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Results for “clonal modeling”

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PubMed2005

Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion.

This paper analyzes data for the osteosarcoma incidence in life-time experiments of (224)Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to (224)Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.

Animals↗

PubMed2003

Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders.

Knowledge of how the brain achieves its diverse central control of basic physiology is severely limited by the virtual absence of appropriate cell models. Isolation of clonal populations of unique peptidergic neurons from the hypothalamus will facilitate these studies. Herein we describe the mass immortalization of mouse primary hypothalamic cells in monolayer culture, resulting in the generation of a vast representation of hypothalamic cell types. Subcloning of the heterogeneous cell populations resulted in the establishment of 38 representative clonal neuronal cell lines, of which 16 have been further characterized by analysis of 28 neuroendocrine markers. These cell lines represent the first available models to study the regulation of neuropeptides associated with the control of feeding behavior, including neuropeptide Y, ghrelin, urocortin, proopiomelanocortin, melanin-concentrating hormone, neurotensin, proglucagon, and GHRH. Importantly, a representative cell line responds appropriately to leptin stimulation and results in the repression of neuropeptide Y gene expression. These cell models can be used for detailed molecular analysis of neuropeptide gene regulation and signal transduction events involved in the direct hormonal control of unique hypothalamic neurons, not yet possible in the whole brain. Such studies may contribute information necessary for the strategic design of therapeutic interventions for complex neuroendocrine disorders, such as obesity.

Animals↗

PubMed2003

Modelling of carcinogenesis and low-dose hypersensitivity: an application to lung cancer incidence among atomic bomb survivors.

Lung cancer incidence among the atomic bomb survivors from Hiroshima and Nagasaki was analysed with the two-step clonal expansion (TSCE) model of carcinogenesis. For the baseline incidence, a new set of model parameters is introduced, which can be determined with a higher precision than the parameter sets previously used. The effect of temporal changes in the smoking behaviour on the lung cancer incidence is modelled by allowing initiation, inactivation and division rates of intermediate cells to depend on the year of birth. The TSCE model is further developed by implementing low-dose hypersensitivity in the survival of lung epithelial cells. According to the model fit to the data, the acute gamma exposure of the atomic bomb survivors does not only result in the conventional initiating effect, but also in a promoting effect for lung cancer. Compared to the model in which radiation acts merely on initiation, the new model is in better agreement with the age-at-exposure dependence in the data, and it does not predict an unexpected increase of the excess relative risk (ERR) at 40 years after exposure. According to the new model, the ERR at low doses increases non-linearly with dose, especially during the first 10 years after exposure to older persons.

Age Factors↗

PubMed1995

Identification of a clonal form of HIV in early Kaposi's sarcoma: evidence for a novel model of oncogenesis, "sequential neoplasia".

We recently reported clonal human immunodeficiency virus (HIV involvement in four acquired immune deficiency syndrome (AIDS)-associated non-B-cell lymphoproliferations. In three of these cases HIV expression was localized to tumor-associated macrophages. Because one of the cases had a major component involved in angioproliferation, we speculated that some form of Kaposi's sarcoma (KS), which also has a major component of angioproliferation, might be involved clonally with HIV. The current study is an evaluation of four cases of KS and control tissues taken from four patients who died with complications of HIV disease. With use of the inverse polymerase chain reaction technique to identify clonal forms of HIV, a clonal form of HIV was found in one of four KS cases. The HIV-positive tumor was an early KS lesion of the bowel, and uninvolved bowel from the same patient showed no clonal HIV. Immunohistochemical analysis demonstrated the presence of prominent HIV-expressing macrophages that also coexpressed high levels of HIV tat, basic fibroblast growth factor, and interleukin-6. These data provide evidence for a pathogenic process termed "sequential neoplasia," wherein a clonal macrophage provides a growth factor milieu stimulating the proliferation of a responder cell population that ultimately becomes autonomous. In the current case, the macrophages expressing HIV were located adjacent to the KS tumor tissue and were found to be producing known KS growth factors. The absence of finding clonal HIV in three more advanced KS lesions suggests that the clonal macrophage may be required only for early pathogenesis and that sequential neoplastic changes occurring in the endothelial cells gave rise to autonomous KS.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed2004

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization.

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.

Animals↗

PubMed2006

Mathematical modelling of aerosolised skin grafts incorporating keratinocyte clonal subtypes.

Severe burns can be very traumatic for the patient, and while burns caused by industrial or domestic accidents are common, there are also increasing numbers of burns associated with terrorism. A novel technique to assist in the healing process is to spray skin cells, keratinocytes, that are cultured from the patient's own tissue, directly onto the burn site. This process involves taking some undamaged skin from the patient, allowing the skin cells to proliferate rapidly in the laboratory over a period of 5-10 days, harvesting and separating the cells and then spraying them onto the burn. This paper deals with keratinocytes that have been cultured in vitro for a short period of time (early passage cultured cells). The spraying process has yet to be optimised with respect to the seeding density required for fastest re-epithelisation and thus there is a need for this process to be modelled. In this paper, we review some of the skin biology and develop a mathematical model of the growth patterns of cell colonies after they have been applied using a aerosolised technique. The model allows us to predict coverage over time and can be used as a decision support tool for clinicians.

Burns↗

PubMed1999

Abnormal growth and clonal proliferation of fibroblasts in an animal model of unilateral ureteral obstruction.

The time course for the development of renal interstitial fibrosis (RIF) in rats between days 5 and 25 after unilateral ureteral obstruction (UUO) was studied. In kidneys with UUO under histological examination, an interstitial fibrosis was observed after more than 10 days with progression up to day 25. On day 5, collagen peptidase activity in homogenates of UUO kidneys was about 50% higher than in controls but gradually declined afterwards until reaching the level obtained from contralateral kidneys (CL) on day 25. 10 days after UUO, renal hydroxyproline content was elevated about twofold as compared to CL and sham-operated rats, and increased considerably by day 25 of UUO. In primary cultures of cells obtained from UUO kidneys, fibroblast proliferation increased regardless of the extent of fibrosis. This could be a result of an early inflammatory process. Renal fibroblasts from rats are heterogenous when studied in vitro. When fibroblasts of passage 1 obtained from kidneys 25 days after UUO were plated at low density, the number of mitotic type I clones was elevated 5.5-fold as compared with cultures from CL kidneys. The majority of type I clones in UUO cultures from fibrotic kidneys developed in an unusual fashion with formation of three-dimensional structures. The changes detectable under the unfavorable conditions of clonal culture suggest phenotypical differentiation of a small fraction of fibroblasts from kidneys with RIF. These cells are able to overgrow cell monolayers forming circular growing colonies. Obviously, one needs to distinguish between intensive proliferation as a consequence of acute inflammation, and the changes in phenotype of a small fraction of renal fibroblasts which are resistant to normal physiologic regulative mechanisms in cell culture. The latter may contribute to matrix disorders and RIF.

Animals↗

PubMed2005

Modeling intercellular interactions during carcinogenesis.

By modulating the microenvironment of malignant or premalignant cells, inhibitory or stimulatory signals from nearby cells can play a key role in carcinogenesis. However, current commonly used quantitative models for induction of cancers by ionizing radiation focus on single cells and their progeny. Intercellular interactions are neglected or assumed to be confined to unidirectional radiation bystander effect signals from cells of the same tissue type. We here formulate a parsimoniously parameterized two-stage logistic (TSL) carcinogenesis model that incorporates some effects of intercellular interactions during the growth of premalignant cells. We show that for baseline tumor rates, involving no radiation apart from background radiation, this TSL model gives acceptable fits to a number of data sets. Specifically, it gives the same baseline hazard function, using the same number of adjustable parameters, as does the commonly used two-stage clonal expansion (TSCE) model, so it is automatically applicable to the many data sets on baseline cancer that have been analyzed using the TSCE model. For perturbations of baseline rates due to radiation, the models differ. We argue from epidemiological and laboratory evidence, especially results for the atomic bomb survivors, that for radiation carcinogenesis the TSL model gives results at least as realistic as the TSCE or similar models, despite involving fewer adjustable parameters in many cases.

Carcinogenicity Tests↗

PubMed2003

Despite efficient intrathymic negative selection of host-reactive T cells, autoimmune disease may develop in porcine thymus-grafted athymic mice: evidence for failure of regulatory mechanisms suppressing autoimmunity.

BACKGROUND: CD4 T-cell reconstitution and xenogeneic tolerance is achieved in T cell-depleted, thymectomized C57BL/6 (B6) mice and nude mice by grafting of fetal pig thymus (FP THY). Sixty percent of grafted nude mice and 10% of grafted thymectomized B6 mice develop a clinical illness resembling chronic graft-versus-host disease. METHODS: Negative selection of mouse T cells in FP THY grafts was studied in "AND" TCR transgenic mice with a negative selecting MHC. Pathologic and immunohistochemical examinations and adoptive transfer assays were performed to determine the role of mouse CD4+ cells in the occurrence of autoimmune disease in this model. RESULTS: Marked clonal deletion of mouse thymocytes bearing a transgenic TCR ("AND"), which recognizes H2s expressed by host hematopoietic cells, was observed in FP THY grafts. Pathologic and immunohistochemical examinations of the liver, skin, lungs, and kidneys of mice with wasting syndrome showed marked mouse CD4+ T-cell infiltration without detectable pig cells. After adoptive transfer of splenocytes, but not of CD4+ cell-depleted splenocytes, from sick mice along with B6 bone marrow cells to lethally irradiated syngeneic B6 mice, the secondary recipients developed a similar autoimmune syndrome as the donors. Cotransfer of naïve syngeneic splenocytes prevented the occurrence of autoimmune disease in secondary recipients of splenocytes from healthy FP THY-grafted BALB/c nude mice. CONCLUSION: These results demonstrate a key role for mouse CD4+ T cells in causing autoimmune disease in this model and suggest the importance of regulatory mechanisms in addition to intrathymic clonal deletion for the maintenance of tolerance to recipient antigens.

Adoptive Transfer↗

PubMed2002

Testing goodness of fit for stochastic models of carcinogenesis.

This paper considers the utility of statistical goodness of fit testing in the context of mechanistic models of carcinogenesis. Two stochastic models of carcinogenesis were tested with several sets of experimental and epidemiological data using a formal goodness of fit test specially designed to accommodate censored observations: these were the two-stage model allowing for clonal expansion of initiated cells and its simpler version with gamma distributed promotion time. The results of this application, supplemented by visual examination of local likelihood kernel estimates of the hazard function and the corresponding model-based estimates, show that mechanistic models of carcinogenesis provide a good fit to the data in the majority of cases under study.

Animals↗

PubMed2001

Characterization of T cell receptor beta chains of accumulating T cells in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice.

Autoimmne mechanisms have been implicated in the pathogenesis of chronic ongoing mycarditis. An earlier study of murine chronic ongoing myocarditis reported that infiltrating T cells and macrophages were prominent in the normal donor heart, in a heterotopic cardiac transplantation model. It was demonstrated that myocarditis was transferred to a normal heart transplanted into a mouse with chronic myocarditis. The present study investigated an autoimmune link to the pathogenesis of chronic ongoing myocarditis by analyzing the T cell clonalities in the model. To characterize the accumulating T cells in the donor heart, the T cell receptor beta genes (TCRBG) were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) from mRNA in the donor hearts and accumulating TCRBG clonotypes were contrasted with those from recipient hearts. Inbred 3-week-old A/J mice were inoculated intraperitoneally with Coxsackievirus B3 (Nancy strain), 2 x 10(4) PFU, and housed for more than 60 days. Normal A/J mouse hearts were transplanted into the same strain of mice without myocarditis, as well as into the mice with chronic ongoing myocarditis. Both recipient and donor hearts were evaluated histologically 2 weeks after the transplantation. TCRBG were amplified by RT-PCR from mRNA of recipient and donor hearts and spleens. The specific accumulating TCRBG clonotypes were identified by their single strand conformation polymorphism. Multiple clonotypic accumulations occurred in the donor heart after cardiac transplantation. Distinct oligoclonal accumulation of TCR Vbeta1, 10, and 13 T cells was found in both recipient and donor hearts in 3 of 4 mice. Moreover, these clonotypes were not observed in spleen cells of the recipient mice. T specific cells expanding clonotypes of TCRBG are responsible for transferring myocarditis to the donor heart. An autoimmune response may, therefore, play a key role in the progression of chronic ongoing myocarditis.

Animals↗

PubMed1990

Risk extrapolation for chlorinated methanes as promoters vs initiators of multistage carcinogenesis.

"Cell-kinetic multistage" (CKM) models account for clonal growth of intermediate, premalignant cell populations and thus distinguish somatic mutations and cell proliferation as separate processes that may influence observed rates of tumor formation. This paper illustrates the application of two versions of a two-stage CKM model (one assuming exponential and the other geometric proliferation of intermediate cells) for extrapolating cancer risk potentially associated with exposure to carbon tetrachloride, chloroform, and dichloromethane, three suspect human carcinogens commonly present in trace amounts in groundwater supplies used for domestic consumption. For each compound, the models were used to calculate a daily oral "virtually safe dose" (VSD) to humans associated with a cancer risk of 10(-6), extrapolated from bioassay data on increased hepatocellular tumor incidence in B6C3F1 mice. Exposure-induced bioassay tumor responses were assumed first to be due solely to "promotion" (enhanced proliferation of premalignant cells, here associated with cytotoxicity), in accordance with the majority of available data on in vivo genotoxicity for these compounds. Available data were used to model dose response for induced hepatocellular proliferation in mice for each compound. Physiologically based pharmacokinetic models were used to predict the hepatotoxic effect (metabolized) dose as a function of parent compound administered dose in mice and in humans. Resulting calculated VSDs are shown to be from three to five orders of magnitude greater than corresponding values obtained assuming each of the compounds is carcinogenic only through induced somatic mutations within the CKM framework. Key issues and uncertainties in applying CKM models to risk assessment for cancer promoters are discussed.

Animals↗

PubMed1986

Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol.

The acute and chronic neurologic effects of ethanol appear to be due to its interaction with neural cell membranes. Chronic exposure to ethanol induces changes in the membrane that lead to tolerance to the effects of ethanol. However, the actual membrane changes that account for tolerance to ethanol are not understood. We have developed a model cell culture system, using NG108-15 neuroblastoma-glioma hybrid cells, to study cellular tolerance to ethanol. We have found that adenosine receptor-stimulated cAMP levels increased markedly upon acute exposure to ethanol. However, the cells became tolerant to ethanol, since chronically treated cells required ethanol to maintain normal adenosine-stimulated cAMP levels. Moreover, the cells appeared to be dependent on ethanol, as evidenced by reduced adenosine-stimulated cAMP levels in the absence of ethanol. Recovery occurred after ethanol was withdrawn. These cellular changes appear to parallel the clinical events of acute ethanol intoxication, tolerance, and dependence.

Animals↗

PubMed2007

Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells.

PURPOSE: Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers. EXPERIMENTAL DESIGN: A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined. RESULTS: Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority(>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only in primary tumors. CONCLUSIONS: The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.

Adult↗

PubMed2004

The nature and origin of the B-chronic lymphocytic leukemia cell: a tentative model.

Chronic lymphocytic leukemia cells have the profile of antigen (Ag) activated memory B cells but also show a constellation of T-cell-associated properties. We suggest that the early transforming events may occur in an early lymphoid progenitor. This precursor differentiates into a mature B cell that, though retaining T-cell features, has a functional B-cell receptor that may allow Ag intervention to trigger clonal expansion. This model has to cope with the existence of at least two subsets of the disease as defined by their IgVH genes mutational status. Mutated cases have a lower capacity to interact with Ag and are reminiscent of anergic cells. This explains their less harmful behavior as compared with unmutated case, which have a more aggressive potential likely because they had the opportunity to acquire additional chromosomal aberrations after repeated rounds of Ag stimulation and replication.

Humans↗

PubMed1990

Two-stage models of carcinogenesis, classification of agents, and design of experiments.

The implications of a clonal two-stage model of carcinogenesis on the design and analysis of 2-year in vivo tumorigenesis experiments are addressed. Using a simple classification scheme for labelling test agents as initiators, promoters, and completers, it is shown that the standard experimental design has very little ability to differentiate between these different modes of action. Even when chemicals in one class (e.g., promoters) follow a highly nonlinear dose-response relationship and chemicals in another class (e.g., initiators) follow a linear dose-response relationship, it is difficult to reject one mode of action versus the other. A simple modification of the design using age-dependent dosing schemes produces patterns of tumor incidence which are unique to the particular class, making it slightly easier to differentiate between the assumed mechanisms of action. The implications of this finding on study design are discussed.

Aging↗

PubMed2025

Modeling Early-Onset Cancer Kinetics Reveals Changes in Underlying Risk and the Impact of Population Screening.

UNLABELLED: Recent studies have reported increases in early-onset cancer cases (diagnosed less than 50 years of age) and raised questions about whether the increase is related to earlier diagnosis from nonspecific medical tests as reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multistage Clonal Expansion (MSCE) model assumes cancer detection at the first malignant cell's emergence, although later modifications have included lag-times or stochasticity in detection to represent the delay in tumor detection. In this study, we introduced an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework accounting for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. The model was structurally identifiable and provided better parameter estimation than the classic model. The model was applied to colorectal, breast, and thyroid cancers to examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). The analyses suggested accelerated carcinogenic events and shorter mean sojourn times (the average time from the first malignant cell emergence to cancer detection) in more recent cohorts. Furthermore, using this model to examine the screening impact on the incidence of breast and colorectal cancers, for which both have established screening protocols, provided results that align with well-documented differences in screening effects between these cancers. These findings underscore the importance of incorporating tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancers. SIGNIFICANCE: A model of early-onset cancer trends that distinguishes true risk from detection effects accurately captures cancer kinetics, trends in cancer progression, and the impact of screening, which could inform cancer prevention strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .

Humans↗

PubMed2004

Maintenance of clonal diversity in Dipsa bifurcata (Fallén, 1810) (Diptera: Lonchopteridae). II. Diapause stabilizes clonal coexistence.

We analyze a selection model analogous to a one-locus, two-allele haploid system that can explain recurrent seasonal changes in diversity for communities with diapausing species or populations with diapausing clones. The model demonstrates the potential influence of differential diapause on the stability of species and clonal coexistence and, by extension, on the maintenance of genetic polymorphism in general. Using estimates of clonal fitness values from populations of the parthenogenetic spear-winged fly Dipsa bifurcata (Fallén, 1810) (Diptera: Lonchopteridae), the model explains the long-term stable oscillation of clonal frequencies exhibited by these populations. In general, clones or species that share the same spatial habitat can persist in stable coexistence if there are differences not only in their temporarily fluctuating fitness values but also in their dormancy patterns.

Animals↗