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A Kopp-Schneider

Publications and source records attributed to A Kopp-Schneider.

At least 19 recordsLinked to original sources
PubMed1998

A model for hepatocarcinogenesis treating phenotypical changes in focal hepatocellular lesions as epigenetic events.

The major paradigm for mathematically describing the carcinogenic process has been through the use of multistage models. Multistage models are made up of numerous compartments representing cells in various stages on the way to malignancy and where movement from one cell class to another is assumed to have exponential waiting time. Once a cell is in a particular class, clonal expansion through a linear birth-death process increases the size of the compartment. These models are characterized by movement of single cells from one compartment to another rather than clonal colonies of cells. However, there is some evidence to suggest that, in certain organs for certain types of agents, preneoplastic lesions with different phenotypes arise directly from an entire clonal colony rather than from a single cell within that colony. This manuscript describes a simple mathematical model of carcinogenesis using both persistent changes of single or several cells (to start the process) and shifting of colonies to describe the stages of the model. Likelihoods for the use of the model with data on colonies of preneoplastic lesions are described and applied to real data.

Animals↗
PubMed1997

Carcinogenesis models for risk assessment.

This article provides an overview of different types of carcinogenesis models and discusses their use for risk assessment. One class of model, the multistage model, is especially suited for risk assessment purposes because it uses biological information about the process of carcinogenesis and the quantities of interest, such as time to tumour and number and size distribution of premalignant tumours, can be derived explicitly, allowing for standard statistical techniques to be used. The mathematical methods necessary for the treatment of multistage models are developed and the application of multistage models in risk assessment is discussed.

Carcinogens↗
PubMed1996

Calculating tumor incidence rates in stochastic models of carcinogenesis.

Multistage models of carcinogenesis are increasingly used in the estimation of risks from exposure to environmental agents. The two-stage model of carcinogenesis is routinely used because it agrees with much of the existing tumor incidence data, parallels the biological two-stage model, and has much of its mathematical details derived. However, recent findings on the mechanisms of carcinogenesis has led researchers to believe that there are a greater number of stages and a more complex structure to these models than a single pathway. In this paper, a method for readily computing tumor incidence rates for arbitrarily complex multistage models is derived. The formulas for the two-stage model with time-varying rates are given explicitly. Simple rules for more complicated models are given, and computer code able to implement these formulas are provided.

Animals↗
PubMed1996

Modeling the number and size of hepatic focal lesions following exposure to 2,3,7,8-TCDD.

Data on the size and number of placental glutathione S-transferase-positive (PGST+) foci were collected from a two-stage hepatocarcinogenesis model in female Sprague-Dawley rats. the study consisted of multiple 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed dose groups including both diethylnitrosomine (DEN)-initiated and uninitiated animals. Groups were observed after 15 or 31 weeks of TCDD exposure. The parameters in the first half of a two-stage mathematical model of carcinogenesis were estimated from these data. If the model is valid, the results suggest that TCDD stimulates the production of PGST+ foci and promotes the growth of PGST+ foci. This finding suggests a complicated mechanism for TCDD-induced production of Hepatic foci that we refer to as activation, labeling TCDD as an activator. The analysis also indicates that there is an interaction between DEN and TCDD which results in dose-related formation of initiated cells throughout the study period. Best-fitting curves (using maximum likelihood methods) for TCDD-induced activation and promotion reached saturation levels at low doses of TCDD. In summary, the model fit the data well, but leads to an interpretation of the data which either questions the validity of the model or implies that our understanding of the effects of TCDD and DEN is incomplete.

Adenosine Triphosphate↗
PubMed1995

Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary aflatoxin B1 in woodchucks.

Interactive hepadnaviral and chemical hepatocarcinogenesis was studied in woodchucks inoculated as newborns with woodchuck hepatitis virus (WHV), which is closely related to the human hepatitis B virus. When the woodchucks reached 12 months of age, aflatoxin B1 (AFB1) was administered in the diet at dose levels of 40 micrograms/kg body weight/day for 4 months and subsequently 20 micrograms/kg body weight/day (5 days/week) for lifetime. WHV DNA was demonstrated by Southern blot hybridization in the serum and by PCR in the serum and/or liver tissue. The histo- and cytomorphology of the liver were investigated by light and electron microscopy. WHV carriers with and without AFB1 treatment developed a high incidence of preneoplastic foci of altered hepatocytes, hepatocellular adenomas, and hepatocellular carcinomas that appeared 6-26 months after the beginning of the combination experiment. Administration of AFB1 to WHV carriers resulted in a significantly earlier appearance of hepatocellular neoplasms and a higher incidence of hepatocellular carcinomas compared to WHV carriers not treated with AFB1. Neither hepatocellular adenomas nor carcinomas (but preneoplastic foci of altered hepatocytes) were detected in woodchucks receiving AFB1 alone, and no preneoplastic or neoplastic lesions were found in untreated controls. These results provide conclusive evidence of a synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary AFB1. Except for the frequent presence of ground glass cells containing surface antigen filaments in the infected woodchucks, the phenotype of preneoplastic foci of altered hepatocytes was similar in WHV carriers with and without exposure to AFB1 and in animals treated with AFB1 alone. Clear cell foci excessively storing glycogen and/or fat, amphophilic cell foci crowded with mitochondria and peroxisomes, and mixed cell foci composed of various cell types including basophilic cells rich in ribosomes predominated. The cellular phenotype in neoplastic lesions varied from clear, amphophilic, and mixed cell populations in highly differentiated adenomas and carcinomas to basophilic cell populations prevailing in poorly differentiated carcinomas. The striking similarities in altered cellular phenotypes of preneoplastic hepatic foci emerging after both hepadnaviral infection and exposure to AFB1 suggest closely related underlying molecular mechanisms that may be mainly responsible for the synergistic hepatocarcinogenic effect of these oncogenic agents.

Aflatoxin B1↗
PubMed1995

Carcinoma formation in NMRI mouse skin painting studies is a process suggesting greater than two stages.

The two-stage model of carcinogenesis, which incorporates clonal growth of intermediate cells, has gained increasing attention in recent years. It was formulated to match tumor incidence data and expanded to encompass observations made in initiation-promotion carcinogenicity experiments. Mouse skin experiments are perceived as supporting this model, with papillomas representing the intermediate cells and carcinomas representing the malignant cells. In this manuscript, the two-stage model is applied to data concerning papilloma and carcinoma formation from an initiation-promotion NMRI mouse skin painting experiment which included stop-promotion. It is shown that the model is not compatible with these data if all papillomas are considered premalignant lesions. The model was modified to allow for a heterogeneous population of papillomas. In this case, unless one assumes that premalignant and terminally benign papillomas are morphologically different in the sense that both types of papillomas at detection limit contain distinct numbers of actively dividing initiated cells, the model predicts larger numbers of papillomas at the end of the experiment than were actually observed. The best explanation is that the model is not in accordance with these data and that the data indicate the need for stages between initiated and malignant cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Malignant progression of papillomas induced by the initiation--promotion protocol in NMRI mouse skin.

Recording of individual responses to initiation-promotion was used to study the relationship between papilloma and carcinoma formation in NMRI mouse skin. This type of analysis is without precedent in that it allows a statistical evaluation of the data which was impossible with previously published analyses based upon cumulative tumor response data evaluated in other mouse strains. Initiation with DMBA and promotion with TPA yielded papillomas consisting of two sub-populations, reversible and persistent papillomas. The ratio of persisting to reversible papillomas was independent of the duration of promotion, indicating comparable growth rates for both types of papillomas. Fifty percent of the persistent and 4% of all papillomas progressed into carcinomas. Promotion for > 20 weeks increased neither the total number of papillomas nor the number of carcinomas. Both the maximum number of persistent and the maximum number of reversible papillomas correlated with the risk of malignant progression, excluding persistent papillomas as being the exclusive precursor lesions for malignant progression.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Effects of low doses of N-nitrosomorpholine on the development of early stages of hepatocarcinogenesis.

Male Sprague-Dawley rats received the hepatocarcinogen N-nitrosomorpholine (NNM) in the drinking water at low dose levels ranging from 6 mg/l to 60 mg/l for 6 and 12 weeks, respectively. Foci of altered hepatocytes (FAH) were demonstrated histochemically using changes in the activities of glucose-6-phosphate dehydrogenase and glycogen phosphorylase, and in the glycogen content as markers. Proliferating cells were detected by the immunohistochemical reaction for proliferating cell nuclear antigen (PCNA). The number and size of foci of altered hepatocytes increased in a time and dose-related manner. The dose-effect curves were non-linear with a slight positive slope at the low doses and a markedly increased slope at higher doses. The number of PCNA positive hepatocytes showed a dose-dependent increase. In addition to the granular distribution of PCNA in the nuclei, hepatocyte nuclei with homogeneously distributed PCNA occurred in animals exposed to 60 mg/l NNM. It is proposed that these cells are related to the occurrence of hepatocytes with higher ploidy induced by NNM and may be regarded as cells in the G2 phase of the cell cycle. The non-linear shape of the dose-response-curve of the FAH suggests that some mechanisms contribute to carcinogenesis over the whole dose range, whereas other mechanisms enhance carcinogenesis only at higher doses. The relevance of the non-linear dose-effect curve for the risk assessment of carcinogens is discussed.

Animals↗
PubMed1994

Porphyrin studies in TCDD-exposed workers.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to inhibit uroporphyrinogen decarboxylase activity resulting in chronic hepatic porphyria. From a cross-sectional study of 170 workers in chemical industry 68 showed elevated coproporphyrin levels, interpreted as secondary coproporphyrinuria. Three persons suffered from chronic hepatic porphyria in subclinical stages. None of the workers showed an overt porphyria cutanea tarda. A low-grade zinc protoporphyrinemia was observed in three persons. Forty-three of the 170 workers were evaluable for investigating the effect of TCDD on porphyrin levels. No significant correlation was found between TCDD concentration in adipose tissue and the level of uroporphyrin and coproporphyrin. The influence of a chloracne history is described.

Adipose Tissue↗
PubMed1994

A stem cell model for carcinogenesis.

A modification to the well-known two-stage model of carcinogenesis with clonal expansion is proposed. A true stem cell is applied to the production of intermediate cells by incorporating a birth-death process with a reflecting barrier into the model. The distribution of the number of detectable intermediate cell clones is derived, and systems of differential equations are formulated for the cumulative distribution function for the appearance of malignant tumors. The model is applied to data on papilloma formation in a mouse skin painting experiment. Tests for the importance of intermediate cells in tumor incidence can be derived.

Animals↗
PubMed1994

Cell proliferation and cell death (apoptosis) in hepatic preneoplasia and neoplasia are closely related to phenotypic cellular diversity and instability.

Preneoplastic and neoplastic hepatic lesions were induced in male Sprague-Dawley rats by oral exposure to N-nitrosomorpholine (12 mg/kg body wt/day) for 7 weeks (stop model). Twelve, 23 and 34 weeks after withdrawal of the carcinogen, cell proliferation and cell death (apoptosis) were studied in defined phenotypes of preneoplastic foci of altered hepatocytes (FAH), hepatocellular adenomas (HCA) and carcinomas (HCC) by autoradiographic determination of the labelling index (LI) resulting from continuous administration of [3H]thymidine for 48 h and by simultaneous counting of apoptotic bodies respectively. Compared with the liver parenchyma of untreated controls and the extrafocal parenchyma of treated animals, the mean LI was elevated in all types of FAH, HCA and HCC, but the extent of this increase differed markedly between the diverse phenotypes. The increase in the LI was significant for clear/acidophilic, intermediate and mixed/basophilic cell foci, but remained insignificant for the relatively rare tigroid and amphophilic cell foci. The previously established progression-linked phenotypic instability in the predominant cell lineage leading to HCC was associated with a gradual increase in the mean LI showing four significantly different proliferative stages: (i) clear/acidophilic and intermediate cell foci excessively storing glycogen, (ii) mixed/basophilic cell populations in FAH and glycogen-storing HCA, (iii) glycogen-poor HCA and glycogen-storing HCC and (iv) glycogen-poor HCC. The inverse correlation between glycogen accumulation and cell proliferation during progression from glycogenotic FAH to glycogen-poor HCC indicates that the fundamental metabolic shift associated with the gradual disappearance of the glycogenosis is essential for the evolution of the malignant phenotype. The mean ratio of necrotic cells (RN) was somewhat higher in all types of FAH compared to the normal and extrafocal liver parenchyma, but this was not statistically significant. Only when HCA and HCC appeared was there a significant increase in the mean RN, proceeding with the progression of neoplastic development. Our results do not support the concept that cell death (apoptosis) plays a major role in counterbalancing cell replication in FAH, but rather suggest that cell death occurs more frequently in the course of hepatocarcinogenesis the more neoplastic development advances.

Animals↗
PubMed1994

Multistage models of carcinogenesis: an approximation for the size and number distribution of late-stage clones.

Multistage models have become the basic paradigm for modeling carcinogenesis. One model, the two-stage model of carcinogenesis, is now routinely used in the analysis of cancer risks from exposure to environmental chemicals. In its most general form, this model has two states, an initiated state and a neoplastic state, which allow for growth of cells via a simple linear birth-death process. In all analyses done with this model, researchers have assumed that tumor incidence is equivalent to the formation of a single neoplastic cell and the growth kinetics in the neoplastic state have been ignored. Some researchers have discussed the impact of this assumption on their analyses, but no formal methods were available for a more rigorous application of the birth-death process. In this paper, an approximation is introduced which allows for the application of growth kinetics in the neoplastic state. The adequacy of the approximation against simulated data is evaluated and methods are developed for implementing the approximation using data on the number and size of neoplastic clones.

Animals↗
PubMed1993

The use of cell proliferation data in modeling of skin carcinogenesis.

A simple model for papilloma formation is used to analyze data from a mouse skin-painting experiment performed with NMRI mice. The results suggest that one of two conclusions may be drawn: Either the model fails to properly describe the growth behavior of papilloma cells or the model suggests that papilloma cells do not have growth advantage over normal cells, even during promotion.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Using cell replication data in mathematical modeling in carcinogenesis.

Risk estimation involves the application of quantitative models of dose versus response to carcinogenicity data. Recent advances in biology, computing, and mathematics have led to the application of mathematically complicated, mechanistically based models of carcinogenesis to the estimation of risks. This paper focuses on two aspects of this application, distinguishing between models using available data and the development of new models to keep pace with research developments.

Animals↗
PubMed1992

Birth and death/differentiation rates of papillomas in mouse skin.

A simple one-stage model for the formation of papillomas is used to evaluate data from a series of initiation/promotion/stop-promotion experiments performed on NMRI mice. These experiments used a single application of 100 nmol 7,12-dimethylbenz[a]anthracene followed by twice weekly applications of 5 nmol 12-O-tetradecanoylphorbol-13-acetate. It is shown that, on the basis of this model, the data considered here provide no evidence for a growth advantage of initiated cells versus normal cells. Although model estimates always have to be treated with utmost caution, they can at least be interpreted in a qualitative way. In consequence, it has to be concluded either that the mechanism upon which the model is based fails to describe properly the growth behaviour of initiated cells, or that initiated cells do not possess a growth advantage over normal cells, even in the presence of a promoter.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

The application of a multistage model that incorporates DNA damage and repair to the analysis of initiation/promotion experiments.

In a previous article, a multistage model of carcinogenesis was introduced that takes into account the role of DNA damage, DNA repair, and cell replication on the incidence of malignancies. For this model the number of detectable clones of initiated cells is derived and model parameters are estimated using data arising from a two-stage skin-painting experiment in mice. The data from this experiment are interpretable in terms of the cellular events involved in initiation and promotion.

Animals↗
PubMed1991

A multistage model of carcinogenesis incorporating DNA damage and repair.

Mathematical models of carcinogenesis are one tool used for research into the mechanisms of carcinogenesis and for assessing risks from exposure to carcinogenic agents. Recent research into carcinogenic mechanisms has focused on the role of cell replication in fixing damage to cellular DNA and increasing the incidence of malignancies. The most commonly used multistage model of carcinogenesis does not explicitly account for DNA damage and the contribution of cell replication rates on the transformation of cells through the various stages. In this manuscript, a generalized multistage model of carcinogenesis is developed in which DNA damage, cell replication, and DNA repair are explicitly included.

Animals↗