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PubMed1987

Autochthonous prostate adenocarcinomas in Lobund-Wistar rats: a model system.

An experimental model system for autochthonous prostate adenocarcinoma (PA) has been developed in Lobund-Wistar (L-W) rats. Large primary PAs were induced in 31 of 40 (77.5%) L-W rats within an average of 10.7 months after a single dose of methylnitrosourea (MNU) and subcutaneous implants of testosterone. Metastatic tumors had developed in over 60% of the tumor-bearing rats. In addition, localized in situ PAs had developed in 5 of the 40 test rats. At 14 months 50 untreated L-W rats were free of demonstrable PAs. Two of 20 (10%) L-W rats developed PA at 14 months after inoculation of MNU alone. Six of 42 (14%) L-W rats developed PAs within 14 months after s.c. administration of testosterone implants. Thus, testosterone acted as a tumor promoter of PA for cells that had been initiated by MNU. The manifestations of the PAs in the L-W rats resembled many aspects of the counterpart disease in man.

Adenocarcinoma↗
PubMed1985

Mechanism of action of diabetogenic zinc-chelating agents. Model system studies.

Using model systems, we have studied the properties of a number of zinc-chelating agents which are known to cause diabetes in laboratory animals. The abilities to permeate membranes and to complex zinc inside liposomes with the release of protons are suggested as chemical properties that can enhance diabetogenicity. When such complexing agents are added to lipid vesicles at pH 6 containing entrapped zinc ions, they acidify the contents of these vesicles. We have demonstrated this effect by measuring intravesicular pH both with a fluorine-containing F NMR probe as well as with the fluorescent probe, quinine. For example, using quinine, we observed that 0.1 mM 8-hydroxyquinoline reduced the intravesicular pH of sonicated phospholipid vesicles containing entrapped Zn2+ (as sulfate) from pH 6.0 to 2.8. These diabetogenic chelating agents also solubilized zinc-insulin precipitates from unbuffered suspensions at pH 6.0. The solubilization results from the acidification of these suspensions. Dithizone and 8-hydroxyquinoline at 4 mM solubilized 97 and 42%, respectively, of the suspended insulin. We suggest that if such proton release occurs within the zinc-containing insulin storage granules of pancreatic beta-cells, solubilization of insulin would be induced. Such an event would lead to osmotic stress and eventually to rupture of the granule. The effects of diethyldithiocarbamate (DDC), an agent that has been found to protect rabbits against the induction of diabetes by some other zinc-chelating agents, were also studied. DDC caused a decrease of 3.5 units in the intravesicular pH of zinc-containing vesicles by a mechanism not involving the release of protons upon chelation of zinc. We have demonstrated several properties of DDC which may contribute to its ability to protect against the induction of diabetes. These include its ability to store zinc as a hydrophobic complex in membranes, its consumption of protons upon spontaneous decomposition, and the ability of one of its decomposition products, diethylamine, to accelerate the dissipation of pH gradients across lipid bilayers. Diethylamine is particularly effective in stimulating a rapid dissipation of such pH gradients, even at micromolar concentrations. We have attempted to estimate quantitatively the extent of proton liberation by various zinc-chelating agents. This analysis demonstrated that partitioning of the ligand between organic and aqueous phases, ligand acidity, and zinc complex stability determine the extent of proton release.

Animals↗
PubMed1984

Transitions between oscillatory modes in a glycolytic model system.

A glycolytic model system consisting of the enzymes phosphofructokinase (EC 2.7.1.11) and pyruvate kinase (EC 2.7.1.40) is analyzed when subject to periodic substrate addition. The calculations are performed by using detailed rate laws that have been derived for the enzymes of Escherichia coli. Due to linear relationships between the metabolite concentrations, the numerical solutions can be displayed inside a trapezium, so that the concentrations of four different metabolites are indicated along the trapezium edges. The analysis reveals a rich variety of time patterns, corresponding to different periodic, quasiperiodic, and chaotic attractors. These patterns undergo complex hysteresis loops when bifurcation parameters are slowly changed-for example, by modulating the input amplitude. By using this technique up to four attractors coexisting in phase space are found. The time patterns corresponding to coexisting attractors can be switched into one another by triggering the system with short substrate pulses. Furthermore, conditions exist at which the triggering is autonomous-i.e., self-sustained (intermittent) switchings occur. The time between these switchings can be set externally by the value of the input amplitude. For conditions in which the periods of the oscillations are in the order of minutes, the self-sustained switching-which modulates these oscillations-can be in the order of hours.

Journal Article↗
PubMed2005

Systems modeling: a pathway to drug discovery.

Systems modeling is emerging as a valuable tool in therapeutics. This is seen by the increasing use of clinically relevant computational models and a rise in systems biology companies working with the pharmaceutical industry. Systems models have helped understand the effects of pharmacological intervention at receptor, intracellular and intercellular communication stages of cell signaling. For instance, angiogenesis models at the ligand-receptor interaction level have suggested explanations for the failure of therapies for cardiovascular disease. Intracellular models of myeloma signaling have been used to explore alternative drug targets and treatment schedules. Finally, modeling has suggested novel approaches to treating disorders of intercellular communication, such as diabetes. Systems modeling can thus fill an important niche in therapeutics by making drug discovery a faster and more systematic process.

Animals↗
PubMed1998

Predictive value of in vitro model systems in toxicology.

The application of in vitro model systems to evaluate the toxicity of xenobiotics has significantly enhanced our understanding of drug- and chemical-induced target toxicity. From a scientific perspective, there are several reasons for the popularity of in vitro model systems. From the public perspective, in vitro model systems enjoy increasing popularity because their application may allow a reduction in the number of live animals employed in toxicity testing. In this review, we present an overview of the use of in vitro model systems to investigate target organ toxicity of drugs and chemicals, and provide selective examples of these model systems to better understand cutaneous and ocular toxicity and the role of drug metabolism in the hepatotoxicity of selected agents. We conclude by examining the value and use of in vitro model systems in industrial development of new pharmaceutical agents.

Animal Testing Alternatives↗
PubMed1997

Detection of mutagenicity in Ames test using a metalloporphyrin/oxidant model system for cytochrome P450.

A chemical model system for cytochrome P450, a porphyrin and an oxidant, was used in Ames assay as a substitute for S9 mix. In the presence of tetrakis(pentafluorophenyl)porphyrinatoiron(III) chloride [Fe(F5P)Cl] and tert-butyl hydroperoxide (t-BuOOH), mutagenicity of N-nitrosodibutylamine (NDB) in Salmonella typhimurium TA1535 was detected. The mutagenicity depended on the pre-incubation period, and also on the concentration of an oxidant and of bacteria. In the chemical model system, pH affected the mutagenicity of NDB, which suggested that as observed in an enzymatic activating system, the mutagenicity was due to the labile alkylating species which was derived from NDB activated in the chemical activation system and was sensitive to pH. Under the optimum conditions; a higher concentration of an oxidant, a higher concentration of bacterial culture, and a weakly acidic medium, mutagenicity of N-nitrosodipropylamine in S. typhimurium TA1535 was also detected. Besides N-nitrosodialkylamines, 2-aminofluorene (2-AF) and benzo[a]pyrene (BaP) were also used as mutagens. Mutagenicity of 2-AF and BaP in S. typhimurium TA1538 were both detected in the same system as used in detecting the mutagenicity of N-nitrosodialkylamines. Ames test using a metalloporphyrin/oxidant model system makes it possible to detect mutagenicity derived from both base pair substitution mutagens and frameshift mutagens without using enzymatic activating system. These results demonstrate that the assay with the chemical model system is useful in detecting unstable unknown active mutagens or investigating the mechanisms of the metabolic pathway of mutagens or carcinogens in a protein-free medium.

Benzo(a)pyrene↗
PubMed2003

Characterization of an Fe III-OOH species and its decomposition product in a bleomycin model system.

To model the mononuclear Fe(III)-OOH species identified in the catalytic cycle of the anticancer drug bleomycin, the iron chemistry of the pentadentate ligand N-[bis(2-pyridylmethyl)aminoethyl]pyridine-2-carboxamide (H-PaPy(3)) has been investigated. The complex [Fe(III)(PaPy(3))OCH(3)](ClO(4)) was reacted with H(2)O(2) to form a red species (lambda(max)=480 nm, epsilon=1800 M(-1) cm(-1)) with an S=1/2 EPR signal at g=2.25, 2.17, and 1.95. This species has been identified by electrospray ionization mass spectrometry as [Fe(III)(PaPy(3))OOH](ClO(4)) and further characterized by resonance Raman and EXAFS analysis. The decomposition of this intermediate leads to the modification of the ligand, as revealed by (1)H NMR. One hydrogen atom is substituted by a solvent-derived methoxy group. The substitution at this site is a result of the two-electron oxidation of the ligand following the heterolytic cleavage of the O-O bond of the Fe(III)-OOH species. This is a plausible mechanism to rationalize related ligand modifications that have been proposed in the decay of activated bleomycin.

Amides↗
PubMed2001

EPR studies of nitric oxide interactions of alkoxyl and peroxyl radicals in in vitro and ex vivo model systems.

A model compound of lipid peroxidation, tert-butyl hydroperoxide (tBOOH), was used in vitro to investigate (i) the generation of tBOOH-derived free radicals by hematin or rat enterocytes and (ii) the modulation of cell-generated free radical production by a nitric oxide (NO) donor, or when these cells were primed to produce NO. In hematin-catalyzed decomposition of tBOOH, NO from nitrosoglutathione, or S-nitroso-N-acetylpenicillamine suppressed the generation of peroxyl radicals (measured by direct electron paramagnetic resonance) and tert-butylalkoxyl, methoxyl, and methyl radicals (measured by electron paramagnetic resonance spin trapping). Similarly, co-incubation of S-nitroso-N-acetylpenicillamine or nitrosoglutathione with tBOOH caused significant decreases in tBOOH-derived free radical generation catalyzed by enterocytes. Epithelial cells are the known source of the inducible form of NO synthase in the intestine of rats challenged with lipopolysaccharide (LPS). Enterocytes isolated from LPS-treated rats produced decreased levels of tBOOH-derived radicals. These decreases in free radical production were further decreased when these cells were treated with LPS in vitro. These findings demonstrated that exogenously added or endogenously produced NO could modulate the extent of tBOOH-derived free radical generation in enterocytes. These decreases in free radical production could, at least in part, describe the protective role of NO from hydroperoxide-induced injury.

Alcohols↗
PubMed1988

The elementary catalytic system model as a building unit of large enzymatic systems. General model.

A model of an elementary catalytic system (ECS) is suggested, derived from the notions of the general theory of systems, which is capable of performing a single elementary catalytic act (ECA). For large chemical systems involving high numbers of ECAs occurring on various ECSs, the system's action becomes increasingly effective when component ECSs are coupled into complex structures. Models are suggested to describe these couples and several fundamental theorems are proved concerning the possible structures. Complex catalytic systems are shown to contain finite numbers of ECSs.

Catalysis↗
PubMedDate not supplied

Model systems of prostate cancer: uses and limitations.

A valid experimental model system reflects the system under study and is reproducible. Model systems of prostate cancer that accurately reflect the different disease stages are necessary to ensure a proper experimental design aimed at increasing our understanding of the biology of the disease and such models are essential tools to accelerate development of new therapies for prostate cancer. Until recently, a limited number of experimental systems were available and more suitable models derived from human specimens have only recently been developed and become available for use. In addition, transgenic techniques have also permitted the development of unique mouse models. The difficulty in establishing model systems may reflect the complex requirements necessary for cancer progression and should lead us to interpret results from model systems with caution. It is unlikely that a single model system that faithfully reflects the whole process of cancer development and progression will be developed. However, thoughtful use of the available model systems will permit the study of a significant portion of prostate cancer progression. In this review we summarize the properties of the prostate cancer model systems in use and defined their utility and limitations. This review will guide the investigator seeking models with which to test specific hypotheses pertaining to prostate cancer.

Animals↗
PubMedDate not supplied

Age-related disruption of classical conditioning: a model systems approach to memory disorders.

The model systems approach to the neurobiology of memory involves studying a well characterized learned response in a relatively simple and well controlled preparation. The best characterized mammalian model system is classical conditioning of the rabbit's eyeblink response. Using this preparation, significant progress has been made toward understanding the neurobiological systems and mechanisms involved in elaboration of the conditioned response. Using a well characterized model system such as classical eyeblink conditioning, it should be possible to both characterize the changes in learning and memory that accompany aging and to investigate their neural substrates. Our strategy for using the conditioned eyeblink preparation for studying age-related memory deficits is four-fold and includes investigating conditioning deficits in: (1) humans across the life span, (2) rabbits across the life span, (3) Alzheimer's disease patients, and (4) rabbits with aluminum-induced neurofibrillary degeneration. In this paper, we present exemplary data from each of these lines of research. If similar deficits occur in each of these groups, it may be possible to begin to form hypotheses about the neurobiology of age-related memory disorders.

Aging↗
PubMed2000

Autoxidation in xylose/lysine model systems.

The volatiles produced in xylose/lysine model systems added with an antioxidant (alpha-tocopherol, 2,6-di-tert-butyl-4-methylphenol, or rosemary extract) or a free radical initiator (alpha, alpha'-azobis(isobutyronitrile), AIBN) were analyzed to investigate the effects of the presence of free radicals on the Maillard reaction. The pH was maintained constant at 4 or 6, by adding a base, and the data were compared by principal component analysis (PCA). The additives were more effective at pH 4 than pH 6. At pH 4, the model system added with AIBN is very well-discriminated by PCA from the models with the antioxidants and the reference model system, indicating that the volatiles are sensitive to compounds that can interfere in an opposite way with free radical formation.

Free Radicals↗
PubMedDate not supplied

Maintaining squamous epithelial architecture in a human cervical epithelium to SCID mouse xenograft model system.

OBJECTIVE: To establish a mouse model system of human cervical epithelium that maintains the stratified squamous architecture overlying a well-defined basement membrane. METHODS: Normal cervical tissue specimens were obtained from the transformation zone of hysterectomy specimens. Small (2 mm) cubes of tissue containing stroma and epithelium were placed subdermally into severe combined immunodeficient (SCID) mice and harvested between 7 and 45 days. Specimens were examined histologically for the presence of stroma, epithelium, and basement membrane. RESULTS: In 49 xenograft attempts in 24 mice, 35 (71%) were identified microscopically. Of these, 28 (80%) had identifiable epithelium and 20 (57%) formed cysts lined with stratified squamous epithelium. A cuboidal basal layer clearly defined the basement membrane. Proliferation within the cyst epithelium was demonstrated by expression of the Ki67 proliferation marker and the presence of mitotic figures. CONCLUSIONS: A human to mouse xenograft model system is described that maintains, in high yield, stratified squamous epithelium overlying a well-defined basement membrane. Advantages of this model system include the following: (1) The tissue originates from readily available human specimens; (2) A stratified squamous epithelial architecture is maintained for a sufficient time to study viral effects on proliferation; (3) The basement membrane of the epithelium is well defined, allowing for investigation of connective tissue factors in cervical intraepithelial neoplasia and cervical cancer.

Animals↗
PubMed2005

Molecularly engineered PEG hydrogels: a novel model system for proteolytically mediated cell migration.

Model systems mimicking the extracellular matrix (ECM) have greatly helped in quantifying cell migration in three dimensions and elucidated the molecular determinants of cellular motility in morphogenesis, regeneration, and disease progression. Here we tested the suitability of proteolytically degradable synthetic poly(ethylene glycol) (PEG)-based hydrogels as an ECM model system for cell migration research and compared this designer matrix with the two well-established ECM mimetics fibrin and collagen. Three-dimensional migration of dermal fibroblasts was quantified by time-lapse microscopy and automated single-cell tracking. A broadband matrix metalloproteinase (MMP) inhibitor and tumor necrosis factor-alpha, a potent MMP-inducer in fibroblasts, were used to alter MMP regulation. We demonstrate a high sensitivity of migration in synthetic networks to both MMP modulators: inhibition led to an almost complete suppression of migration in PEG hydrogels, whereas MMP upregulation increased the fraction of migrating cells significantly. Conversely, migration in collagen and fibrin proved to be less sensitive to the above MMP modulators, as their fibrillar architecture allowed for MMP-independent migration through preexisting pores. The possibility of molecularly recapitulating key functions of the natural extracellular microenvironment and the improved protease sensitivity makes PEG hydrogels an interesting model system that allows correlation between protease activity and cell migration.

Biocompatible Materials↗
PubMed2005

Developing a model system for teaching goniotomy.

PURPOSE: To design a model-system instruction course to prepare trainees for performing goniotomy on patients. DESIGN: Experimental study. PARTICIPANTS: Three pediatric ophthalmology fellows and 1 recent graduate of the fellowship program. METHODS: We piloted 3 model systems: human cadaver eyes with and without Marty the Surgical Simulator (Iatrotech Inc., Del Mar, CA, hereafter referred to as Marty Head) eye supporting system and artificial eyes in Marty Head. For improving intraocular view in cadaver eyes, we used epithelial scrapping, intracameral viscoelastic, and/or intracameral lubricating jelly. Each trainee underwent a training course, including background reading, didactic lecture, and video review followed by goniotomy on model systems with the operating microscope. MAIN OUTCOME MEASURES: Each trainee evaluated each step of the course using modified 5-point Likert scales. Reading material and videos were evaluated for usefulness, readability/quality, and new information obtained. Each model system was evaluated for visibility, ease of setup, surgical feel, and transferability to live surgery. In the end, each trainee was asked to assess the overall course for usefulness. RESULTS: Trainees rated the reading materials and video highly for their usefulness and quality, yet they believed they did not learn substantial amounts of new information. Visibility and ease of setup was best with artificial eyes in the Marty Head model. Human cadaver eyes in the Marty Head provided somewhat less visibility and ease of setup, but the perceived feel and transferability to live surgery was slightly better than with artificial eyes. Cadaver eyes without the Marty Head got the lowest rating in all categories. At the end of the course, all participants felt more confident and ready to perform goniotomy on patients. All recommended this course as part of pediatric ophthalmology fellowship training programs. CONCLUSIONS: This model system instruction course can assist trainees in learning to perform goniotomy while potentially lessening the risks to patients.

Gonioscopy↗
PubMed2002

Development of a risk-based TMDL assessment approach using the integrated modeling system GIBSI.

Using the integrated modeling system GIB SI and a case study, this paper presents the development of a risk-based TMDL assessment approach that links wet (nonpoint/diffuse) and dry weather (point) sources to a probability of exceeding water quality standards (WQS) governing wateruses. The case study focused on determining whether WQS defining recreational uses of water requiring direct and prolonged contact were attainable if the waste water effluent of a small town was treated using aerated lagoons and if the agricultural nonpoint source (NPS) loads were reduced using different fertilization rates. Dry weather sources were assumed to solely contribute to bacteriological impairment of the studied river reach. Meanwhile, both wet and dry weather sources were assumed to contribute to aesthetic impairment. Simulation results showed that treating the waste water effluent while reducing the agricultural NPS loads by 27% allowed on average over a four-year study period for attainment of the bacteriological WQS 100% of the summer time while lowering the probability of exceeding the aesthetic WQS from 0.32 to 0.19 (30 to 18 days). The results of this study showed this risk-based assessment approach was well suited to establish TMDL. These probabilities should be evaluated using long meteorological series.

Forecasting↗
PubMed2006

Molecular profiling reveals myeloid leukemia cell lines to be faithful model systems characterized by distinct genomic aberrations.

To model and investigate different facets of leukemia pathogenesis, a widely accepted approach is to use immortalized leukemia cell lines. Although these provide powerful tools to our knowledge, few studies have addressed the question whether hematopoietic cell lines represent accurate and reliable model systems. To improve the molecular characterization of these model systems, we analyzed 17 myeloid leukemia cell lines using DNA microarray technology. By array-based comparative genomic hybridization, we identified recurrent genomic DNA gains and losses, as well as high-level amplifications. Parallel analysis of gene expression helped delineate potential candidate genes, and unsupervised analysis of gene expression data revealed cell lines to cluster in part based on underlying cytogenetic abnormalities. Comparison with clinical leukemia specimens showed that key signatures were retained, as myeloid cell lines with characteristic cytogenetic aberrations co-clustered with leukemia samples carrying the respective abnormality. Signatures were also quite robust, as expression data from cell lines correlated highly with published data. Thus, our analyses demonstrate myeloid cell lines to exhibit conserved and stable signatures reflecting the underlying primary cytogenetic aberrations. Our refined molecular characterization of myeloid cell lines supports the utility of cell lines as faithful and powerful model systems and provides additional insights into the molecular mechanisms of leukemogenesis.

Acute Disease↗
PubMed2006

The scope of integrated modelling: system boundaries, sub-systems, scales and disciplines.

Integrated modelling has become an urgent issue of urban drainage and wastewater treatment planning. The scope of integrated modelling, system boundaries and disciplines to be involved are addressed in view of future developments and new paradigms in urban drainage, demanding the inclusion of the full urban water cycle. A system analysis is demonstrated to identify relevant sub-systems and components, processes and interactions within the urban water system. The permissibility to exclude subsystems or neglect interactions is evaluated. Integrated modelling of urban water system is characterised as an ambitious task in regard to system complexity, heterogeneous scales and interface problems. The methodical status quo is characterised in preliminary approaches towards integrated modelling. It is concluded that it does not seem promising to create and apply one entity model for the scope of integrated urban water modelling. Instead, the development of adequate and efficient IT frameworks is identified as the key issue of integrated modelling. Harmonising interfaces to facilitate the linking of existing models is presented as the objective of a European research project HarmonlT and the U.S. EPA Multimedia Integrated Modelling System project MIMS.

Cities↗