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PubMed2005

Genetic characterization of commonly used glioma cell lines in the rat animal model system.

OBJECT: Animal models have been used extensively to discern the molecular biology of diseases and to gain insight into treatments. Nevertheless, discrepancies in the effects of treatments and procedures have been encountered during the transition from these animal models to application of the information to clinical trials in humans. To assess the genetic similarities between human gliomas and four cell lines used routinely in animal models, the authors used microarray technology to characterize the similarities and differences in gene expression. METHODS: To define the changes in gene expression, normal rat astrocytes were compared with four rat glioma cell lines (C6, 9L, F98, and RG2). The data were analyzed using two different methods: fold-change analysis and statistical analysis with t statistics. The gene products that were highlighted after intersecting the lists generated by the two methods of analysis were scrutinized against changes in gene expression reported in the literature. Tumorigenesis involves three major steps: the accumulation of genetic alterations, uncontrolled growth, and selected survival of transformed cells. The discussion of the results focuses attention on genes whose primary function is in pathways involved in glioma proliferation, infiltration, and neovascularization. A comparative microarray analysis of differentially expressed genes for four of the commonly used rat tumor cell lines is presented here. CONCLUSIONS: Due to the variances between the cell lines and results from analyses in humans, caution must be observed in interpreting as well as in the translation of information learned from animal models to its application in human trials.

Animals↗

PubMed1997

Designing of plant artificial chromosome (PAC) by using the Chlorella smallest chromosome as a model system.

As a model for plant-type chromosomes, we have been characterizing molecular organization of the Chlorella vulgaris C-169 chromosome I. To identify chromosome structural elements including the centromeric region and replication origins, we constructed a chromosome I specific cosmid library and aligned each cosmid clones to generate contigs. So far, more than 80% of the entire chromosome I has been covered. A complete clonal physical reconstitution of chromosome I provides information on the structure and genomic organization of plant genome. We propose our strategy to construct an artificial chromosome by assembling the functional chromosome structural elements identified on Chrorella chromosome I.

Centromere↗

PubMed2001

Using conceptual models of nursing to guide nursing research: the case of the Neuman systems model.

Conceptual models of nursing inform thinking and give meaning and direction to nursing research. The Neuman systems model is used to exemplify the following five steps, which provide specific direction for conceptual model-based research: (a) Develop a comprehensive understanding of the substantive content and research rules of the conceptual model, (b) review existing research guided by the conceptual model, (c) construct a conceptual-theoretical-empirical structure, (d) clearly communicate the conceptual-theoretical-empirical structure, and (e) conclude the report with an evaluation of the empirical adequacy of the middle-range theory and the credibility of the conceptual model.

Humans↗

PubMedDate not supplied

Applying the new concepts of the Neuman Systems Model.

The latest version of the Neuman Systems Model contains new terminology--"spiritual variable" and "created environment"--and an emphasis on the concepts of primary prevention and wellness. A case study of a client who has tested positive for HIV explores the new terms and demonstrates the expanded concepts of primary prevention and wellness. Nurses can utilize this framework and the concept of wellness with terminally ill or healthy individuals. Nursing frameworks can be practical and useful to nurses and not just words in a theory book.

Adult↗

PubMed2002

Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.

To explore molecular mechanisms of prostate cancer progression, we applied tissue microarrays (TMAs) to analyze expression of candidate gene targets discovered by cDNA microarray analysis of the CWR22 xenograft model system. A TMA with 544 clinical specimens from different stages of disease progression was probed by mRNA in situ hybridization and protein immunohistochemistry. There was an excellent correlation (r = 0.96; n = 16) between the expression levels of the genes in the xenografts by cDNA microarray and mRNA in situ hybridization on a TMA. One of the most highly overexpressed genes in hormone-refractory CWR22R xenografts was the S100P gene. This gene, coding for a calcium signaling molecule implicated in the loss of senescence, was also significantly associated with progression in clinical tumors by TMA analysis (P < 0.001), suggesting dysregulation of this pathway in hormone-refractory and metastatic prostate cancers. Conversely, two genes that were down-regulated during tumor progression in the CWR22 model system were validated in vivo: crystallin mu (CRYM) and a LIM-domain protein LMO4 both showed significantly lower mRNA levels in hormone-refractory tumors as compared with primary tumors (P < 0.001). These results illustrate a strategy for rapid clinical validation at the mRNA and protein level of gene targets found to be differentially expressed in cDNA microarray experiments of model systems of cancer.

Animals↗

PubMed2006

Xenopus as a model system for vertebrate heart development.

The African clawed frog, Xenopus laevis, is a valuable model system for studies of vertebrate heart development. In the following review, we describe a range of embryological and molecular methodologies that are used in Xenopus research and discuss key discoveries relating to heart development that have been made using this model system. We also discuss how the sequence of the Xenopus tropicalis genome provides a valuable tool for identification of orthologous genes and for identification of evolutionarily conserved promoter elements. Finally, both forward and reverse genetic approaches are currently being applied to Xenopus for the study of vertebrate heart development.

Animals↗

PubMedDate not supplied

Organizational re-engineering using systems modelling: rediscovering the physics of the health service.

This paper explores the general role of systems modelling and its specific use in the UK National Health Service for providing a balanced overview of change management which links organizational structure, strategy, and process. The maps and modelling tools of the method are described, together with an outline of how they can be used to simulate and test alternative interventions in complex organizations and to create a management focus on generic insights, accelerated business learning, and improved financial performance. A case study involving the use of systems modelling at the interface between the health service and community care is presented as a specific example of the method in action.

Community Health Services↗

PubMed2006

Parameter estimation in biochemical systems models with alternating regression.

BACKGROUND: The estimation of parameter values continues to be the bottleneck of the computational analysis of biological systems. It is therefore necessary to develop improved methods that are effective, fast, and scalable. RESULTS: We show here that alternating regression (AR), applied to S-system models and combined with methods for decoupling systems of differential equations, provides a fast new tool for identifying parameter values from time series data. The key feature of AR is that it dissects the nonlinear inverse problem of estimating parameter values into iterative steps of linear regression. We show with several artificial examples that the method works well in many cases. In cases of no convergence, it is feasible to dedicate some computational effort to identifying suitable start values and search settings, because the method is fast in comparison to conventional methods that the search for suitable initial values is easily recouped. Because parameter estimation and the identification of system structure are closely related in S-system modeling, the AR method is beneficial for the latter as well. Specifically, we show with an example from the literature that AR is three to five orders of magnitudes faster than direct structure identifications in systems of nonlinear differential equations. CONCLUSION: Alternating regression provides a strategy for the estimation of parameter values and the identification of structure and regulation in S-systems that is genuinely different from all existing methods. Alternating regression is usually very fast, but its convergence patterns are complex and will require further investigation. In cases where convergence is an issue, the enormous speed of the method renders it feasible to select several initial guesses and search settings as an effective countermeasure.

Computational Biology↗

PubMed2005

Pharmacogenetics in model systems: defining a common mechanism of action for mood stabilisers.

Defining the underlying causes of psychiatric disorders has provided an ongoing and intractable problem. The analysis of the genetic basis of manic depression, in particular, has been impeded by the absence of a suitable model system and by the lack of candidate causative genes. One recent approach to overcome these problems has involved identifying those genes which control the sensitivity to anti-manic drugs in a model organism. Characterisation of the role of these genes and their encoded proteins in this model has allowed the analysis of their mammalian homologues to elucidate the therapeutic role of these drugs and the possible aetiology of manic depression. This approach has been used successfully with the cellular slime mould, Dictyostelium discoideum. This article introduces the use of model systems for pharmacogenetics research. It describes the identification of prolyl oligopeptidase in D. discoideum as a modulator of inositol phosphate signalling, and the subsequent identification of a common mechanism of action of three anti-manic drugs in mammalian neurons. The use of pharmacogenetics in model systems will provide a powerful tool for the ongoing analysis of both the treatment and cause of psychiatric disorders.

Animals↗

PubMed1994

Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern.

Adequate tumour models are a prerequisite in experimental cancer research. The purpose of the present work was to establish and assess the validity of four new orthotopic human melanoma xenograft model systems (A-07, D-12, R-18, U-25). Permanent cell lines were established in monolayer culture from subcutaneous metastases of four different melanoma patients by using an in vivo-in vitro procedure, and cells from these lines were inoculated intradermally in Balb/c nu/nu mice to form tumours. Individual xenografted tumours of the same line differed substantially in growth and pathophysiological parameters, probably as a consequence of differences between inoculation sites in host factors which influence tumour angiogenesis. Nevertheless, xenografted tumours of different lines showed distinctly different biological characteristics. Several biological characteristics of the donor patients' tumours were retained in the xenografted tumours, including angiogenic potential; growth, histopathological and pathophysiological parameters; and sensitivity to radiation, heat and dacarbazine treatment. Moreover, the organ-specific metastatic pattern of the xenografted tumours reflected the pattern of distant metastases in the donor patients. The organs of preference for distant metastases were lungs (A-07, D-12), lymph nodes (R-18) and brain (U-25). R-18 lymph node metastases and U-25 brain metastases developed in the absence of lung involvement. The four orthotopic human melanoma xenograft model systems show great promise for future studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern.

Adult↗

PubMed1994

A model system for evaluating filing technique.

The aim of this study was to develop a model system to demonstrate the pattern of load and how much is applied. A lower molar was mounted on a beam and attached to a mandibular phantom head jaw. A strain gauge fitted to the beam allowed loading of the molar to be recorded, during root canal preparation. Ten operators were asked to instrument the distal root canal; after preparation the operators were shown a graphical representation of the loads applied. This formed the basis of discussion and instruction in filing technique. The operators then repeated the filing. The results showed that prior to instruction operators used a push-pull motion, applying a constant lateral force to the canal wall. After instruction and discussion of the graphical representation of the loads applied the stroke rates used were slower and loads applied were higher (two-sample t-test, n = 10, P < 0.01). The experiment was repeated 1 year later and this showed that the change in technique had been retained. In conclusion, this model system allows visual feedback to the operator and can be used as an aid to teaching filing technique.

Analysis of Variance↗

PubMed1996

A model system for the investigation of urinary stone formation.

OBJECTIVE: To develop an in vitro model system for the investigation of calcium oxalate urinary stones under conditions of spontaneous precipitation. MATERIALS AND METHODS: Using a calcium-ion selective electrode and automatic titrator, a test solution was kept supersaturated with calcium oxalate and the rate of crystallization measured. RESULTS: During the spontaneous precipitation at constant supersaturation at 37 degrees C, the induction times required for the precipitation of calcium oxalate monohydrate were inversely proportional to the supersaturation of the solution. No transient phases were identified and the interfacial energy determined from kinetic analysis was 28.4 mJ/m2. The rates of precipitation showed a first-order dependence on the degree of supersaturation and were in good agreement with those reported for the in vivo formation of calcium oxalate monohydrate stones. CONCLUSION: This experimental model system allows precise measurements of the kinetics of calcium oxalate monohydrate. From the dependence of the rates of precipitation on supersaturation, a mechanism controlled by surface diffusion is suggested.

Calcium Oxalate↗

PubMed1986

Hydrolysis of 2-hydroxy-4-(methylthio)butanoic acid dimer in two model systems.

Hydrolysis of 2-hydroxy-4-(methylthio)butanoic acid (HMB) dimer was observed in two model systems that were designed to emulate in vivo conditions. A physiologically feasible rate of hydrolysis of this methionine precursor has not previously been demonstrated in vivo. In the first model, simulated intestinal fluid (SIF) was used, and in the second model, sections of chick small intestine were incubated in vitro with the compound under study. When HMB dimer was incubated with SIF, hydrolysis was very rapid until half of the dimer was hydrolyzed. Subsequent hydrolysis was negligible in that model system. In contrast, hydrolysis neared completion when sections of small intestine were incubated with HMB dimer. These results indicate that studies of HMB dimer cleavage must include consideration of enzymatic hydrolysis factors.

Animals↗

PubMed1999

A model system of primary murine hepatocytes infected by murine cytomegalovirus.

In order to establish a model system of the murine hepatocyte infection by murine cytomegalovirus (MCMV), the primary cultured murine hepatocytes were obtained in a modified low-serum medium system by a non-perfusion method, and then infected by Smith strain MCMV. Infected hepatocytes showed characteristic cytopathic effect (CPE) at 30 h after infection, in which a large number of viral particles was found and ultrastructures were destroyed (as revealed by disappearance of bile canalicula and organelles) under the electron microscope and MCMV immediate-early genes were detected by in situ hybridization. Meanwhile, infected cells produced albumin significantly less than corresponding uninfected controls. On the contrary, uninfected controls simultaneously cultured under the same conditions showed normal function and ultrastructure (glycogen rosettes, bile canalicula, wheel-like mitochondria and well-developed rough and smooth endoplasmic reticula). These results demonstrated that a model system of primary cultured murine hepatocytes infected by MCMV was successfully set up.

Animals↗

PubMed2003

Bioelectronic DNA detection of human papillomaviruses using eSensor: a model system for detection of multiple pathogens.

BACKGROUND: We used human papillomaviruses (HPV) as a model system to evaluate the utility of a nucleic acid, hybridization-based bioelectronic DNA detection platform (eSensor) in identifying multiple pathogens. METHODS: Two chips were spotted with capture probes consisting of DNA oligonucleotide sequences specific for HPV types. Electrically conductive signal probes were synthesized to be complementary to a distinct region of the amplified HPV target DNA. A portion of the HPV L1 region that was amplified by using consensus primers served as target DNA. The amplified target was mixed with a cocktail of signal probes and added to a cartridge containing a DNA chip to allow for hybridization with complementary capture probes. RESULTS: Two bioelectric chips were designed and successfully detected 86% of the HPV types contained in clinical samples. CONCLUSIONS: This model system demonstrates the potential of the eSensor platform for rapid and integrated detection of multiple pathogens.

Biosensing Techniques↗

PubMed2004

Mating system and population structure of the primitively eusocial wasp Ropalidia revolutionalis: a model system for the evolution of complex societies.

Mating systems are important determinants of genetic structure in cooperative groups, and their effects can influence profoundly the interactions of group members. The primitively eusocial wasp, Ropalidia revolutionalis, has an interesting genetic and social structure that makes it an excellent model system for examining the evolution of more complex societies. In particular, its colonies sometimes have multiple queens, a key characteristic of more advanced wasp societies. In this study, we have characterized the mating system of the social wasp Ropalidia revolutionalis to understand better its colony genetic structure. R. revolutionalis females nearly always mate singly and they are unrelated to their mates. However, different females in the same colony do mate with males, on average, who are related as cousins. Single mating will help to maintain high relatedness, which should be important for continued cooperation in multiple queen societies, but it creates potential conflicts in single queen colonies over the production of males as well as over the timing of male production. We have also characterized the population structure of R. revolutionalis from Townsville, in tropical north Queensland, to Brisbane in the subtropics. Even at such a large scale, the population is remarkably unstructured with an average F(ST) of 0.0546. There is weak isolation by distance, and evidence for subtle differentiation between a southern region with no dry season, which extends as far north as Rockhampton, and a northern region with a severe to moderate dry season. This may reflect historical effects of extreme aridity on the population structure.

Analysis of Variance↗

PubMed1991

Antigenic relationship between oval cells and a subpopulation of hepatic foci, nodules, and carcinomas induced by the "resistant hepatocyte" model system.

Although proliferation of small ductular-like cells, designated oval cells, is often observed during the early stages of chemically induced hepatocarcinogenesis, their role during the carcinogenic process remains controversial. To investigate the possibility that oval cells may give rise to preneoplastic lesions that ultimately progress to hepatocellular carcinomas, we have carried out phenotypic analysis with a panel of monoclonal antibodies to determine if there is an antigenic relationship between oval cells and hepatic foci, nodules, and tumors induced by the resistant hepatocyte model system. In this model, rats are given a single dose (200 mg/kg) of diethylnitrosamine, followed by a brief exposure to 2-acetylaminofluorene and a partial hepatectomy. We found that approximately 10% of the early focal lesions observed 28 days after diethylnitrosamine expressed either one or both of the oval cell antigens designated OC.2 and OV-6. By 28 weeks after diethylnitrosamine, 16 of 16 hepatic nodules heterogeneously expressed OV-6 whereas 5-10% of the persistent nodules contained scattered small hepatocyte-like cells that expressed OC.2. Examination of resistant hepatocyte-induced primary hepatocellular carcinomas with an expanded panel of monoclonal antibodies demonstrated that most cells comprising 29 of 29 tumors expressed OV-6 and that 15-20% of the OV-6-positive tumors contained subpopulations of cells also expressing 3 additional oval cell antigens, OC.2, OC.3, and OV-1. All of the tumors examined expressed normal levels of the hepatocyte antigens, H.1 and HBD.1, and had dramatically reduced levels of H.2, H.4, and cell CAM 105 but showed elevated levels of the transferrin receptor, gamma-glutamyltranspeptidase, and the normal hepatocyte antigen, H.5. In conclusion, our findings demonstrate an antigenic relationship between oval cells and a subpopulation of hepatic foci, nodules, and tumors in the resistant hepatocyte model, suggesting that at least some primary tumors may be derived from oval cells in this model system.

Animals↗

PubMedDate not supplied

Profile of patients lost to follow-up in the Burn Injury Rehabilitation Model Systems' longitudinal database.

We sought to identify whether patterns exist in the Burn Injury Rehabilitation Model Systems' database among participants lost to follow-up at 6, 12, or 24 months after injury and to define characteristics that reliably discriminate between persons who are lost to follow-up and those who are not. All participants met the American Burn Association criteria for major burn injury, were 18 years of age or older, received care from one of four burn model systems, and consented to participate in a 2-year prospective data-collection process. Step-wise logistic regression was used to develop three prediction models for the probability of loss to follow-up. The percent of individuals successfully contacted for follow-up were 64% at 6 months, 54% at 12 months, and 42% at 24 months after injury. Individuals who were younger, not employed at time of burn, with less than a high school level education, a history of drug abuse, circumstances of injury involving suspected assault, and having no insurance for care were lost to follow-up. Longer stay in the hospital, on the other hand, increased the likelihood of follow-up. The same risk factors remained significant with or without adjusting for site indicating that these factors are independent and significant in spite of any potential site differences. Successful follow-up at 6- and 12-month intervals increased the likelihood of achieving a follow-up at 24 months after injury. The sociodemographic risk factors for attrition identified in this study represent significant enduring vulnerabilities. The findings necessitate a close examination of several factors and the use of strategies to reduce the risk of attrition.

Adult↗