Analysis of cancer incidence data on the basis of multistage and clonal growth models.
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Age Factors↗
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Results for “clonal modeling”
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Modulation of nitric oxide, hydrogen peroxide and cytokine production in a clonal macrophage model by the trichothecene vomitoxin (deoxynivalenol).
Characterization of how vomitoxin (VT) and other trichothecenes affect macrophage regulatory and effector function may contribute to improved understanding of mechanisms by which these mycotoxins impact the immune system. The RAW 264.7 murine cell line was used as a macrophage model to assess effects of the VT on proliferation and the production of nitric oxide (NO), hydrogen peroxide (H2O2) and cytokines. Using the MTT cleavage assay, VT at concentrations of 50 ng/ml or higher was found to significantly decrease proliferation and viability of RAW 264.7 cells without stimulation or with stimulation by lipopolysaccharide (LPS) or interferon (IFN)-gamma. In the absence of an activation agent, VT (25-250 ng/ml) had negligible effects on the production of NO, H2O2, and cytokines. Upon activation with LPS at concentrations of 10 to 100 ng/ml, VT at 25-100 ng/ml markedly enhanced production of H2O2 but was inhibitory at 250 ng/ml. VT enhancement of H2O2 production was observed as early as 12 h after LPS stimulation. When IFN-gamma was used as the stimulant, VT (25-250 ng/ml) delayed peak H2O2 production. VT (25-250 ng/ml) also markedly decreased NO production in cells activated with LPS or IFN-gamma. Interestingly, VT superinduced TNF-alpha and IL-6 production in LPS-stimulated cells and also elevated TNF-alpha in IFN-gamma stimulated cells. These results suggest that VT can selectively and concurrently upregulate or downregulate critical functions associated with activated macrophages.
Analysis of Variance↗
Three-receptor, clonal expansion model for selection of self-recognition in the thymus.
The postulate is made that dual recognition by T lymphocytes is due to two types of receptor, one encoded by antibody genes and one by a distinct multigene family with simple rules for expression. This postulate leads to a model explaining ontogenic and evolutionary selection for self recognition, T lymphocyte effector function, the apparent high frequency of alloreactive T cells and immune response gene activity. The model is contrasted with previous explanations of self-recognition phenomena.
Animals↗
Physiologic and pathologic drug resistance in ovarian carcinoma--a hypothesis based on a clonal progression model.
Conventional models for successful chemotherapy suggest that early-stage ovarian cancer should be more responsive to cytotoxic drugs than advanced disease, that multiple drugs will prove more efficacious than single agents and that more intensive chemotherapy will prove superior to conventional doses. The purpose of numerous clinical studies has been to test these predictions and the results often fall short of the expectations. In trials to date, adjuvant chemotherapy for high-risk, early-stage ovarian cancer has provided only a modest, equivocal increase in disease-free survival. Combination chemotherapy produces higher response rates but this has not consistently resulted in prolonged survival. Dose intensification with high-dose chemotherapy increases rate of response further, but most responses are of short duration. The objective of this review is to integrate clinical and molecular biological observations into a novel model of drug resistance. We hypothesize that drug sensitivity is an acquired characteristic of neoplastic cells, and that there are two broad cellular forms of resistance to cytotoxic drugs. 'Physiological drug resistance' is a cellular state when drug sensitivity of cancer cells is similar to that of the corresponding normal tissue. This form of drug resistance can precede the acquisition of drug sensitivity and may be predominant in the early stages of neoplastic progression. A distinct, 'pathological drug resistance' can reappear later during tumor progression or during chemotherapy as a result of increased detoxification, upregulation of repair pathways or defective apoptosis. Tumors are formed of heterogeneous cell populations and in terms of drug sensitivity three distinct cell types may be present: drug-sensitive, physiologically drug-resistant and pathologically drug-resistant. Clinical response to chemotherapy is determined by the relative contribution of these different cell populations to the total cellular mass. Depending on the predominant type of surviving population, distinct patterns of clinical failure may develop that require different treatment strategies for optimal management. For chemosensitive cells that survived insufficient chemotherapy, consolidation with further, perhaps, high-dose chemotherapy is a rational option. For pathologically drug-resistant cells, pharmacological manipulation of drug resistance, and signaling pathways in combination with chemotherapy could be exploited. For physiologically drug-resistant cells, non-chemotherapy-based, 'chemopreventive' strategies to arrest tumor progression may prove beneficial.
Apoptosis↗
Distinct recognition phenotypes exist for T cell clones specific for small peptide regions of proteins. Implications for the mechanisms underlying major histocompatibility complex-restricted antigen recognition and clonal deletion models of immune response gene defects.
Using synthetic peptides as antigens, it was found that T cell clones of a given haplotype specific for 13-16 amino acid peptides could be clearly distinguished by the varied influence of amino acid substitutions on recognition. This was true for different antigenic determinants within peptides 81-96 and 74-86 of hen egg-white lysozyme, recognized in the context of the I-Ab and I-Ak molecules, respectively. Considerable complexity was demonstrated in the induced T cell repertoire specific for apparently single determinants, which implies that diversity of T cell recognition approaches that for B cells. The implications of the degeneracy of T cell recognition are discussed in the context of mechanisms through which Ia molecules restrict recognition and theories of Ir gene defects.
Animals↗
Implications of a two-stage clonal expansion model to indoor radon risk assessment.
Spreadsheet macro programs for calculations of exact hazard and probability of having contracted cancer were used to study the implications of the lung cancer model of Moolgavkar et al. Excess lifetime risk ELR and loss of life expectancy LLE were calculated from the annual values of hazard and probability, using published life tables. The influence of various factors on ELR and LLE was studied, as well as the lifetime risk projection in epidemiological studies. At indoor concentrations, ELR and LLE are coarsely proportional to lifetime exposure. The main factors determining the proportionality coefficient are 1. Smoking status, 2. General life expectancy, 3. Exposure schedule, and 4. Sex. For constant domestic exposure, the sex is less important, because the longer life of women is compensated by the lower hazard. ELR and LLE for a population with 30% smokers and life expectancies of 72.1 y and 79.5 y for men and women, respectively, are 56 per million per WLM and 860 y per million per WLM, respectively. For an exposure schedule with one high radon period, the mean age during the period becomes important, and the age-specific values for men and women differ from each other. Furthermore, the model predicts that case-control epidemiological studies overestimate the lifetime risk by an amount which may arise to several tens of percent.
Age Factors↗
A clonal deletion model for Ir gene control of the immune response.
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Animals↗
An examination of MHC restriction in the context of a minimal clonal abortion model for self tolerance.
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Animals↗
[Model of clonal evoluation of the karyotype in neoplastic pleural effusion].
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Chromosome Aberrations↗
Discrete systems, cell-cell interactions and color pattern of animals. I. Conflicting dynamics and pattern formation.
The morphogenesis of the color pattern of animals is modeled within the framework of a clonal model. The model takes into account the, sometimes conflicting, cell-cell and cell-background interactions. The color patterns of some reptiles and mammals are found to be consistent with the predictions of the model.
Animals↗
Genotoxicity of retroviral integration in hematopoietic cells.
The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many unique variables may have contributed to an increased risk in X-SCID patients, clonal dominance or frank neoplasia in animal models, clonal dominance in humans with chronic granulomatous disease, and the ability of retroviral integration to immortalize normal bone marrow cells or convert factor-dependent cells to factor independence suggest that transduction of cells with an integrating retrovirus has the potential for altering their subsequent biologic behavior. The selective pressure imposed during in vitro culture or after engraftment may uncover a growth or survival advantage for cells in which an integration event has affected gene expression. Such cells then carry the risk that subsequent mutations may lead to neoplastic evolution of individual clones. Balancing that risk is that the vast majority of integration events seem to be neutral and that optimizing vector design may diminish the probability of altering gene expression by an integrated vector genome. Several cell culture systems and animal models designed to empirically evaluate the safety of vector systems are being developed and should provide useful data for weighing the relative risks and benefits for specific diseases and patient populations. Gene therapy interventions continue to have enormous potential for the treatment of disorders of the hematopoietic system. The future of such efforts seems bright as we continue to evolve and improve various strategies to make such interventions both effective and as safe as possible.
Adaptor Proteins, Signal Transducing↗
In vitro vomitoxin exposure alters IgA and IgM secretion by CH12LX B cells. Relationship to proliferation and macromolecular synthesis.
The CH12LX cell line was used as a clonal model to assess the direct effects of vomitoxin on IgM and IgA secretion in B cells. When vomitoxin was included in LPS-driven CH12LX B cell cultures, it had multiple effects on Ig secretion. Whereas vomitoxin doses of 115 and 120 ng/ml caused 50% inhibition (ID50) of IgA and IgM production, respectively, toxin concentrations in the 5 to 50 ng/ml range slightly stimulated IgA production. However, low vomitoxin doses did not induce switching of membrane IgM+ CH12LX B cells to membrane IgA+. Total cell number was unaffected at vomitoxin concentrations up to 100 ng/ml but dropped markedly at 200 ng/ml (ID50 = 170 ng/ml). Using the MTT reduction assay as another measure of viability and cell function, vomitoxin was also inhibitory (ID50 = 130 ng/ml). Both thymidine incorporation and leucine incorporation were also inhibited by the toxin with estimated ID50s being 120 and 110 ng/ml, respectively. The results indicate that although at high doses, vomitoxin inhibits proliferation, Ig secretion and DNA/protein synthesis in the clonal B cell model, the toxin marginally stimulated IgA secretion at lower doses.
Animals↗
Quantitative genetic variation in Daphnia: temporal changes in genetic architecture.
Nonadditive genetic variation and genetic disequilibrium are two important factors that influence the evolutionary trajectory of natural populations. We assayed quantitative genetic variation in a temporary-pond-dwelling population of Daphnia pulex over a full season to examine the role of nonadditive genetic variation and genetic disequilibrium in determining the short-term evolutionary trajectory of a cyclic parthenogen. Quantitative traits were influenced by three factors: (1) clonal selection significantly changed the population mean phenotype during the course of the growing season; (2) sexual reproduction and recombination led to significant changes in life-history trait means and the levels of expressed genetic variation, implying the presence of substantial nonadditive genetic variation and genetic disequilibrium; and (3) Egg-bank effects were found to be an important component of the realized year-to-year change. Additionally, we examined the impact of genetic disequilibria induced by clonal selection on the genetic (co)variance structure with a common principal components model. Clonal selection caused significant changes in the (co)variance structure that were eliminated by a single bout of random mating, suggesting that a build-up of disequilibria was the primary source of changes in the (co)variance structure. The results of this study highlight the complexity of natural selection operating on populations that undergo alternating phases of sexual and asexual reproduction.
Animals↗
The expression of progesterone receptors coincides with an arrest of DNA synthesis in human breast cancer.
Two main models to account for the heterogeneous expression of estrogen receptors (ER) and progesterone receptors (PR) in human breast cancer have been proposed: the clonal model and the stem cell model. The authors previously provided evidence supporting the stem cell model since it was found that most of the proliferating cells in ER-positive (ER+) human breast cancer lack ER and that the ER-negative (ER-) and ER+ subpopulations are interrelated. The authors have analyzed in eighteen ER+/PR+ primary breast tumors the simultaneous expression of ER or PR (by immunohistochemistry) and DNA synthesis (by autoradiography) after 30 minutes of 3H-thymidine incorporation. The authors demonstrated that: (1) the average numbers of ER+ and PR+ cells were similar (36.8 +/- 10.7% and 39.3 +/- 17.6%, respectively); (2) The thymidine-labeling indexes of the ER+, ER-, PR+, and PR- subpopulations were 0.53 +/- 0.69%, 0.74 +/- 0.49%, 0.21 +/- 0.21 and 0.94 +/- 0.54%, respectively; and (3) 75.2% of the DNA-synthesizing cells were ER-, and 88.8% of them were PR-. The authors conclude that the cellular subpopulations expressing ER and PR were not identical, and the expression of PR was associated with a lower rate of cellular proliferation than was ER expression.
Breast Neoplasms↗
7th Jan Waldenström Lecture. The biology of human cancer metastasis.
The process of cancer metastasis is dynamic and consists of sequential, interrelated steps. Malignant cells that produce metastases have survived a series of potentially lethal interactions that are regulated by both the intrinsic properties of the tumor cells and host factors. Although some of the steps in this process contain stochastic elements, metastases develop from the nonrandom survival of a few subpopulations of cells that preexist within the parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of different cells. The orthotopic implantation of human cancer cells derived from surgical specimens into nude mice provides a biological model of metastasis. Using this model, clonal analysis of a human renal carcinoma, colon carcinoma, and melanoma has revealed that these tumors are heterogeneous for metastatic properties. Damage to an organ's environment is followed by inflammation and repair, and these homeostatic processes facilitate the proliferation of normal (physiology), and in some cases, tumor cells (pathology). Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be usurped by neoplastic cells. Collectively, the factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis.
Animals↗
Assessment of polyclonal antibody binding of ligand by Sips' equation or by the exact polyclonal equation. Comparison of models.
Different possibilities of modelling equilibrium data on polyclonal antibody binding of ligand were investigated. The binding curves of the exact polyclonal model, based upon the mass-action law, and the Sips' model were compared. The basic assumption was that the free energy of binding is distributed according to the Gauss normal distribution. Using a few equations, the values of binding site concns and affinity constants of the individual clones were converted to the parameters of Sips' equation (that is, A = Ab binding site concn, K0 = average affinity, Hi = heterogeneity index). It was demonstrated that the binding curves from the exact polyclonal and the Sips' equations were very similar for simulated, approximately normally distributed antibody populations. Even when only two or three Ab-clones are involved, the Sips' and the exact polyclonal binding curves are very similar as long as the ratio between affinity constants does not exceed 10. Equilibrium data plotted as bound ligand concn on a linear scale vs free ligand concn on a logarithmic scale (or alternatively after logarithmic transformation of free ligand concn) form the well known sigmoid saturation curve. A mathematical relationship was demonstrated between half-height slope of such curves, resulting from approximately normally distributed antibody populations, and parameters of Sips' equation. The half-height slope is Hi X A/4 when natural logarithms are used. The ideas described were illustrated by weighted nonlinear curve-fittings applied to actual equilibrium data on anti-DNP antibodies. Tested in this way, the Sips' and a 2-clonal model gave equally good fit but somewhat different average affinities. It was concluded that it is often impossible to distinguish between a 2-clonal, a 3-clonal or an approximately normally distributed antibody population by curve-fitting to experimental equilibrium data.
2,4-Dinitrophenol↗
Biologically based analysis of lung cancer incidence in a large Canadian occupational cohort with low-dose ionizing radiation exposure, and comparison with Japanese atomic bomb survivors.
Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using the two-stage clonal expansion model (TSCE) and extensions of the model with up to 10 initiation steps. Models with clonal expansion turned off provide very poor fits and are rejected. Characteristic and distinct temporal patterns of excess relative risk (ERR) are found for dose response affecting early, middle, or late stages of carcinogenesis, that is, initiation with one or more stages, clonal expansion, or malignant conversion. Both fixed lag and lag distributions are used to model time from first malignant cell to incidence. Background rates are adjusted for gender and birth cohort. Lacking individual smoking data, surrogate annual smoking doses based on U.S. annual per capita cigarette consumption appear to account for much of the birth cohort effect, leaving radiation dose response relatively unchanged. The mean cumulative exposure for males receiving nonzero cumulative doses of gamma and tritium radiation was 18.2 mSv. The males have a significant dose response with 33 out of a total of 322 lung cancer cases attributable to radiation. There were 78 incident lung cancer among females, (with mean cumulative exposure of 3.8 mSv among females with nonzero exposure). The dose response for females appears smaller than for males but does not differ significantly from zero or from the male dose response. Findings for males include significant dose-response relationships for promotion and malignant conversion, but not initiation, and a protraction effect (sometimes called an inverse-dose-rate effect, where risk increases with protraction of a given dose). The dose response predicted by our analysis appears consistent with the risk for lung cancer incidence in the Japanese atomic bomb survivors cohort, provided that proper adjustments are made for duration of exposure and differences in background rate parameters.
Canada↗
4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity.
4-1BB is expressed on activated T cells. We analyzed the role of 4-1BB during the CD8 T cell response of OT-I TCR-transgenic T cells to ovalbumin. In vitro, blocking 4-1BB during peptide presentation reduced proliferation of naive CD8 T cells, but did not affect the generation of CTL. Using an in vivo adoptive transfer model, clonal expansion of CD8 T cells to whole protein in adjuvant was significantly reduced when 4-1BB was blocked, with 50-70% fewer CD8 T cells accumulating. This was due to a reduction in T cell division and to enhanced apoptosis of CD8 T cells that had undergone many divisions. T cells generated in the absence of 4-1BB were impaired in their ability to secrete IFN-gamma whereas CTL activity of the T cells that survived was unaffected. These findings demonstrate that 4-1BB contributes to clonal expansion, survival, and development of Tc1 cells when protein antigen is encountered by primary CD8 T cells in an inflammatory environment in vivo.
Adoptive Transfer↗