PubMed Health⌕ Search

Biomedical subjects

L B Ellwein

Publications and source records attributed to L B Ellwein.

At least 19 recordsLinked to original sources
PubMed1992

Simulation modeling of carcinogenesis.

A discrete-time simulation model of carcinogenesis is described mathematically using recursive relationships between time-varying model variables. The dynamics of cellular behavior is represented within a biological framework that encompasses two irreversible and heritable genetic changes. Empirical data and biological supposition dealing with both control and experimental animal groups are used together to establish values for model input variables. The estimation of these variables is integral to the simulation process as described in step-by-step detail. Hepatocarcinogenesis in male F344 rats provides the basis for seven modeling scenarios which illustrate the complexity of relationships among cell proliferation, genotoxicity, and tumor risk.

Age Factors↗
PubMed1992

Cellular proliferation and genetic events involved in the genesis of Burkitt lymphoma (BL) in immune compromised patients.

A mathematical model simulating lymphomagenesis based on the two-hit theory of carcinogenesis is presented by contrasting the biologic variables responsible for a high risk of developing Burkitt lymphoma (BL) in three immunosuppressed groups with that of nonendemic BL. In this model, the pro-B lymphocyte is considered to be the target for BL-specific translocations such as t(8;14). With repeated mitosis, the target cell pool expands in the high-risk individual, and, thereby, the opportunities for a spontaneous translocation to arise are increased. The chromosomal translocation endows the target cell with survival advantages, and, hence, lymphoma develops. Modeling results demonstrate that this increased cell proliferation is sufficient in accounting entirely for the increase in tumor prevalence. Preventing enhanced cellular proliferation by obviating immune deficiency and treating patients with agents that restore immunity or have antiviral and antiproliferative properties prior to conversion from polyclonal B-cell proliferation to monoclonal malignancy could obviate the development of BL.

B-Lymphocytes↗
PubMed1991

Carcinogens.

Explore the source record for details and available documents.

Animals↗
PubMed1991

Comparative bladder tumor promoting activity of sodium saccharin, sodium ascorbate, related acids, and calcium salts in rats.

Sodium saccharin and sodium ascorbate are known to promote urinary bladder carcinogenesis in rats following initiation with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine. Sodium salts of other organic acids have also been shown to be bladder tumor promoters. In addition, these substances increase urothelial proliferation in short term assays in rats when fed at high doses. When they have been tested, the acid forms of these salts are without either promoting or cell proliferative inducing activity. The following experiment was designed to compare the tumor promoting activity of various forms of saccharin and to evaluate the role in promotion of urinary sodium, calcium, and pH as well as other factors. Twenty groups of 40 male F344 rats, 5 weeks of age, were fed either FANFT or control diet during a 6-week initiation phase followed by feeding of a test compound for 72 weeks in the second phase. The chemicals were administered to the first 18 groups in Agway Prolab 3200 diet and the last 2 groups were fed NIH-07 diet. The treatments were as follows: (a) FANFT----5% sodium saccharin (NaS); (b) FANFT----3% NaS; (c) FANFT----5.2% calcium saccharin (CaS); (d) FANFT----3.12% CaS; (e) FANFT----4.21% acid saccharin (S); (f) FANFT----2.53% S; (g) FANFT----5% sodium ascorbate; (h) FANFT----4.44% ascorbic acid; (i) FANFT----5% NaS plus 1.15% CaCO3; (j) FANFT----5.2% CaS plus 1.34% NaCl; (k) FANFT----5% NaS plus 1.23% NH4Cl; (l) FANFT----1.15% CaCO3; (m) FANFT----1.34% NaCl; (n) FANFT----control; (o) control----5% NaS; (p) control----5.2% CaS; (q) control----4.21% S; (r) Control----control; (s) FANFT----5% NaS (NIH-07 diet); (t) FANFT----control (NIH-07 diet). NaS, CaS and S without prior FANFT administration were without tumorigenic activity. NaS was found to have tumor promoting activity, showing a positive response at the 5 and 3% dose levels, with significantly greater activity at the higher dose. CaS had slight tumor promoting activity but without a dose response, and S showed no tumor promoting activity. In addition, NaCl showed weak tumor promoting activity, but CaCO3 was without activity. NH4Cl completely inhibited the tumor promoting activity of NaS when concurrently administered with it. NaCl administered with CaS or CaCO3 administered with NaS showed activity similar to that of NaS. Sodium ascorbate was also shown to have tumor promoting activity, with slightly less activity than NaS. Ascorbic acid showed no tumor promoting activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The cost effectiveness of strategies to reduce barriers to cataract surgery. The Operations Research Group.

The cost and effectiveness of eight approaches to reducing barriers to cataract surgery were evaluated in a rural area of South India during 1987-1989. The approaches were based on four intervention alternatives--aphakic motivator (AM), basic eye health worker (BW), screening van (SV), and mass media (MM). Each intervention was offered at two levels of economic incentive: partial, which provides free surgery and hospital stay, and full, which also provides transport from the recipient's village to the hospital and free food during the hospital stay. Evaluations took place in a probability selection of 90 villages, including ten control villages not subjected to either of the interventions. Only costs unique to patients from the intervention villages were considered: Health education and screening costs were included, surgery costs were not. Percentage reductions in the cataract blind backlog and increases in surgical coverage were used as effectiveness measures. Analyses suggest that the SV and AM interventions, both with full economic incentive, offer the greatest advantage. The AM intervention is the more effective of the two, but also the more costly.

Adult↗
PubMed1991

Effects of in utero and postnatal sodium saccharin exposure on the nutritional status of the young rat. I. Effects at 30 days post-birth.

The incidence of sodium saccharin (NaS)-associated bladder tumours in male rats increases when exposure to high doses begins in utero or at birth compared with treatment after weaning. The present experiment evaluated the effect of NaS exposure on selected physiological parameters in young second generation rats. 6-wk-old male and female Sprague-Dawley rats were placed on either a diet supplemented with 7.5% NaS or an untreated diet, and mated 4-6 wk later. Treatment was continued through lactation and the offspring were weaned on to the same diet. Body weights were significantly depressed in NaS-treated litters by 4 days after birth, and were 35% lower than controls by 30 days when the animals were killed. NaS treatment of the offspring was associated with an increase in faecal moisture content and caecal content weight, changes in several urinary analytes, a 50% increase in serum cholesterol a 10-fold increase in serum triglycerides and decreases in serum and hepatic vitamins. In addition, NaS-treated dams and pups were anaemic. Relatively few differences between males and females were noted, but significant inter-litter differences existed. The numerous physiological changes indicate that 7.5% dietary NaS exceeds the maximum tolerated dose for weanling rats.

Animals↗
PubMed1991

Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis.

Cancer develops secondary to multiple genetic events. Each time a cell divides there is a rare chance that a genetic error related to the carcinogenic process will occur. Thus, environmental agents or disease processes that produce sustained increased cell proliferation can enhance the likelihood of cancer development by providing additional cell divisions, each with an opportunity for spontaneous genetic error. Studies of hereditary cancers and of various DNA-damaging agents, such as radiation and certain viruses and chemicals, have provided insight into identification of the essential genes, but many examples of carcinogenesis in humans do not involve direct DNA damage. Also, most preneoplastic lesions in human carcinogenesis show increased proliferation compared with normal tissues, whether from increased mitotic rate, blocked differentiation, prolonged cell survival, or other mechanisms. Selected examples of proliferation-related carcinogenesis are described, including certain infectious agents, defective immune surveillance, hormonal imbalances, chronic inflammatory-regenerative processes, and exposure to various chemicals. A common biologic mechanism for these diverse stimuli is increased cell proliferation as a prelude to cancer. This mechanism seems essential to the genesis of many cancers in humans.

Animals↗
PubMed1990

Cell proliferation in carcinogenesis.

Chemicals that induce cancer at high doses in animal bioassays often fail to fit the traditional characterization of genotoxins. Many of these nongenotoxic compounds (such as sodium saccharin) have in common the property that they increase cell proliferation in the target organ. A biologically based, computerized description of carcinogenesis was used to show that the increase in cell proliferation can account for the carcinogenicity of nongenotoxic compounds. The carcinogenic dose-response relationship for genotoxic chemicals (such as 2-acetylaminofluorene) was also due in part to increased cell proliferation. Mechanistic information is required for determination of the existence of a threshold for the proliferative (and carcinogenic) response of nongenotoxic chemicals and the estimation of risk for human exposure.

2-Acetylaminofluorene↗
PubMed1990

Proliferative and genotoxic cellular effects in 2-acetylaminofluorene bladder and liver carcinogenesis: biological modeling of the ED01 study.

The development of tumors in relationship to 2-acetylaminofluorene (AAF) dose and time on study has been evaluated in an experiment conducted by the National Center for Toxicological Research (NCTR) using more than 24,000 female BALB/c mice. By using a biologically based model of two-event carcinogenesis accounting explicitly for both genotoxic and nongenotoxic proliferative effects at the cellular level, we provide a unifying explanation for the apparently disparate dose-response results observed in the urinary bladder and liver. Experimental observations of dose-related DNA adduct levels in both tissues and hyperplasia in the bladder were utilized in estimation of model parameters. Analyses demonstrate that tumor prevalence in the liver can be explained entirely by the influence of AAF on the first of two genetic events, and in the bladder by the synergy between AAF genotoxicity affecting both genetic events and cellular proliferation at higher doses. These results are consistent across the entire ED01 data set.

2-Acetylaminofluorene↗
PubMed1990

Screening and surgical intervention results from cataract-free-zone projects in Campinas, Brazil and Chimbote, Peru.

Two cataract-free-zone projects, one in Brazil and the other in Peru, were designed to provide surgery to all those who need and want it within a defined geographic area. In-home visual acuity screening was accepted by three-fourths of the enumerated population aged 50 years or more. Those with reduced bilateral visual acuity were referred to a community health post for ophthalmic examination. Among those diagnosed as bilaterally blind (less than or equal to 20/200), comprising 5% of the screened population, two-thirds were thought to be blind from cataract. Because of other ocular pathology and general health conditions, surgery was not indicated for 30-50%. Two-thirds of those recommended for out-patient surgery accepted. Motivational efforts to convince the refusers were uniformly unsuccessful. The average age of those accepting and those refusing surgery was in the mid-seventies. Those already aphakic were 7-8 years younger. Post-operative acuity was greater than or equal to 20/50 for only one-half of those operated. A significant number of cases had previously undetected macular degeneration and other causes of decreased vision. These projects have given increased attention to cataract blindness and the need for further operational research to develop effective methods for its control using outpatient surgery.

Aged↗
PubMed1990

Bladder cancer screening: lessons from a biologically based model of bladder cancer progression and therapeutic intervention.

The screening of asymptomatic high-risk populations has been evaluated using a biologically based model of bladder cancer. The model is built upon a mathematical representation of the induction of precursor bladder lesions with possible progression through clinical disease states. Screening strategies are based on regimens that include voided urine cytology. Diagnostic and therapeutic components of the model provide the basis for end results evaluation. Cytology screening is projected to increase average life expectancy by 1 to 3 years among those diagnosed while reducing deaths from bladder cancer by more than 50%. The additional contribution to be realized with a screening test of perfect sensitivity would be primarily in the increased identification of dysplasia and low-grade superficial papillary neoplasms, lesions that are much less life-threatening than the high-grade lesions already detectable by cytology. The theoretical potential of screening is not realizable because of diagnostic inaccuracies and treatment failures.

Adult↗
PubMed1990

The health risks of saccharin revisited.

Almost from its discovery in 1879, the use of saccharin as an artificial, non-nutritive sweetener has been the center of several controversies regarding potential toxic effects, most recently focusing on the urinary bladder carcinogenicity of sodium saccharin in rats when fed at high doses in two-generation studies. No carcinogenic effect has been observed in mice, hamsters, or monkeys, and numerous epidemiological studies provide no clear or consistent evidence to support the assertion that sodium saccharin increases the risk of bladder cancer in the human population. Mechanism of action studies in the one susceptible species, the rat, continue to provide information useful in assessing potential risk to the human from saccharin consumption. Unlike typical carcinogens which interact with DNA, sodium saccharin is not genotoxic, but leads to an increase in cell proliferation of the urothelium, the only target tissue. It also appears that the effect of saccharin is modified by the salt form in which it is administered, despite equivalent concentrations of saccharin in the urine. The chemical form of saccharin in the urine is unaffected, and there is no evidence for a specific cell receptor for the saccharin molecule. Changes in several urinary parameters, such as pH, sodium, protein, silicates, volume, and others, appear to influence the reaction of the urothelium to sodium saccharin administration. Silicon-containing precipitate and/or crystals appear to be generated in the urine under specific circumstances, acting as microabrasive, cytotoxic material. Using a mathematical model of carcinogenesis, which encompasses the temporal dynamics and complexity of the process at a cellular level, including spontaneous genetic transitions, it has been shown that the effects of sodium saccharin can be explained entirely in terms of its non-genotoxic influence on cell proliferation. In interpreting these analytical studies in the human context, particularly as they pertain to the urinary milieu which appears to be pivotal in the effect of sodium saccharin, we are led to the conclusion that there is a threshold effect in male rats and that an effect on the human urothelium is unlikely at even the highest levels of human consumption.

Animals↗
PubMed1989

Assessing research productivity: evaluating journal publication across academic departments.

Publications produced by faculty over a three-year period are used in analyzing the relative research productivity of basic and clinical science departments in a college of medicine. The citation ratings of the journals, the number of authors, and the byline position of the faculty member are used in various publication evaluation schemes. The departments vary almost tenfold in research productivity per faculty member. Results of the analysis demonstrate that the number of authors and the byline position influence departmental productivity rankings very little. Rankings are substantially affected, however, when the journals are weighted based heavily on citation ratings.

Faculty, Medical↗
PubMed1988

Cell growth dynamics in long-term bladder carcinogenesis.

A biologically based probabilistic model of the carcinogenic process has been developed based on a two-stage theory of carcinogenesis. The model has been validated utilizing experimental urinary bladder carcinogenesis studies in the rat, with an emphasis on quantification of cell dynamics. Critical parameters tracked through this process include mitotic rates, cell loss and birth rates, and irreversible cellular transitions from normal to initiated to transformed states. Analyses demonstrate the sensitivity of tumor incidence to the timing and magnitude of changes to these cellular variables. Modeling has been applied to genotoxic compounds, such as N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, and non-genotoxic compounds, such as sodium saccharin. For the latter compounds, complex administration regimens have been studied, including two-generation experiments, initiation-promotion experiments, and sodium saccharin administration following ulceration and regenerative hyperplasia. Modeling indicates that the effects of such compounds can be explained entirely on the basis of cytotoxicity and consequent hyperplasia. Quantitative modeling based on biological processes has the potential for direct application to carcinogenic risk assessment.

Cell Division↗