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PubMed2005

Activation of the canonical Wnt pathway during genital keratinocyte transformation: a model for cervical cancer progression.

Cervical carcinoma, the second leading cause of cancer deaths in women worldwide, is associated with human papillomavirus (HPV). HPV-infected individuals are at high risk for developing cervical carcinoma; however, the molecular mechanisms that lead to the progression of cervical cancer have not been established. We hypothesized that in a multistep carcinogenesis model, HPV provides the initial hit and activation of canonical Wnt pathway may serve as the second hit. To test this hypothesis, we evaluated the canonical Wnt pathway as a promoting factor of HPV-induced human keratinocyte transformation. In this in vitro experimental cervical carcinoma model, primary human keratinocytes immortalized by HPV were transformed by SV40 small-t (smt) antigen. We show that smt-transformed cells have high cytoplasmic beta-catenin levels, a hallmark of activated canonical Wnt pathway, and that activation of this pathway by smt is mediated through its interaction with protein phosphatase-2A. Furthermore, inhibition of downstream signaling from beta-catenin inhibited the smt-induced transformed phenotype. Wnt pathway activation transformed HPV-immortalized primary human keratinocytes even in the absence of smt. However, activation of the Wnt pathway in the absence of HPV was not sufficient to induce transformation. We also detected increased cytoplasmic and nuclear staining of beta-catenin in invasive cervical carcinoma samples from 48 patients. We detected weak cytoplasmic and no nuclear staining of beta-catenin in 18 cases of cervical dysplasia. Our results suggest that the transformation of HPV expressing human keratinocytes requires activation of the Wnt pathway and that this activation may serve as a screening tool in HPV-positive populations to detect malignant progression.

Antigens, Polyomavirus Transforming↗
PubMed1996

The pH 6.7 Syrian hamster embryo cell transformation assay for assessing the carcinogenic potential of chemicals.

Cell transformation models have been established for studying the cellular and molecular basis of the neoplastic process. Transformation models have also been utilized extensively for studying mechanisms of chemical carcinogenesis and, to a lesser degree, screening chemicals for their carcinogenic potential. Complexities associated with the conduct of cell transformation assays have been a significant factor in discouraging broad use of this approach despite their reported good predictivity for carcinogenicity. We previously reported that many of the experimental difficulties with the Syrian hamster embryo (SHE) cell transformation assay could be reduced or eliminated by culturing these cells at pH 6.7 culture conditions compared to the historically used pH 7.1-7.3. We and others have shown that morphological transformation (MT), the earliest recognizable phenotype in the multi-step transformation process and the endpoint used in the standard assay to indicate a chemical's transforming activity, represents a pre-neoplastic stage in this model system. In the collaborative study reported here, in which approx. 50% of the chemicals were tested under code in one laboratory (Hazelton) and the other 50% evaluated by several investigators in the second laboratory (P & G), we have evaluated 56 chemicals (30 carcinogens, 18 non-carcinogens, 8 of inconclusive carcinogenic activity) in the SHE cell transformation assay conducted at pH 6.7 culture conditions with a standardized, Good Laboratory Practices-quality protocol. An overall concordance of 85% (41/48) between SHE cell transformation and rodent bioassay results was observed with assay sensitivity of 87% (26/30) and specificity of 83% (15/18), respectively. The assay exhibited a sensitivity of 78% (14/18) for Salmonella assay negative carcinogens, supporting its value for detecting non-mutagenic carcinogens. For maximum assay sensitivity, two exposure durations were required, namely a 24-h exposure and a 7-day exposure assay. Depending on the duration of chemical treatment required to induce transformation, insight into the mechanism of transformation induction may also be gained. Based on the data reported here, as well as the larger historical dataset reviewed by Isfort et al. (1996), we conclude that the SHE cell transformation assay provides an improved method for screening chemicals for carcinogenicity relative to current standard genotoxicity assays.

3T3 Cells↗
PubMedDate not supplied

Using computational modeling to transform nursing data into actionable information.

Transforming organizational research data into actionable information nurses can use to improve patient outcomes remains a challenge. Available data are numerous, at multiple levels of analysis, and snapshots in time, which makes application difficult in a dynamically changing healthcare system. One potential solution is computational modeling. We describe our use of OrgAhead, a theoretically based computational modeling program developed at Carnegie Mellon University, to transform data into actionable nursing information. We calibrated the model by using data from 16 actual patient care units to adjust model parameters until performance of simulated units ordered in the same way as observed performance of the actual units 80% of the time. In future research, we will use OrgAhead to generate hypotheses about changes nurses might make to improve patient outcomes, help nurses use these hypotheses to identify and implement changes on their units, and then measure the impact of those changes on patient outcomes.

Computational Biology↗
PubMed1981

A searching procedure for transformations and models in a classical Mendelian cross breeding study.

Adopting Wright's four criteria (homogeneity, normality, additivity of effects, and parsimony of parameters needed) concerning a good scale of measurement, a systematic procedure is presented to find an adequate transformation for the data of a classical Mendelian cross. By using Cavalli's least-squares fitting procedure, fits of all possible genetical (sub)models are compared to each other. The model yielding the best fit with as few parameters as possible is selected. More complex models are accepted only if they fit significantly better than simpler ones. Four worked examples are presented from a classical cross study in rats: time till onset of a learned bar-press response under a continuous-reinforcement schedule and protein content, acetylcholinesterase activity, and butyrylcholinesterase activity in the occipital cortex. Using several transformations, invariance of resulting models was found if the criterion of homogeneity of variance was met.

Animals↗
PubMed1994

Induction of senescence and control of tumorigenicity in BK virus transformed mouse cells by human chromosome 6.

Viral transformation models may be useful to detect and map human tumor suppressor genes. BK virus (BKV), a human papovavirus, readily transforms rodent cells but is unable to transform human cells, suggesting that oncosuppressive functions expressed in human cells control BKV oncogenic activity. We have transferred human chromosome 6 to BKV-transformed mouse pRPcT1ss1 cells. The great majority of the colonies growing in selective medium degenerated by senescence. Only five hybrid pRPcT1ss1/H6 clones maintained the immortalized phenotype of the recipient cell line. All the immortalized clones had two common regions of deletion involving bands 6q21-22 and the SOD2 gene in 6q25. Senescent colonies carried an intact chromosome 6. A specific human sequence in 6q21-22 was amplified by PCR in senescent cells, suggesting that this region harbors a gene inducing senescence. The SOD2 deletion confirms recent data on the role of the Mn-dependent superoxide dismutase in inhibition of proliferation. The monochromosomic hybrids bearing a deleted chromosome 6 showed a reverted phenotype in vitro and a significantly longer latency period before they were tumorigenic in nude mice, indicating the presence of a tumor suppressor gene in the residual regions of chromosome 6. Molecular mapping suggests that this gene is located in 6q27. The BKV transformation model detects genes inducing senescence and tumor suppressor genes on human chromosome 6 and may represent a useful system to isolate and clone such genes.

Animals↗
PubMed2005

Mouse models of transforming growth factor beta impact in breast development and cancer.

It is now recognized that transforming growth factor beta (TGF-beta) is an important factor that regulates normal breast development as well as breast cancer. Genetically engineered mouse models have been used to determine the role and mechanism of TGF-beta action in normal development and diseases of the breast. Using these models, it has been determined that TGF-beta regulates many steps of normal mammary gland development including branching morphogenesis, functional differentiation, cell-lineage decisions, and involution. Effects of TGF-beta on normal development are mediated through signaling in both the epithelial and stromal compartments. In cancer, mouse models have indicated that TGF-beta has biphasic effects on tumor progression, acting as a tumor suppressor in early stages of cancer and promoting invasion and metastasis at later stages. In addition, TGF-beta may play a role in tumor progression through effects on the microenvironment. Recently, experiments in several mouse models have suggested that antagonism of TGF-beta signaling may provide a therapeutic target for late-stage breast cancer, blocking metastasis without detrimental side effects. In the future, genetically altered mice will be used to establish models of human breast disease providing opportunities to test strategies for disease prevention and treatment.

Animals↗
PubMed1985

Molecular pathways in the transformation of model discoidal lipoprotein complexes induced by lecithin:cholesterol acyltransferase.

Incubation (24 h, 37 degrees C) of discoidal complexes of phosphatidylcholine and apolipoprotein A-I (molar ratio 95 +/- 10 egg yolk phosphatidylcholine-apolipoprotein A-I; 10.5 X 4.0 nm, long X short dimension; designated, class 3 complexes) with the ultracentrifugal d greater than 1.21 g/ml fraction transformed the discoidal complexes to a small product with apparent mean hydrated and nonhydrated diameter of 7.8 and 6.6 nm, respectively. Formation of the small product was associated with marked reduction in phosphatidylcholine-apolipoprotein AI molar ratio of the complexes (on average from 95:1 to 45:1). Phospholipase A2 activity of lecithin:cholesterol acyltransferase participated in the depletion process, as evidenced by production of unesterified fatty acids. In the presence of the d greater than 1.21 g/ml fraction or partially purified lecithin:cholesterol acyltransferase and a source of unesterified cholesterol, the small product could be transformed to a core-containing (cholesteryl ester) round product with a hydrated and nonhydrated diameter of 8.6 and 7.5 nm, respectively. By means of cross-linking with dimethylsuberimidate, the protein moiety of the small product was shown to contain primarily two apolipoprotein A-I molecules per particle, while the large product contained three apolipoprotein A-I molecules per particle. The increase in number of apolipoprotein A-I molecules per particle during transformation of the small to the large product appeared to result from fusion of the small particles during core build-up and release of excess apolipoprotein A-I from the fusion product. The results obtained with the model complexes were consistent for the most part with recent observations (Chen, C., Applegate, K., King, W.C., Glomset, J.A., Norum, K.R. and Gjone, E. (1984) J. Lipid Res. 25, 269-282) on the transformation, by lecithin:cholesterol acyltransferase, of the small spherical high-density lipoproteins of patients with familial lecithin:cholesterol acyltransferase deficiency.

Apolipoproteins A↗
PubMedDate not supplied

Automated image registration: II. Intersubject validation of linear and nonlinear models.

PURPOSE: Our goal was to validate linear and nonlinear intersubject image registration using an automated method (AIR 3.0) based on voxel intensity. METHOD: PET and MRI data from 22 normal subjects were registered to corresponding averaged PET or MRI brain atlases using several specific linear and nonlinear spatial transformation models with an automated algorithm. Validation was based on anatomically defined landmarks. RESULTS: Automated registration produced results that were superior to a manual nine parameter variant of the Talairach registration method. Increasing the degrees of freedom in the spatial transformation model improved the accuracy of automated intersubject registration. CONCLUSION: Linear or nonlinear automated intersubject registration based on voxel intensities is computationally practical and produces more accurate alignment of homologous landmarks than manual nine parameter Talairach registration. Nonlinear models provide better registration than linear models but are slower.

Adult↗
PubMed2001

A semiparametric estimate of treatment effects with censored data.

A semiparametric estimate of an average regression effect with right-censored failure time data has recently been proposed under the Cox-type model where the regression effect beta(t) is allowed to vary with time. In this article, we derive a simple algebraic relationship between this average regression effect and a measurement of group differences in k-sample transformation models when the random error belongs to the G(rho) family of Harrington and Fleming (1982, Biometrika 69, 553-566), the latter being equivalent to the conditional regression effect in a gamma frailty model. The models considered here are suitable for the attenuating hazard ratios that often arise in practice. The results reveal an interesting connection among the above three classes of models as alternatives to the proportional hazards assumption and add to our understanding of the behavior of the partial likelihood estimate under nonproportional hazards. The algebraic relationship provides a simple estimator under the transformation model. We develop a variance estimator based on the empirical influence function that is much easier to compute than the previously suggested resampling methods. When there is truncation in the right tail of the failure times, we propose a method of bias correction to improve the coverage properties of the confidence intervals. The estimate, its estimated variance, and the bias correction term can all be calculated with minor modifications to standard software for proportional hazards regression.

Biometry↗
PubMed2004

Genetic models for transforming growth factor beta superfamily signaling in ovarian follicle development.

The transforming growth factor beta (TGFbeta) superfamily has wide-ranging and profound effects on many aspects of cellular growth and development. Many TGFbeta-related ligands, receptors, and intracellular signaling proteins are expressed in the ovary and are critical for normal follicle development. Our laboratory and others have analyzed the in vivo function of the TGFbeta superfamily signal transduction pathways by using gene knockout and knockin approaches. Two TGFbeta superfamily ligands, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), are expressed in developing oocytes. Based on in vivo data using knockout models, GDF9 is critical at both the primary and preovulatory stages of follicle development, and physiologically interacts with BMP15 during the latter stages of folliculogenesis. A knockin model of activin betaB expressed from the activin betaA locus, revealed that activin betaB can act as a hypomorphic protein and rescue some but not all of activin betaAs functions. Questions of functional redundancy of signaling components and multiple receptor utilization by different ligands still need to be addressed for these pathways. Answers will likely come from using existing single null mouse models to generate combinatorial ligand and receptor null mice. These new models may reveal the in vivo genetic interactions of TGFbeta superfamily ligands, receptors, binding proteins, and downstream signaling pathways.

Animals↗
PubMed2001

Modelling nitrogen transformations in surface flow wastewater treatment wetlands in Sweden.

The purpose of this study was to describe and compare the fate of nitrogen (N) in two Swedish wastewater treatment wetlands in the cities of Oxelösund and Hässleholm. Specifically, we wanted to see if a fairly simple model, developed with regard to common data availability, could satisfactorily describe the concentration dynamics at the outlet from the wetlands. A first-order area-based model, with two alternative expressions for temperature dependence, was set up to describe three major processes: ammonification, nitrification and denitrification. The N concentration dynamics at the outlet of the Oxelösund wetland was not satisfactorily described, R2(NH4+-N) = 0.33 and R2(NO3(-)-N) = 0.10, while the modelled concentrations corresponded quite well with measured concentrations in the Hässleholm wetland, R2(NH4+-N) = 0.83 and R2(NO3(-)-N) = 0.58. The NO3(-)-N concentrations, in both wetlands, could be slightly better described when introducing a temperature coefficient as an additional free parameter. The explained variances reported above were achieved when the model was calibrated individually for the two wetlands, when the resulting (optimised) reaction rate coefficients for each of the three processes were quite different between the two wetlands. To improve model performance, the rate equations may have to be changed to include factors in addition to concentration and temperature, such as dissolved oxygen and hydraulic efficiency. It may also be important to include other processes, such as plant uptake/decay and ammonia volatilisation.

Ammonia↗
PubMed1983

Model for transformations of the clathrin lattice in the coated vesicle pathway.

Transport of receptors by the coated vesicle pathway entails assembly of clathrin triskelions into a lattice in conjunction with receptors in a membrane. The processes by which the receptors are concentrated, the lattice is assembled, transformed into a cage during vesiculation, and subsequently removed from pinched off vesicles are not understood in regard to mechanism, energetics or control. Tubulin and actin assembly are looked to for analogies applicable to clathrin. The present model supposes that clathrin assembly is energy linked and can be described by kinetic equations of the same general form as those for treadmilling in linear polymers. The coat lattice assembles in a steady state involving the degradation of a high energy form of the clathrin triskelions. Diffuse endocytosis receptors are assumed to be associated with individual triskelions and to be able to trigger clustering and coated pit formation by influencing the assembly kinetics of the bound triskelions. A generalization of the treadmilling scheme is proposed by which the kinetic parameters associated with clathrin polymerization can shift simultaneously for an entire lattice to favor alternatively net assembly or disassembly. This shift is effected by a coordinated conversion of the lattice bound receptors. The conversion of the receptors in turn depends on some global property of the membrane compartments (arguably pH, calcium concentration or transmembrane voltage) which is likely to change as a consequence of vesiculation. Thereby, lattice disassembly can be coordinated with the topological conversion from coated pit to coated vesicle.

Adenosine Diphosphate↗
PubMed1993

The Rainbow Model of health as ongoing transformation.

A model is proposed that suggests new directions for achieving well-being that meet the emergent self-transformational needs of individuals. The Rainbow Model is a systematic framework for showing the relationship between approaches to health and total, whole-of-life development, including the spiritual dimension. It uses the colors of the rainbow and the chakras to denote progressively expansive understandings and actions regarding wellness and health care. Red, the longest wavelength, corresponds to one's present state of health or disease. Orange reflects a concern with reducing risk factors. Yellow, the third wavelength, signifies a rational approach to health: Beliefs and habits of thinking are examined. Green means health through emotional balance, supportive relationships, and values that support health. Blue is the layer of health through involvement with one's higher purpose. Indigo is the wavelength of health through metaphysical awareness, and violet, the shortest wavelength, shows health to be most profound when one attains universal consciousness: the sense of unity with all life.

Attitude to Health↗
PubMed1984

A procedure for the statistical evaluation of Ames Salmonella assay results. Comparison of results among 4 laboratories.

Ames Salmonella test data collected in our laboratory and 3 National Cancer Institute contract laboratories were analyzed to study the distribution of experimental errors associated with the test. It is shown that the Poisson distribution is not appropriate, and that the power transformation model Y = (revertants/plate)lambda, with lambda = 0.2 as estimated by the methods of Box and Cox, produced a measurement scale on which the experimental errors could be adequately described by a normal (Gaussian) distribution with a constant variance. The modeling procedure enables one to properly use analysis of variance, regression analysis, and Student's t test to analyze Ames Salmonella test results, and well-known statistical quality control procedures to monitor laboratory performance. The method detects weak mutagenic activity and measures the amount and uncertainty of the increase in revertants/plate. The development of the power transformation model is discussed and examples of its use in the interpretation of Ames Salmonella assay results are included.

Laboratories↗