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PubMed1989

Cyclic AMP regulation of P0 glycoprotein and myelin basic protein gene expression in semi-differentiated peripheral neurinoma cell line D6P2T.

We have analyzed the effects of cAMP-elevating drugs (dibutyryl cAMP, forskolin, and isobutyl methylxanthine) on growth properties and myelin-specific gene expression in the peripheral neurinoma cell line D6P2T. The steady-state levels of RNA and polypeptide for the two major PNS myelin proteins, P0 glycoprotein (P0) and myelin basic protein (MBP), were measured by Northern blotting and immunoblotting, respectively. The levels of the two RNAs in individual cells were examined by in situ hybridization. The transcriptional activities of the P0 and MBP genes were analyzed by nuclear run-off experiments. Treatment with cAMP-elevating agents caused cell aggregation and dose-dependent increase in growth control. Expression of P0 RNA was constitutive in untreated cells and was repressed at high doses. Expression of MBP RNA was induced at low doses and repressed at higher doses. For both MBP and P0 the effects on gene expression were first detected after a lag of approximately 6 h, were manifested in all cells and were mediated, at least in part, at the transcriptional level. The level of P0 polypeptide was proportional to the level of P0 RNA, but MBP polypeptide was not detectable even under conditions where MBP RNA was induced. The results with this clonal model suggest that cAMP plays a pivotal role in regulation of growth and gene expression during Schwann cell differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed2004

Trypanosoma cruzi: genetic structure of populations and relevance of genetic variability to the pathogenesis of chagas disease.

Chagas disease, caused by the protozoan Trypanosoma cruzi, has a variable clinical course, ranging from symptomless infection to severe chronic disease with cardiovascular or gastrointestinal involvement or, occasionally, overwhelming acute episodes. The factors influencing this clinical variability have not been elucidated, but it is likely that the genetic variability of both the host and the parasite are of importance. In this work we review the the genetic structure of T. cruzi populations and analyze the importance of genetic variation of the parasite in the pathogenesis of the disease under the light of the histotropic-clonal model.

Animals↗
PubMed2005

Speciation through competition: a critical review.

We examined causes of speciation in asexual populations in both sympatry and parapatry, providing an alternative explanation for the speciation patterns reported by Dieckmann and Doebeli (1999) and Doebeli and Dieckmann (2003). Both in sympatry and parapatry, they find that speciation occurs relatively easily. We reveal that in the sympatric clonal model, the equilibrium distribution is continuous and the disruptive selection driving evolution of discrete clusters is only transient. Hence, if discrete phenotypes are to remain stable in the sympatric sexual model, there should be some source of nontransient disruptive selection that will drive evolution of assortment. We analyze sexually reproducing populations using the Bulmer's infinitesimal model and show that cost-free assortment alone leads to speciation and disruptive selection only arises when the optimal distribution cannot be matched--in this example, because the phenotypic range is limited. In addition, Doebeli and Dieckmann's analyses assumed a high genetic variance and a high mutation rate. Thus, these theoretical models do not support the conclusion that sympatric speciation is a likely outcome of competition for resources. In their parapatric model (Doebeli and Dieckmann 2003), clustering into distinct phenotypes is driven by edge effects, rather than by frequency-dependent competition.

Biological Evolution↗
PubMed1984

Immunomodulation of host resistance by tumor variants.

Immunomodulation of host resistance by tumor cell variants has been investigated in the context of immunological effects of tumor cell heterogeneity using a murine tumor model. Clonal variation in the susceptibility to specific T cell-mediated cytotoxicity (TC), which is inversely related to tumorigenicity in syngeneic animals, was demonstrated among clones derived from a cultured line of DBA/2 lymphoma L1210 by limiting dilution. Thus, although a majority of such clones were TC-resistant and highly tumorigenic, some clones were TC-susceptible and non-tumorigenic. Moreover, an inoculation of the variant clones bearing the latter phenotype was shown to elicit protective immunity in host mice against a challenge with the parent L1210, whereas an inoculation of spleen cells (or extracts) from hosts bearing tumorigenic clones would abrogate the priming effects of the non-tumorigenic variants, presumably through splenic suppressor cells. These results suggest that heterogeneity among variant clones may influence the regulation of host resistance against tumors.

Animals↗
PubMed1993

Cytotoxicity of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines.

The in vivo effects of dopamine-derived alkaloids, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, salsolinols, and their N-methylated derivatives on a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells, were examined by culture in the presence of various concentrations of the agents. The effects were evaluated in comparison with those by 1,2,3,4-tetrahydroisoquinoline and its N-methylated derivatives. Among 1,2,3,4-tetrahydroisoquinolines, only N-methylisoquinolinium ion had cytotoxic effect on PC12h cells. In general, 6,7-dihydroxyisoquinolines had more potent cytotoxic effect than N-methylisoquinolinium ion, and they reduced protein amounts of PC12h cells at 100 microM and 1 mM concentration. The specific activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, decreased with these isoquinolines at concentrations lower than those required to reduce the protein amount. The toxicity of N-methylated derivatives seems to be more potent than non-methylated isoquinolines. Salsolinols were proved to be accumulated in the mitochondrial fraction of the cells after 3 days in culture. N-methyl-1,2,3,4-tetrahydroisoquinoline depleted ATP from PC12h cells and it was prevented by preincubation with an inhibitor of type-A monoamine oxidase, clorgyline. These results indicate that N-methylated and oxidized derivatives of dopamine-derived alkaloids may be potent dopaminergic neurotoxins similar to 1-methyl-4-phenylpyridinium ion in the human brain and may induce Parkinson's disease after long years of accumulation.

Animals↗
PubMed2000

Adaptive dynamics in diploid, sexual populations and the evolution of reproductive isolation.

Evolutionary branching is the process whereby an initially monomorphic population evolves to a point where it undergoes disruptive selection and splits up into two phenotypically diverging lineages. We studied evolutionary branching in three models that are ecologically identical but that have different genetic systems. The first model is clonal, the second is sexual diploid with additive genetics on a single locus and the third is like the second but with an additional locus for mate choice. Evolutionary branching occurred under exactly the same ecological circumstances in all three models. After branching the evolutionary dynamics may be qualitatively different. In particular, in the diploid, sexual models there can be multiple evolutionary outcomes whereas in the corresponding clonal model there is only one. We showed that evolutionary branching favours the evolution of (partial) assortative mating and that this in turn effectively restores the results from the clonal model by rendering the alternative outcomes unreachable except for the one that also occurs in the clonal model. The evolution of assortative mating during evolutionary branching can be interpreted as the initial phase of sympatric speciation with phenotypic divergence and partial reproductive isolation.

Adaptation, Physiological↗
PubMed1994

Computer simulation of cell growth governed by stochastic processes: application to clonal growth cancer models.

Cancer is a multistage process in which cell proliferation determines the growth of cells within stages and is associated with the transition of cells from one stage to the next. The usual model for cancer risk assessment, the linearized multistage model, does not explicitly include cell proliferation. More realistic cancer models are needed to reduce uncertainty in cancer risk assessment and to provide basic insights into the quantitative roles of cell proliferation and mutation. This report describes a simulation model for the transition of cells from one stage to the next and for clonal growth within stages. The model is intended to facilitate the use of experimental data on cell replication and preneoplastic lesions in risk assessment. When a population of cells is small its growth may be governed by stochastic processes. Such a population may disappear by chance even when the probability of cell division on a given time interval exceeds the probability of cell death. Procedures for estimating cell proliferation and mutation parameters from data for use in risk assessment should account for this random aspect of growth. The present model describes cell growth governed by stochastic processes, is consistent with earlier analytical expressions for such growth (Dewanjii et al., Risk Anal. 9, 179, 1989), and is flexible with respect to time-dependent data. A data set for spontaneous basophilic clones in male F344 rats (Popp et al., Fundam. Appl. Toxicol. 5, 314, 1985) is analyzed and predictions are made for (a) the probability of mutation to the basophilic genotype per division of a normal hepatocyte (3.5 x 10(-8)), (b) number of basophilic clones too small to be detected, and (c) number of basophilic clones that disappear by chance. This work illustrates the potential of computer simulation for quantitative analysis of the roles of cell division, cell death, and mutation in cancer.

Animals↗
PubMed1997

Computer simulation of clonal growth cancer models. I. Parameter estimation using an iterative absolute bisection algorithm.

Quantitative models of the relationship between exposure to chemical carcinogens and carcinogenic response are useful for hypothesis evaluation and risk assessment. The degree to which such models accurately depict the underlying biology is often a function of the need for mathematical tractability. When closed-form expressions are used, the need for tractability may significantly limit their complexity. This problem can be minimized by using numerical computer simulation methods to solve the model, thereby allowing more complex and realistic descriptions of the biology to be used. Unfortunately, formal methods of parameter estimation for numerical models are not as well developed as they are for analytical models. In this report, we develop a formal parameter estimation routine and apply it to a numerical clonal growth simulation (CGS) model of the growth of preneoplastic lesions consisting of initiated cells. An iterative bisection algorithm was used to estimate parameters from time-course data on the number of initiated cells and the number of clones of these cells. The algorithm successfully estimated parameter values to give a best fit to the observed dataset and was robust vis-à-vis starting values of the parameters. Furthermore, the number of data points to which the model was fit, the number of stochastic repetitions and other variables were examined with respect to their effects on the parameter estimates. This algorithm facilitates the application of CGS models for hypothesis evaluation and risk assessment by ensuring uniformity and reproducibility of parameter estimates.

Algorithms↗
PubMed2000

A model for hepatocarcinogenesis with clonal expansion of three successive phenotypes of preneoplastic cells.

The two-stage model with clonal expansion of intermediate cells has often been used to describe the carcinogenesis process. The model hypothesizes that cells have to undergo two mutations on their way from the normal to the malignant stage. Biological experiments indicate the existence of three types of preneoplastic cells in hepatocarcinogenesis representing three successive intermediate stages in the development of malignant cells from normal cells. This finding suggests that hepatocarcinogenesis should be described by a multi-stage model with three intermediate stages, leading to a four-stage mutation model with clonal expansion of all types of intermediate cells. This model is presented and mathematical approximations for the number and size of nonextinct premalignant clones of the different cell types are derived. The model is applied to focal lesion data from a rat hepatocarcinogenesis experiment.

Animals↗
PubMed2005

A stochastic model to analyze clonal data on multi-type cell populations.

This article presents a stochastic model designed to analyze experimental data on the development of cell clones composed of two (or more) distinct types of cells. The proposed model is an extension of the traditional multi-type Bellman-Harris branching stochastic process allowing for nonidentical time-to-transformation distributions defined for different cell types. A simulated pseudo likelihood method has been developed for the parametric statistical inference from experimental data on cell clones under the proposed model. The method uses simulation-based approximations of the means and the variance-covariance matrices of cell counts. The proposed estimator for the vector of unknown parameters is strongly consistent and asymptotically normal under mild regularity conditions, while its variance-covariance matrix is estimated by the parametric bootstrap. A Monte Carlo Wald test is proposed for the test of hypotheses. Finite sample properties of the estimator have been studied by computer simulations. The model and associated methods of parametric inference have been applied to the analysis of proliferation and differentiation of cultured O-2A progenitor cells that play a key role in the development of the central nervous system. It follows from this analysis that the time to division of the progenitor cell and the time to its differentiation (into an oligodendrocyte) are not identically distributed. This biological finding suggests that a molecular event determining the type of cell transformation is more likely to occur at the start rather than at the end of the mitotic cycle.

Biometry↗
PubMed1980

Immunoglobulin synthesis by neoplastic cells: models of a clonal transition from IgM to IgG synthesis.

Tumour populations from two B cell neoplasms were investigated for their capacity to synthesise immunoglobulin in vitro. Neoplastic cells from a patient with chronic lymphocytic leukaemia and an IgG lambda paraproteinaemia co-expressed surface IgG lambda and IgM lambda and synthesised both IgG lambda and IgM lambda in short-term culture. In the second patient with non-Hodgkin's lymphoma, the neoplastic cells expressed surface IgM lambda but synthesised both IgM lambda and IgG lambda in vitro. The findings are discussed in terms of a model for the clonal switch from IgM to IgG synthesis.

Aged↗
PubMed2006

A mutagenetic tree hidden Markov model for longitudinal clonal HIV sequence data.

RNA viruses provide prominent examples of measurably evolving populations. In human immunodeficiency virus (HIV) infection, the development of drug resistance is of particular interest because precise predictions of the outcome of this evolutionary process are a prerequisite for the rational design of antiretroviral treatment protocols. We present a mutagenetic tree hidden Markov model for the analysis of longitudinal clonal sequence data. Using HIV mutation data from clinical trials, we estimate the order and rate of occurrence of seven amino acid changes that are associated with resistance to the reverse transcriptase inhibitor efavirenz.

Alkynes↗
PubMed1998

Characterization of a composite tissue model that supports clonal growth of human melanocytes in vitro and in vivo.

To aid in the investigation of factors that control the proliferation and function of melanocytes, we have characterized a skin equivalent model that supports melanocyte growth and function in vitro and in vivo. Passenger melanocytes survive and proliferate at low numbers when keratinocytes of the epidermis are cultured in serum-containing medium using a fibroblast feeder layer. When the surface of de-epidermalized acellular dermis was seeded with these cultured cells, the keratinocytes formed a stratified epithelium in vitro containing rete ridges, and the melanocytes were preferentially located in the bottom of these rete ridges. Melanocyte cell number was much less than in normal skin, but in some areas the melanocytes were in clusters, consistent with clonal growth of the cells. When transplanted to athymic mice, the grafts formed foci of pigmentation at 3 wk that expanded and repigmented the entire graft by 8 wk. Histologic examination of these foci revealed that they corresponded to clusters of melanocytes that proliferated and migrated to eventually repopulate the entire graft. In grafts of mixed cells from light and dark skin donors, distinct foci of pigmentation were obvious at 3 wk and, instead of progressing to complete repigmentation, these foci remained stable for over 6 wk. Histologic examination confirmed that these grafts of mixed cells were entirely repopulated with melanocytes and that the grafts contained distinct zones of melanocytes that were of exclusively dark or light skin origin. This model should be valuable for studying the clonal growth of melanocytes in the context of the epidermis.

Animals↗
PubMed1976

Clones of B lymphocytes: their natural selection and expansion.

The operation of clonal selection for cells of the B-lymphocyte line is discussed with regard to: 1) The clonal repertoire determined by antigen binding to B lymphocytes, which is much larger than that determined by limiting dilution cloning assays. This quantitative difference is interpreted in terms of the multiple shared specificities of each antibody molecule. 2) Multiclonal responses and initial selection by antigen of particular clones (preferential primary selection). 3) Clonal dominance. During an immune response one clone (or a small number of clones) of B cells is preferentially selected and proliferated, apparently at random, from a heterogeneous population of cells capable of responding to the given antigen. Co-dominance of two or more clones simultaneously can be obtained by mixing selected clones. Secreted antibody is seen as playing a role in the establishment of clonal dominance. A model for clonal expansion is presented. The model attempts to explain the generation of memory and antibody secreting cells within each clonal expansion in terms of the ratio of two signals, one for proliferation and one for differentiation. The delivery of these signals is proposed to involve the receptor antibody-antigen interaction for proliferation and a self-recognition site interaction for differentiation.

Antibodies↗
PubMed1998

Altered gene expression in a clonal epidermal cell model of carcinogenesis identified by RNA differential display.

We have developed a multistage model system in which a normal mouse keratinocyte clone has been initiated with 7,12-dimethylbenz[a]anthracene and variant clones derived with benign or malignant phenotypes. To identify specific genes altered during mouse skin carcinogenesis, the gene expression patterns of the normal parental epidermal cell, an initiated cell, a benign papilloma, and a poorly differentiated squamous cell carcinoma were compared using RNA differential display. Most alterations in gene expression were observed at malignant conversion, that is, in the poorly differentiated squamous cell carcinoma that is known to have deregulated expression of p53. The sequence of a cloned cDNA fragment lost in the poorly differentiated squamous cell carcinoma was nearly identical to the 3' region of an adhesion-related kinase which is involved in homophilic cell aggregation. It is found in normal epidermal progenitor cells as well as tumorigenic cells with differentiation potential, but not in tumorigenic cells with a poorly differentiated phenotype, suggesting that this adhesion-related kinase may be involved in epidermal cell differentiation. Differential display within the cloned epidermal cell model appears to be useful in detecting and identifying malignant conversion-associated genes which then can be tested directly for their potential role in epithelial carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

The L beta T2 clonal gonadotrope: a model for single cell studies of endocrine cell secretion.

We have used single gonadotropes from the newly derived line, LbetaT2, to investigate the modulation of Ca2+ signaling and exocytosis by the steroid hormone environment. This cell line, derived by targeted oncogenesis in transgenic mice, has recently been shown to secrete LH in response to GnRH. We have characterized the effects of both GnRH and membrane depolarization on exocytosis and intracellular [Ca2+] ([Ca2+]i) in individual LbetaT2 cells. GnRH (1-100 nM) evoked concentration-dependent increases in [Ca2+]i and secretion, as monitored by measurement of plasma membrane capacitance (Cm) using the whole-cell perforated-patch technique, and the extent of these changes were dependent upon steroid hormone background. GnRH treatment of cells cultured in medium containing charcoal-treated FBS (ct-FBS) showed smaller changes in [Ca2+]i than cells cultured in untreated FBS. However, when estradiol (E2) and dexamethasone (Dex) were added to the ct-FBS medium (E2/Dex-ct-FBS), the elevations in [Ca2+]i stimulated by GnRH increased almost 2-fold. Additionally, the rates of secretion in the E2/Dex-ct-FBS-cultured cells were greater than in either ct-FBS- or FBS-cultured cells. The increase in secretory response observed with E2/Dex-ct-FBS appeared to be due to both an increase in the peak [Ca2+]i stimulated by GnRH and a shift toward increased sensitivity of the Ca2+ dependency of exocytosis. In contrast to GnRH-evoked responses, the increases in [Ca2+]i elicited by depolarization were greater in cells cultured in ct-FBS than in E2/Dex-ct-FBS; however, the secretory rates were no different in the two groups. Likewise, there was no apparent effect of steroid treatment on the Ca2+ dependency of depolarization-evoked exocytosis. In summary, these results 1) clearly demonstrate the utility of this cell line for single-cell studies of both agonist- and depolarization-evoked secretion; 2) reveal that steroid hormone background has profound effects on LbetaT2 cells, both on stimulus-induced calcium mobilization and on the apparent Ca2+ -sensitivity of exocytosis; and 3) show that expression of the steroid hormone effect on Ca2+ -sensitivity is dependent upon receptor occupation by GnRH.

Animals↗