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PubMed1993

Radon, cigarette smoke, and lung cancer: a re-analysis of the Colorado Plateau uranium miners' data.

Much of our knowledge regarding the interaction of radon and tobacco smoke in the etiology of human lung cancer derives from studies of uranium miners. In this article, we present a re-analysis of lung cancer mortality in the Colorado Plateau miners' cohort within the framework of the two-mutation clonal expansion model of carcinogenesis. This analysis takes into account the patterns of exposure to radon and cigarette smoke experienced by individuals in the cohort. A simultaneous re-analysis of the British doctors' cohort indicated that those model parameters relating to the effects of tobacco were comparable in the two data sets. We found no evidence of interaction between radon and tobacco smoke with respect to their joint effect on the first or second stage mutation rates or on the rate of proliferation of initiated cells. The age-specific relative risks associated with joint exposure to radon and cigarette smoke, however, were supra-additive but submultiplicative. The analysis also confirmed that fractionation of radon exposures leads to higher lung cancer risks. Finally, we present some estimates of lung cancer risk from environmental radon exposure for non-smokers and smokers.

Adult↗

PubMedDate not supplied

Thymic stromal cells eliminate T cells stimulated with antigen plus stromal Ia molecules through their cross-talk involving the production of interferon-gamma and nitric oxide.

We previously established a thymic stromal cell clone capable of inducing differentiation of immature thymocytes and described a clonal elimination model in which T cell clones are killed on the monolayer of this stromal clone by stimulation of their T cell receptors (TCR) with antigen plus stromal Ia molecules. This study investigated molecular mechanisms underlying this phenomenon. Antigenic stimulation on thymic stromal cells produced large amounts of interferon-gamma (IFN-gamma) and small amounts of tumor necrosis factor-alpha (TNF-alpha). Addition of anti-IFN-gamma monoclonal antibody (mAb) to these cultures largely prevented death of TCR-stimulated T cells. T cell death was also induced when cultures were treated with recombinant IFN-gamma (rIFN-gamma) or rTNF-alpha instead of the relevant antigen, showing that these lymphokines are involved in the process of T cell death. It was further demonstrated that these lymphokines, especially IFN-gamma, induced the expression of mRNA for the inducible type of nitric oxide (NO) synthase in thymic stromal cells and that enhanced levels of NO were produced by stromal cells cultures with T cells plus antigen or stimulated with rIFN-gamma or rTNF-alpha. NO was found to be critically responsible for inducing T cell death on the stromal cell monolayer following stimulation of T cells with antigen or of stromal cells with rIFN-gamma or rTNF-alpha, because T cells death was completely prevented by addition of NG-monomethyl-L-arginine (L-NMMA), which is capable of inhibiting NO production. These results indicate that elimination of TCR-stimulated T cells on thymic stromal monolayers with the capacity to support thymocyte differentiation is induced by the cross-talk between IFN-gamma/TNF-alpha-producing T cells and stromal cells capable of producing NO in response to these lymphokines.

Cell Communication↗

PubMed2003

Environmental chemical-induced pro/pre-B cell apoptosis: analysis of c-Myc, p27Kip1, and p21WAF1 reveals a death pathway distinct from clonal deletion.

Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that suppress the immune system in part by inducing pro/pre-B cell apoptosis. The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig(+) B cells in that apoptosis is mediated by NF-kappa B down-regulation. Because a PAH-induced, clonally nonrestricted deletion of B cells would have important implications for B cell repertoire development, the nature of the PAH-induced intracellular death signal was studied further. Particular emphasis was placed on the roles of growth arrest and c-Myc, p27(Kip1), and p21(WAF1) expression, because all of these elements contribute to clonal deletion. As in clonal deletion models, and as predicted by the down-regulation of NF-kappa B, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation. Furthermore, whereas dexamethasone induced a G(0)/G(1) cell cycle arrest, PAH had no effect on pro/pre-B cell growth, indicating that growth arrest and apoptosis occur by separable signaling pathways in this early phase of B cell development. Finally, in contrast to clonal deletion, PAH-induced pro/pre-B cell death was not dependent on p27(Kip1) or p21(WAF1) up-regulation but did coincide with p53 induction. These results distinguish the PAH-induced apoptosis pathway from that activated during clonal deletion and indicate that signaling cascades leading to growth arrest and/or apoptosis in pro/pre-B cells differ from those active at later B cell developmental stages.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2004

Prediction of clonal chromosome aberration frequency in human blood lymphocytes.

We recently conducted a large-scale screening for clonal aberrations among atomic bomb survivors and proposed a model for the gross clonal composition of blood lymphocytes. Here we show an application of the model indicating that the number, m,of clones detectable by cytogenetic methods in an individual is predictable by the equation m= (1.8 + 6.4FG) x FP x n/500, where FG represents the estimated translocation frequency in the 46 chromosome set, FP is the observed translocation frequency with FISH or other methods, and nis the number of cells examined. Application of the equation to the results of seven other reports gave close agreement between the observed and calculated numbers of clones. Since the model assumes that clonal expansion is ubiquitous, and any translocation can be the constituent of a clone detectable by cytogenetic means, the vast majority of observed clonal expansions of these somatic cells are likely the result of random-hit events that are not detrimental to human health. Furthermore, since our model can predict the majority of clonal aberrations among Chernobyl workers who were examined 5-6 years after irradiation, clonal expansion seems to occur primarily within a few years after exposure to radiation, most likely being coupled with the process of recovery from radiation-induced injury in the lymphoid and hematopoietic systems.

Chromosome Aberrations↗

PubMed1990

Hormonal regulation of cytosolic free calcium and its functional consequences: the GH-cell model.

Use of clonal strains of prolactin (PRL)- and growth hormone-producing rat pituitary cells has proven informative in elucidating a number of the early biochemical, ionic, and secretory events regulated by the hypothalamic tripeptide, thyrotropin-releasing hormone (TRH). TRH causes biphasic changes in the concentration of cytosolic free calcium [( Ca2+]i) in GH4C1 cells and biphasic changes in hormone secretion. Early changes occur on a msecond to second scale and late changes, on a time scale of minutes. Although increases in [Ca2+]i are essential for enhanced secretion, at least in the case of the rapid initial phase, the TRH-induced increase in [Ca2+]i is necessary, but not sufficient to enhance secretion. A co-mediator with calcium appears to be diacylglycerol. The majority of the calcium involved in the early phase of rise in [Ca2+]i induced by TRH is derived from intracellular sources, while essentially all of the calcium rise observed in the late phase is derived from extracellular calcium entering the cell through both voltage-dependent and voltage-independent conductances. Because TRH causes an elevation of inositol(1,4,5) trisphosphate [Ins(1,4,5)P3] within seconds, but not mseconds, further studies are required before it can be concluded unequivocally that Ins(1,4,5)P3 is the sole mediator of the rapid phase of rise in [Ca2+]i induced by TRH in GH-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Adaptation in sexuals vs. asexuals: clonal interference and the Fisher-Muller model.

Fisher and Muller's theory that recombination speeds adaptation by eliminating competition among beneficial mutations has proved a popular explanation for the advantage of sex. Recent theoretical studies have attempted to quantify the speed of adaptation under the Fisher-Muller model, partly in an attempt to understand the role of "clonal interference" in microbial experimental evolution. We reexamine adaptation in sexuals vs. asexuals, using a model of DNA sequence evolution. In this model, a modest number of sites can mutate to beneficial alleles and the fitness effects of these mutations are unequal. We study (1) transition probabilities to different beneficial mutations; (2) waiting times to the first and the last substitutions of beneficial mutations; and (3) trajectories of mean fitness through time. We find that some of these statistics are surprisingly similar between sexuals and asexuals. These results highlight the importance of the choice of substitution model in assessing the Fisher-Muller advantage of sex.

Adaptation, Biological↗

PubMed2005

Lung cancer in Mayak workers: interaction of smoking and plutonium exposure.

Lung cancer mortality among 5,058 male workers of the Mayak Production Association has been analyzed with emphasis on the interaction of smoking and radiation exposure by using the two-step clonal expansion (TSCE) model of carcinogenesis. The cohort consists of all Mayak workers with known smoking status, who were employed in the period 1948-1972, and who either had the plutonium concentration in urine measured or who worked in the reactors, where plutonium exposure was negligible. Those who died during the first two years after the first urine sampling were excluded. The follow-up extended until the end of 1998. During this time, 2,176 workers died, including 244 lung cancer cases. Mayak workers were exposed to external (gamma and neutron) radiation, and in the radiochemical and plutonium plants to plutonium. In the preferred TSCE model, internal radiation and smoking act on the clonal expansion of pre-carcinogenic clones. Assuming a plutonium radiation weighting factor of 20, the excess relative risk per lung dose was estimated to be 0.11 (95% CI: 0.08; 0.17) Sv(-1). Most of the lung cancer deaths are found to be due to smoking. The second main factor is the interaction of smoking and internal radiation. The model is sub-multiplicative in relative risks due to smoking and radiation. In a multiplicative version of the TSCE model, internal radiation acts on initiation and transformation rates. This model version agrees with conventional epidemiological risk models, because it also suggests a higher risk estimate than the preferred TSCE model. However, it fits the data less well than the preferred model.

Biophysical Phenomena↗

PubMed1998

Heterogeneity in the clonal T cell response. Implications for models of T cell activation and cytokine phenotype development.

The T cell can be defined in the context of two properties--the recognition specificity of the T cell receptor (TCR) heterodimer and the functional response of the T cell after TCR stimulation. Once a particular TCR heterodimer is expressed and successfully selected during thymic development, the antigen specificity is fixed for all the clonal progeny of that cell. In contrast, the potential functional responses that may be generated in response to specific antigen in the postthymic environment are quite extensive. These range from programmed cell death to initiation of alternate programs of phenotype development that generate effector populations with distinct cytokine expression patterns and regulatory properties. Recent advances in analytical methods that have permitted multiparametric characterizations of the T cell response at the single cell, rather than population level, have necessitated a modified view of T cell activation and the clonal T cell response, and have generated new insights into the regulation of immunity. In this brief review, we highlight studies that have characterized heterogeneity of the CD4+ T cell clonal response based on single-cell analyses, and discuss implications for models of T cell activation and cytokine phenotype development.

Animals↗

PubMed2000

Expression of porcine adipocyte transcripts during differentiation in vitro and in vivo.

Transcript concentrations for the transcription factors, CCAAT enhancer binding protein beta and alpha (C/EBPbeta and C/EBPalpha), plus the adipocyte-characteristic proteins, fatty acid synthase (FAS), glucose transporter 4 (Glut 4), hormone-sensitive lipase (HSL), insulin receptor (InsR), lipoprotein lipase (LPL), and leptin were measured during differentiation of porcine stromal-vascular (S/V) cells in vitro. These same transcripts, excluding FAS and InsR, were measured in porcine adipose tissue from birth to 7 weeks of age. In S/V cells, C/EBPbeta and InsR were continuously elevated. At day 0, C/EBPalpha was approximately 20% of the day 9 value. The LPL increased gradually from day 0 to 9, whereas most other transcripts had a lag period of several days. In tissue, C/EBPbeta was substantial at birth and increased gradually. The C/EBPalpha was relatively low at birth and increased at day 17. The LPL and leptin increased continuously. The Glut 4 was low at birth and increased at day 28. The HSL was relatively low at birth, increased at day 10, and plateaued at day 28. Transcripts in porcine S/V cells develop somewhat differently from adipocyte differentiation models established in clonal cells, but the porcine cells represent a model that should be more applicable to pigs.

Adipocytes↗

PubMed1984

A new clonal strain of rat pituitary tumour cells: a model for non-regulated secretion of prolactin.

A new clonal strain of Prl-secreting cells derived from the transplantable rat pituitary tumour, 7315a, has been established in culture. The cells of this strain, designed 235-1, have a highly developed Golgi complex, an extensive rough endoplasmic reticulum, and a few small but no large dense-core granules. When inoculated into athymic mice and rats of the Buffalo strain, the 235-1 cells produce tumours, and the host animals have hypertrophied mammary glands that produce milk, indicating that Prl secreted by these cells has mammotrophic activity. In monolayer culture, the doubling time of 235-1 cells is 31 +/- 1 h (mean +/- SE). The cells secrete Prl, a trace quantity of GH, but no LH, FSH, TSH, ACTH, or alpha-MSH. Prl is released at a rate of 257 +/- 12 fg per h per cell. The cellular content of Prl is 424 +/- 23 fg per cell. Prl secretion by 235-1 cells is not affected by dopaminergic agonists and antagonists, TRH, or oestradiol-17 beta but is inhibited in the presence of EGTA or monensin, an ionophore that is believed to act at the level of the Golgi complex. The subcellular distribution of Prl in 235-1 cells is different from that in rat pituitary cells. In 235-1 cells, Prl is associated not with a single set of dense particles as it is in pituitary cells but with 2 sets of subcellular particles, of which 1 set cosedimented with particles having lysosomal enzyme activity. These findings suggest that Prl secretion by 235-1 cells involves secretory pathways that are different from those seen in normal lactotrophs.

Animals↗

PubMed1985

Clonal attenuation in chick embryo fibroblasts. Experimental data, a model and computer simulations.

When cells from mass cultures of chick embryo fibroblasts are grown at very low density, some cells yield large clones while others produce smaller clones, and some cells fail to divide at all. The distribution of clone sizes is related to the number of population doublings which the donor mass culture has undergone: the more doublings which have occurred, the smaller the average clone size. In this report we describe a model which analyses this phenomenon, referred to as 'clonal attenuation', in detail. The model is based on the concept that a cell with hypothetically unlimited replicative potential--i.e. a 'stem' cell--can become 'committed' to a programme of limited replicative potential. This event is assumed to be stochastic and to have a fixed probability per stem cell division. The parameters of the model are: Pc, the probability of commitment; N, the number of differentiative divisions; and Tc, the cell-cycle times. By computer simulation, it is shown that Pc increases roughly exponentially at each successive stem cell division. According to the model, when the daughter of a stem cell becomes committed, its progeny proceed through N obligatory divisions before becoming terminally differentiated (post-mitotic). The best-fit value of N was found to be seven. The simulations also reveal that the absolute number of stem cells in the total population increases for most of the lifespan of the culture. When Pc becomes much greater than 0.5, the number of stem cells declines rapidly to zero, and the culture nears senescence. Sensitivity analysis shows that Pc can assume only a limited range of values at each stem-cell division.

Animals↗

PubMed1997

Simulation of the clonal growth of Bostrychia radicans (Ceramiales-Rhodophyta) using Lindenmayer systems.

A mathematical model for the clonal growth of the alga Bostrychia radicans was constructed based on architectural growth rules and Lindenmayer systems. The sequence of theoretical growth and invasive strategy of space is shown in several graphical schemes which represent different steps of the model. We postulate that Bostrychia radicans has a 'phalanx' strategy of colonization (Lovett Doust, L. 1981. J. Ecol. 69, 743-755.) based on the biological interpretation of the model and field observations.

Eukaryota↗

PubMed2003

The use of biologically based cancer risk models in radiation epidemiology.

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiological datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada.

Canada↗

PubMed2002

Divergent models of lymphoid lineage specification: do clonal assays provide all the answers?

Hematopoietic stem cells that drive blood development in mouse and man have been well characterized in recent years. In contrast, detailed analysis of the next stages of development, the progenitor cells that have begun to differentiate along specific hematopoietic lineages, is now only in its infancy. The process of myeloid differentiation has been relatively accessible to experimental manipulation due to the availability of culture systems able to support the progenitors for myeloid lineages, and the identification of cytokines capable of driving myeloid differentiation. Studies of early lymphoid differentiation, however, have lagged behind. In particular, the characterization of the first progenitors for the lymphoid lineages is far from complete, due mainly to inefficient assay systems for growing these cell lineages in vitro. Two laboratories have published conflicting data regarding the specification of lymphoid lineages in the mouse. Both groups of investigators utilize elegant clonal approaches to characterize progenitor cell subsets. While these experiments define lineage potential in the most rigorous manner possible, the divergent results suggest that clonal assays must be supplemented with more physiologic studies in order to define the actual differentiation pathways that function in vivo.

Animals↗

PubMed1987

Effects of time-variant exposure on toxic substance response.

Sources of time-variant exposure to toxic substances are identified and examined for their effects on the estimation of response. It is shown that only time-averaged target tissue concentrations are required to obtain rigorous risk estimates from the one-hit and multihit models. In contrast, detailed concentration histories need to be retained throughout analyses involving two-event models with intermediate-stage clonal growth advantage (clonal two-stage) and multistage models. Cumulative incidence ratios, based on the exact to time-averaged treatment of concentration time dependencies, are evaluated for substances whose toxic responses exhibit moderate (arsenic) and strong (ethylene dibromide) dependence on time of actual exposure. These ratios reveal that time-averaged dose approximations may lead to several orders of magnitude error in both the multistage and clonal two-stage models if exposure periods are short, and that 3.4-fold (arsenic) and 8-fold (ethylene dibromide) errors still exist even when an actual two-thirds lifetime exposure is averaged over a full lifetime. Finally, the effects of time-variant exposure on risk estimation due to migration and birth-death in an epidemiological setting are examined. A residence time distribution calculation shows that, if these effects are ignored for a population orally exposed to arsenic and characterized by an out-migration rate in excess of 5%/yr, response errors will exceed an order of magnitude.

Animals↗

PubMed1997

Estimating clonal heterogeneity and interexperiment variability with the bifurcating autoregressive model for cell lineage data.

We utilize an extension of the variance-components models for cell lineage data in Huggins and Staudte (R.M. Huggins and R.G. Staudte, Variance components models for dependent cell populations. J. Am. Stat. Assoc. 89:19-29 (1994) to analyze NIH3T3 cells grown in two different media. This modeling approach has the advantage of a simple built-in correlation structure between familial members and allows for estimating experimental effects, rather than treating them as random effects. In addition, this methodology gives robust estimates of model parameters together with standard errors required for statistical inference. The importance of clonal heterogeneity and interexperiment variability in modeling eukaryotic cell cycles was previously pointed out by Kuczek and Axelrod (T. Kuczek and D.E. Axelrod, The importance of clonal heterogeneity and interexperimental variability in modeling the eukaryotic cell cycle. Math. Biosci. 79:87-96 (1986). This analysis confirms significantly positive sister-sister correlation when cells are grown in rich or poor medium and negative mother-daughter correlation when cells are grown in poor medium. However, for cells grown in rich medium, Kuczek and Axelrod's analysis gives negative mother-daughter correlations, whereas this analysis gives significant positive mother-daughter correlations.

3T3 Cells↗

PubMed2003

Clonal expansion and not cell interconversion is the basis for the neuroblast and nonneuronal types of the SK-N-SH neuroblastoma cell line.

The ability of neuroblastoma (NB) cells to interconvert bidirectionally, in vitro, from a neuroblast (N) to a nonneuronal (S) form is a well-studied biologic phenomenon of great clinical importance. Differences in the morphologic/ biochemical characteristics and gene expression patterns of the two cell populations have been investigated extensively in an effort to unravel the transdifferentiation process. Subcloning of the SK-N-SH NB cell line has led to two morphologically distinct cell types: SH-SY5Y (N-type) and SH-EP (S-type). Karyotypic analysis combined with G-banding and SKY showed a difference between these two cell types in the copy number of the 2p15 approximately pter segment, including the MYC-N gene. FISH analysis showed an extra copy of MYC-N present in all three lines: in SK-N-SH and SH-SY5Y the majority of cells had three copies of MYC-N, whereas in SH-EP the majority had two copies and only a small cell population with three copies was present. We suggest that the simultaneous coexistence of both cell types and the subsequent clonal expansion of one over the other is a possible explanation for the phenomenon observed and not the accepted interconversion model. According to the clonal expansion model, both N and S cells are simultaneously present in both cell lines. Under certain conditions, the less-aggressive S cells can dominate over the highly aggressive N cells, which eventually lead to the formation of the SH-EP and vice-versa.

Cell Differentiation↗

PubMed2002

Mechanistic modelling in large case-control studies of lung cancer risk from smoking.

The two-step clonal expansion (TSCE) model is applied to large case-control studies, frequency matched for age, which allow estimation of the RR of lung tumour risk caused by smoking. For estimating background hazard rates, mortality data from the study areas are used to supplement the case-control data. Two approaches are used to analyse the data, based on the unconditional and the conditional likelihoods. They are demonstrated to give nearly identical results. Some model diagnostics are performed and demonstrate a good model fit. Our results indicate that smoking acts on the promotion and transformation parameters, but not on the initiation parameter of the TSCE model. The fitted relative risk of current smokers peaks between ages 50 and 60 years. The relative risk of male ex-smokers decreases strongly with time since end of exposure, but does not reach the risk of non-smokers, and does not decrease as much as for female ex-smokers.

Adult↗