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Results for “clonal modeling”

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PubMed1991

A clonal selection based timecourse model for antibody responses to killed vaccine, with applications to foot and mouth disease.

Published models for the timecourse of the immune response are reviewed for their applicability to data from animals that have been injected with killed vaccine. Simple models are required so that statistical fitting procedures become straightforward. A class of models that incorporates the concept of clonal selection has been found useful. Immune memory is described in terms of persistence of mean antibody affinity when the overall concentration of antibody has declined towards background. The model is demonstrated on multipoint affinity distributions and initial negative exponential densities, from which conditions for boundedness can be developed. Predictions are made that are consistent with experiments on the evolution of immunoassay data using foot and mouth disease vaccine.

Animals↗

PubMed1997

Down-modulation of c-myc expression induces apoptosis of B lymphocyte models of tolerance via clonal deletion.

Whereas overexpression of the c-myc gene was found to promote apoptosis in fibroblasts, myeloid, and T cells, physiologic cell death of immature B cell lymphomas correlated with a drop in c-myc expression. Here, the author reviews recent evidence demonstrating that inhibition of c-myc expression activates apoptosis of B cell models of clonal deletion and that rescue from apoptosis by CD40 ligand leads to maintenance of c-Myc levels. A model of differential functional expression of the c-myc gene is discussed.

Animals↗

PubMed2005

How old are the extant lineages of Toxoplasma gondii?

Most known isolates of Toxoplasma gondii belong to one of only three lineages, which are presumed to be clonal. Three models have been proposed for the evolutionary relationship of these lineages to the other extant lineages: Model (a) proposing that all lineages are derived from a most recent common ancestor (MRCA) in the distant past, Model (b) that all lineages are derived from a MRCA in the very recent past, and Model (c) that the clonal lineages share a recent MRCA but are related to the other lineages only in the distant past. Here, I test these models using DNA intron and coding-sequence data for loci at 14 genes, using three different methods to calculate the time of the MRCA. All of the calculations agree that the MRCA of the clonal lineages was > 70% of the age of the MRCA of all lineages, thus favouring Model (a). The MRCA may have existed approximately 150,000 years ago, with the clonal lineages expanding in prevalence approximately 10,000 years ago.

Animals↗

PubMed1991

Distinguishing between models of carcinogenesis: the role of clonal expansion.

Several multistage models have been proposed to describe the process of carcinogenesis. The model attributed to Armitage and Doll (1954, Brit. J. Cancer 8, 1-12) assumes that a normal cell is transformed into a malignant cell by k greater than or equal to 1 fundamental biological events. The model usually attributed to Moolgavkar and colleagues (1979, Math. Biosci. 47, 54-77; 1981, J. Natl. Cancer Inst. 66, 1037-1052) assumes that carcinogenesis is a two-stage process, taking into account the ability of premalignant cells to proliferate. In this paper, we investigate our ability to distinguish between these models using animal carcinogenicity data. Three different approaches are considered: one based on actual tumor incidence data from National Toxicology Program experiments and two based on simulated data. The results show that both models will adequately fit most tumor incidence data. This implies that we must be cautious in accepting the biological basis of either of these models simply because it "fits the data." Suggestions for experimental designs and toxicological endpoints (other than tumor incidence) which might provide for better discrimination between models are given.

Animals↗

PubMed2000

Bioassays of shortened duration for drugs: statistical implications.

Declining survival rates in rodent carcinogenesis bioassays have raised a concern that continuing the practice of terminating such studies at 24 months could result in too few live animals at termination for adequate pathological evaluation. One option for ensuring sufficient numbers of animals at the terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting carcinogenic potential. The present study was conducted to evaluate the loss of power associated with early termination. Data from drug studies in rats were used to formulate biologically based dose-response models of carcinogenesis using the 2-stage clonal expansion model as a context. These dose-response models, which were chosen to represent 6 variations of the initiation-promotion-completion cancer model, were employed to generate a large number of representative bioassay data sets using Monte Carlo simulation techniques. For a variety of tumor dose-response trends, tumor lethality, and competing risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 21 months, and compared to the power at the normal 24-month stopping time. The results showed that stopping at 18 months would reduce power to an unacceptable level for all 6 submodels of the 2-stage clonal expansion model, with the pure-promoter and pure-completer models being most adversely affected. For the 21-month stopping time, the results showed that, unless pure promotion can be ruled out a priori as a potential carcinogenic mode of action, the loss of power is too great to warrant early stopping.

Animals↗

PubMed1989

Quantitative models for lung cancer induced by cigarette smoke.

This discussion paper gives a limited history of work done at this Institute on quantitative modeling relating to lung cancer and cigarette smoking, a health hazard whose study has been given much encouragement by Norton Nelson. It first starts with the proposal that life shortening be considered as a measure of the impact of lung cancer using log normal and Weibull types of distributions of time to occurrence; second, it continues with an examination of the fits of the log normal and Weibull distributions to the Doll and Hill data on smoking and lung cancer in British physicians and a systematic review and development of mathematical models of carcinogenesis; and third, it reports on the current work that points out inconsistencies in the Armitage-Doll multistage model with the Doll and Hill data and suggests a two-stage clonal growth model that assumes promotion of clonal growth is restricted to cells initiated by the smoke. This proposal and related work support a current trend in risk assessment to adopt a two-stage clonal growth model that incorporates birth and death rates of cells and the transitional probabilities of the stages.

Cell Division↗

PubMed2003

Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The human health implications of this effect are of significant interest since human exposure to environmental formaldehyde is widespread, though at lower concentrations than those that cause cancer in rats. In this article, which is part of a larger effort to predict the human cancer risks of inhaled formaldehyde, we describe biologically motivated quantitative modeling of the exposure-tumor response continuum in the rat. An anatomically realistic, three-dimensional fluid dynamics model of the F344 rat nasal airways was used to predict site-specific flux of formaldehyde from inhaled air into tissue, since both SCC and preneoplastic lesions develop in a characteristic site-specific pattern. Flux into tissue was used as a dose metric for two modes of action, direct mutagenicity and cytolethality-regenerative cellular proliferation (CRCP), which in turn were linked to key parameters of a two-stage clonal growth model. The direct mutagenicity mode of action was represented by a low dose linear dose-response model of DNA-protein cross-link (DPX) formation. An empirical J-shaped dose-response model and a threshold model fit to the empirical data were used for CRCP. In the clonal growth model, the probability of mutation per cell generation was a function of the tissue concentration of DPX while the rate of cell division was calculated from the CRCP data. Maximum likelihood methods were used to estimate parameter values. Survivor (a nontumor outcome) and tumor data for controls from the National Toxicology Program database and from two formaldehyde inhalation bioassays were used for likelihood calculations. The J-shaped dose-response for CRCP provided a better description of the SCC data than did the threshold model. Sensitivity analyses indicated that the rodent tumor response is due to the CRCP mode of action, with the directly mutagenic pathway having little, if any, influence. When evaluated in light of modeling and database uncertainties, particularly the specification of the clonal growth model and the dose-response data for CRCP, this work provides suggestive though not definitive evidence for a J-shaped dose-response for formaldehyde-mediated nasal SCC in the F344 rat.

Administration, Inhalation↗

PubMed2003

X-inactivation patch size in human female tissue confounds the assessment of tumor clonality.

Most models of tumorigenesis assume that tumors are monoclonal in origin. This conclusion is based largely on studies using X chromosome-linked markers in females. One important factor, often ignored in such studies, is the distribution of X-inactivated cells in tissues. Because lyonization occurs early in development, many of the progeny of a single embryonic stem cell are grouped together in the adult, forming patches. As polyclonality can be demonstrated only at the borders of X-inactivation patches, the patch size is crucial in determining the chance of demonstrating polyclonality and hence the number of tumors that need to be examined to exclude polyclonality. Previously studies using X-linked genes such as glucose-6-phosphate dehydrogenase have been handicapped by the need to destroy the tissues to study the haplotypes of glucose-6-phosphate dehydrogenase [Fialkow, P.-J. (1976) Biochim. Biophys. Acta 458, 283-321] or to determine the restriction fragment length polymorphisms of X chromosome-linked genes [Vogelstein, B., Fearon, E. R., Hamilton, S. R. & Feinberg, A. P. (1985) Science 227, 642-645]. Here we visualize X-inactivation patches in human females directly. Results show that the patch size is relatively large in both the human colon and breast, confounding assessment of tumor clonality with traditional X-inactivation studies.

Adult↗

PubMed2003

A dose-response model for refractory ceramic fibers.

Refractory ceramic fibers (RCFs) are man-made vitreous fibers commonly used in insulation applications above 1000 degrees C. Although they have been subjected to considerable toxicologic evaluation, only the pooled results from two rat inhalation studies provide data that may be suitable for performing a numerical risk assessment. Even in these inhalation studies, good evidence exists that the maximum tolerated dose (MTD) was exceeded and that pulmonary overload occurred, a condition that will cause tumors whatever the dust responsible. Indeed, a significant yield of tumors was only obtained at the highest dose tested. If these results are omitted, there is no statistically significant evidence of carcinogenicity within the RCF results. Although there is little evidence that overload-related tumors are relevant to human risk, we adopted a conservative approach to obtain the estimates of risk regardless of overload, using a biologically based model, the two-stage clonal expansion model, as well as various statistical models, including the benchmark dose model. We argue that the data favor the use of a biologically based model, which gives the best fit when the highest dose RCF exposures are omitted. Continuing with this model, we show that available data from the RCF experiment, less outliers, coupled with results from other experiments with man-made mineral fibers (MMVFs), demonstrate that all MMVFs are potentially carcinogenic, with any risk mediated by the fibers' biopersistence. Application of this "all MMVF data set" model yields a maximum likely estimate for RCF excess unit risk of 4.6 x 10(-5) (95% upper confidence limit = 9.2 x 10(-5) per fiber/ml). This implies that the risk from occupational exposure to RCFs at 1 fiber/ml for a typical working lifetime would not exceed 10(-4).

Administration, Inhalation↗

PubMed1994

Role of bcl-2 and IL-5 in the regulation of anti-IgM-induced growth arrest and apoptosis in immature B cell lines. A cooperative regulation model for B cell clonal deletion.

Recent studies of transgenic mice have confirmed that clonal deletion is involved in the development of B cells. However, little is known about intercellular and intracellular molecular events regulating B cell clonal deletion. We investigated the role of bcl-2 and cytokines in the regulation of B cell clonal deletion using anti-IgM-induced growth arrest and apoptosis in immature B cell lines as a model. We show here that overexpression of Bcl-2 protein in stably transfected immature B cells partially inhibits anti-Ig M-induced apoptosis but does not affect growth arrest. Similarly, IL-5 has a strong inhibitory effect on anti-IgM-mediated apoptosis but has a weak inhibitory effect on growth arrest. Finally, although both bcl-2 overexpression and exogenous IL-5 cooperate with bacterial LPS to block apoptosis, bcl-2 overexpression and exogenous IL-5 have no additive inhibitory effect on anti-Ig induced apoptosis. These findings indicate that anti-IgM-induced apoptosis is independently regulated from growth arrest and is controlled by at least two independent pathways: One is regulated by either Bcl-2 protein or IL-5 and the other is regulated by LPS. Activation of both the bcl-2/IL-5 and LPS pathways is necessary for complete inhibition of apoptosis, and presumably, clonal selection of the immature B cells.

Animals↗

PubMed2004

Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional dosimetry of formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by the CFD model, with formation of DNA-protein cross-links (DPX) and with cytolethality/regenerative cellular proliferation (CRCP); and (3) use of a two-stage clonal growth model to link DPX and CRCP with tumor formation. With this structure, the prediction of the tumor dose response was extremely sensitive to cell kinetics. The raw dose-response data for CRCP are J-shaped, and use of these data led to a predicted J-shaped dose response for tumors, notwithstanding a concurrent low-dose-linear, directly mutagenic effect of formaldehyde mediated by DPX. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for the human nose with a one-dimensional typical path model for the lower respiratory tract. In other respects, the human model was structurally identical to the rat model. The predicted human dose response for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and rhesus monkey data. The rat dose response for CRCP was used "as is" for the human model, since no preferable alternative was identified. Three sets of baseline parameter values for the human clonal growth model were obtained through separate calibrations against respiratory tract cancer incidence data for nonsmokers, smokers, and a mixed population of nonsmokers and smokers, respectively. Additional risks of respiratory tract cancer were predicted to be negative up to about one ppm for all three cases when the raw CRCP data from the rat were used. When a hockey-stick-shaped model was fit to the rat CRCP data and used in place of the raw data, positive maximum likelihood estimates (MLE) of additional risk were obtained. These MLE estimates were lower, for some comparisons by as much as 1,000-fold, than MLE estimates from previous cancer dose-response assessments for formaldehyde. Breathing rate variations associated with different physical activity levels did not make large changes in predicted additional risks. In summary, this analysis of the human implications of the rat SCC data indicates that (1) cancer risks associated with inhaled formaldehyde are de minimis (10(-6) or less) at relevant human exposure levels, and (2) protection from the noncancer effects of formaldehyde should be sufficient to protect from its potential carcinogenic effects.

Animals↗

PubMed2004

[Biomass structure and quantitative relationship models of modules in clonal population of Puccinillia chinampoensis in Songnen plain].

In this paper, quantitative analysis was conducted at module level on the biomass structure of modules in clonal population of Puccinillia chinampoensis, the relationship between modules' biomass and turf sizes, and the relationship between one module's biomass and another one's. Based on these, the corresponding models of these relationships were established. The results showed that the regularities on the biomass of all functional modules and their ratio were the same at earing stage and at vegetative stage after fruiting. There existed linear correlation between functional modules and turf sizes at earing stage, and exponential correlation at vegetative stage after fruiting. Among all quantitative relationship models, only the one between photosynthesis modules and supporting modules was linear function at earing stage and exponential correlation at vegetative stage after fruiting. The relationship models between any other two functional models were all exponential correlation at two stages.

Biomass↗

PubMed1990

Interclonal and intraclonal diversity among anti-DNA antibodies from an (NZB x NZW)F1 mouse.

The immunologic basis for the generation of autoantibodies that are characteristic of systemic autoimmunity in mice and humans remains obscure. Experiments directed toward the analysis of serum antibody and the cell populations that combine to generate antibody in autoimmune mice have led to the proposition that autoantibody production, including anti-DNA, results from the nonselective, polyclonal activation of B cells. The present results from the molecular analyses of anti-DNA autoantibodies from an individual (NZB x NZW)F1 autoimmune mouse, however, are inconsistent with a clonally nonselective model for autoantibody production and are most consistent with a clonally selective, Ag-driven model for anti-DNA autoantibody production. These results demonstrate that Ig V region structures contributed by germ-line V region genes; recombinational diversity, including unusual DH gene usage and DH-DH recombination; and somatic mutation during B cell clonal expansion are all important for generating antibody and presumably B cell Ig receptor specificity for nucleic acids including native, duplex DNA.

Amino Acid Sequence↗

PubMed1979

GABA receptors in clonal cell lines: a model for study of benzodiazepine action at molecular level.

A "recptor unit" for gamma-aminobutyric acid (GABA), which includes brainlike receptor binding sites for tritium-labeled GABA and benzodiazepines (diazepam, clonazepam, and flunitrazepam) and a thermostable endogenous protein (GABA modulin) that inhibits both GABA and benzodiazepine binding, has been demonstrated in membranes prepared from NB2a neuroblastoma and C6 glioma clonal cell lines. In these cells, as in brain, diazepam (1 micromolar) prevents the effect of GABA modulin, and in turn GABA (0.oma and, to a lesser extent, the glioma cells represent a suitable model to study the interactions and the sequence of membrane and intracellular events triggered by the stimulation of benzodiazepine and GABA receptors.

Animals↗

PubMed1999

Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.

Age Factors↗

PubMed1995

Familial and sporadic human renal cell carcinoma: evidence against a double-loss mechanism of carcinogenesis.

It has been speculated that renal cell carcinoma (RCC) is an example of a double-loss mutation. We analyzed the age distribution of 71 cases of familial RCC and of 11 population-based cancer registries [German Democratic Republic, Denmark, Finland, Norway, Sweden, U.S.A. Whites, U.S.A. Blacks, Miyagi and Osaka Prefectures (Japan), Hong Kong, and Israeli Jews] according to the multi-hit and clonal growth models of carcinogenesis. The analysis rules out a double-loss mechanism for RCC. On both of the two models analyzed, carcinogenesis in the familial cases of RCC arises as a result of a three- to ten-fold increase in the average rate of mutation at the susceptible loci, as compared with the sporadic cases. In general, the clonal growth model provides a somewhat better fit to the age-distribution of RCC incidence than does the multi-hit model.

Adult↗

PubMed1984

In vitro induction and expression of interleukin 2 receptor in a clonal T helper cell differentiation model.

Induction and expression of interleukin 2 (IL 2) receptor have been studied using a poly( Glu60 Ala30 Tyr10 ) (GAT)-specific T cell clone of mouse origin. This clone (52-3) has been characterized and it exhibits functional properties of T helper (TH) cells: it leads to a specific anti-DNP response in the presence of DNP-GAT and DNP-primed B cells and it secretes biological activities which can induce polyclonal B cell proliferation and IgM secretion. In vitro this clone mimics the activation stages of normal T lymphocytes and can be obtained under two states of differentiation. depending on the antigen-specific signal provided by antigen-presenting cells (APC). The expression of IL 2 receptor by this clone has been studied by (i) its response to IL 2, (ii) its capacity to absorb IL 2 bioactivity, and (iii) its reactivity with monoclonal antibody 7D4 specific for mouse IL 2 receptor. All the results indicate that the unstimulated state does not express the IL 2 receptor while the activated state does. Clone 52-3 has been compared with clone 14-1.6 that derives from a TH cell line and expresses the IL 2 receptor constitutively. 52-3 offers a good experimental model for studying in vitro, in a clonal TH cell population, the detailed mechanism of IL 2 receptor induction.

Animals↗

PubMed1999

Quantitative assessment of the risk of lung cancer associated with occupational exposure to refractory ceramic fibers.

We present the results of a quantitative assessment of the lung cancer risk associated with occupational exposure to refractory ceramic fibers (RCF). The primary sources of data for our risk assessment were two long-term oncogenicity studies in male Fischer rats conducted to assess the potential pathogenic effects associated with prolonged inhalation of RCF. An interesting feature of the data was the availability of the temporal profile of fiber burden in the lungs of experimental animals. Because of this information, we were able to conduct both exposure-response and dose-response analyses. Our risk assessment was conducted within the framework of a biologically based model for carcinogenesis, the two-stage clonal expansion model, which allows for the explicit incorporation of the concepts of initiation and promotion in the analyses. We found that a model positing that RCF was an initiator had the highest likelihood. We proposed an approach based on biological considerations for the extrapolation of risk to humans. This approach requires estimation of human lung burdens for specific exposure scenarios, which we did by using an extension of a model due to Yu. Our approach acknowledges that the risk associated with exposure to RCF depends on exposure to other lung carcinogens. We present estimates of risk in two populations: (1) a population of nonsmokers and (2) an occupational cohort of steelworkers not exposed to coke oven emissions, a mixed population that includes both smokers and nonsmokers.

Administration, Inhalation↗