we show that purified E18 precursor cells proliferating in culture progressively change their properties to resemble postnatal cells, suggesting that progressive maturation is an intrinsic property of the precursors. Finally, we show that precursor cells, especially mature ones, sometimes divide unequally, such that one daughter cell is larger than the other; in each of these cases the larger daughter cell divides well before the smaller one, suggesting that the precursor cells, just like single-celled eucaryotes, have to reach a threshold size before they can divide. These and other findings raise the possibility that such stochastic unequal divisions, rather than the stochastic events occurring in G1 proposed by "transition probability" models, may explain the random variability of cell cycle times seen within clonal cell lines in culture.

Age Factors↗

PubMed2000

Is the Prunella (Lamiaceae) hybrid zone structured by an environmental gradient? Evidence from a reciprocaltransplant experiment.

Hybrid zones may be structured by environmentally independent selection against intrinsically unfit hybrids (tension zone models), or by environmentally dependent fitness differences among parental species and hybrids (ecological selection-gradient models). A 30-m slope in a mountain grassland harbors a hybrid zone of the clonal perennials, Prunella grandiflora and P. vulgaris (Lamiaceae), with P. grandiflora in the upper, P. vulgaris in the lower, and both parental species and P. grandiflora × P. vulgaris Hybrids in a narrow middle part. We found gradients for soil depth and water content, and vegetation height and biomass along the slope. A reciprocal transplant experiment yielded crossing reaction norms for vegetative reproduction. Parental species were locally adapted to their home sites, while the three taxa did not differ in vegetative reproduction in the Hybrid transplant site. Local adaptation for vegetative reproduction of P. grandiflora was mediated through higher survival and that of P. vulgaris through higher ramet number, indicating adaptation of their clonal growth strategies (phalanx vs. guerrilla) to the different habitats. Hybrid performance was intermediate between that of the parental species in all three sites, although Hybrids flowered more often than the parental species in the Hybrid site. Our results support ecological selection-gradient rather than tension zone models.

Journal Article↗

PubMed2004

Open-nucleus breeding strategies compared with population-wide positive assortative mating: I. Equal distribution of testing efforts.

Positive assortative mating (PAM) can enhance the additive genetic variance in a breeding population(BP). This increases the potential for gains in the production population (PP, selected subset of the BP) for recurrent selection programs in forest trees. The assortment of mates can be either: (1) by individual tree rank across the whole BP (PAM), or (2) trees of similar rank can be merged into larger hierarchical groups and then mated randomly within group ("open"-nucleus breeding,NB). The objective of this study was to compare PAM and NB in quantitative terms. The NB simulation model assumed two tiers (nucleus, main) with unrestricted migration between the tiers. Clonal tests were used to predict breeding values and test resources per mate were kept constant for all mates. Both gain and diversity were combined into a single selection criterion, "group-merit selection." Alternatives were compared over five breeding cycles by considering genetic gain and diversity in a selected PP established in a seed orchard. The assortment of mates in both alternatives enhanced additive variance and increased the additive effect in the BP, leading to additional gain in the PP. Gains generated under PAM always exceeded gains under NB. Thus, the main message from this study is that PAM in both the short- and long-term results in more gain at any target level of diversity in the PP (the breeder's target) than is achieved by the NB alternative. The optimum size of the nucleus varies with the desired level of seed orchard diversity. At lower target diversity, smaller nucleus sizes are favorable, while larger sizes result in more gain when seed orchard diversity is considered more important.

Breeding↗

PubMed2004

Antigen-specific CD4 T cell clonal expansion and differentiation in the aged lymphoid microenvironment. II. The memory T cell response is diminished.

We investigated the ability of the aged host environment to support a memory CD4 T cell response to a secondary immunization with a specific antigen. Using an adoptive transfer model, we previously reported that young CD4 T cells, transferred into the young or the aged lymphoid microenvironment, clonally expand and differentiate in a similar fashion after primary immunization with a specific antigen. In this report, we have monitored the clonal expansion of the donor-derived memory CD4 T population following a secondary challenge with the specific antigen. We show that antigen-specific memory T cell clonal expansion is diminished in the aged hosts. However, upon in vitro re-stimulation, antigen-specific CD4 T cells isolated from young and from aged hosts were equally responsive to antigen, thus indicating an inhibitory effect in the aged host environment. We provide evidence that factors specifically present in previously immunized aged hosts must be responsible for the diminished response of otherwise functional, antigen-specific memory CD4 T cells. Our results suggest that the decline in immunologic memory to foreign antigens may be due not only to intrinsic defects in aged T cells, but also to age-related differences in the lymphoid microenvironment of previously immunized hosts.

Adoptive Transfer↗

PubMed1981

Experimental study of hormone receptor development in a unicellular model system.

It was shown earlier that diiodotyrosine (T2) stimulates the growth of Tetrahymena. In the present study clonal populations of Tetrahymena, derived from subcultures propagated in the presence of T2, showed a highly significant increase of intra-clone variance over the control, while inter-clone variation was significant, but not decisive. This suggests that genetic factors play a smaller role in the development of the cell membrane receptor pattern tha the genetic variability of the membrane itself, which seems to account for the stabilization of the adequate receptors on first exposure to a hormone.

Analysis of Variance↗

PubMed2004

The accumulation of deleterious mutations within the frozen niche variation hypothesis.

The frozen niche variation hypothesis proposes that asexual clones exploit a fraction of a total resource niche available to the sexual population from which they arise. Differences in niche breadth may allow a period of coexistence between a sexual population and the faster reproducing asexual clones. Here, we model the longer term threat to the persistence of the sexual population from an accumulation of clonal diversity, balanced by the cost to the asexual population resulting from a faster rate of accumulation of deleterious mutations. We use Monte-Carlo simulations to quantify the interaction of niche breadth with accumulating deleterious mutations. These two mechanisms may act synergistically to prevent the extinction of the sexual population, given: (1) sufficient genetic variation, and consequently niche breadth, in the sexual population; (2) a relatively slow rate of accumulation of genetic diversity in the clonal population; (3) synergistic epistasis in the accumulation of deleterious mutations.

Biological Evolution↗