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At least 883 records · Page 49Linked to original sources
PubMed1997

Muscle transformation of the sartorius muscle in a canine model: clinical impact for electrodynamic graciloplasty as a "neosphincter".

PURPOSE: Transformation of fast-twitching skeletal muscles to slow-twitching, slowly fatigable muscles has become of clinical interest in the recent past. Transposition and transformation of the gracilis muscle to use it as a substitute for a resected or defected anal sphincter (graciloplasty) have been reported as achieving promising results in the treatment of fecal incontinence caused by sphincter defects or following abdominoperineal anorectal excision for cancer. METHOD: This experimental study used a canine model and the sartorius muscle to evaluate the functional efficiency of two different configurations of the muscle loop to compare the presently applied transformation program (8 weeks) with a shorter (5 weeks) protocol. In six beagle dogs, both sartorius muscles were wrapped around two stomas, either in an alpha fashion or in the so-called split-sling technique. Muscle transformation was achieved by controlled neuromuscular stimulation either during eight (Program A) or five weeks (Program B). After completion of the transformation period, the function of the muscle slings was evaluated by manometry, and histomorphologic evaluation of the sartorius muscles was performed. RESULTS: It was shown that muscle transformation led to a slowly fatigable muscle that made it possible to perform continuos (tetanic) contraction, regardless of the configuration or the duration of the transformation. Median pressures created by these muscles also did not differ significantly. In accordance with these functional findings, the histologic evaluation showed the typical, significant increase of Type I fibers in both muscle slings and following both transformation protocols. Although the decrease of fast-twitching Type II fibers was more pronounced following the conventional (8 weeks) program, this finding did not influence the functional results. CONCLUSIONS: Results of our experiment indicate the possibility for using a shorter transformation protocol for transformation of the gracilis muscle during graciloplasty in the clinical setting. Furthermore, the efficacy and safety of the modified (split-sling) wrap technique was demonstrated.

Anal Canal↗
PubMed1995

Extracellular domain of type I receptor for transforming growth factor-beta: molecular modelling using protectin (CD59) as a template.

We have observed that the extracellular domain of T beta RI and protectin (CD59), an inhibitor of the membrane attack complex of complement, share structural features, a distinct spacing of ten cysteines and a C-terminal 'Cys-box'. Based on these common features and the recently determined NMR-structure of protectin, a three-dimensional model for the extracellular domain of T beta RI was constructed. After energy minimization and molecular dynamics simulation, a structure with four extending fingers (pes quattvordigitorum) and two clusters of charged residues was obtained. This model provides a view to the understanding of interactions between T beta RI, T beta RII and TGF beta during ligand recognition and signal transduction.

Amino Acid Sequence↗
PubMed1988

Possible involvement of protease inhibitor ras proteins in malignant transformation.

Based on our recent finding that human c-Ha-ras gene products (p21s) inhibit the activities of thiol proteinases, a possible new model for malignant transformation is proposed. The model involves a new concept that p21s can cause effects on the protein kinase activities of growth factor receptors by affecting down regulation of the receptors.

Cathepsin L↗
PubMedDate not supplied

Predicting the cost of illness: a comparison of alternative models applied to stroke.

Predictions of cost over well-defined time horizons are frequently required in the analysis of clinical trials and social experiments, for decision models investigating the cost-effectiveness of interventions, and for macro-level estimates of the resource impact of disease. With rare exceptions, cost predictions used in such applications continue to take the form of deterministic point estimates. However, the growing availability of large administrative and clinical data sets offers new opportunities for a more general approach to disease cost forecasting: the estimation of multivariable cost functions that yield predictions at the individual level, conditional on intervention(s), patient characteristics, and other factors. This raises the fundamental question of how to choose the "best" cost model for a given application. The central purpose of this paper is to demonstrate how to evaluate competing models on the basis of predictive validity. This concept is operationalized according to three alternative criteria: 1) root mean square error (RMSE), for evaluating predicted mean cost; 2) mean absolute error (MAE), for evaluating predicted median cost; and 3) a logarithmic scoring rule (log score), an information-theoretic index for evaluating the entire predictive distribution of cost. To illustrate these concepts, the authors conducted a split-sample analysis of data from a national sample of Medicare-covered patients hospitalized for ischemic stroke in 1991 and followed to the end of 1993. Using test and training samples of about 500,000 observations each, they investigated five models: single-equation linear models, with and without log transform of cost; two-part (mixture) models, with and without log transform, to directly address the problem of zero-cost observations; and a Cox proportional-hazards model stratified by time interval. For deriving the predictive distribution of cost, the log transformed two-part and proportional-hazards models are superior. For deriving the predicted mean or median cost, these two models and the commonly used log-transformed linear model all perform about the same. The untransformed models are dominated in every instance. The approaches to model selection illustrated here can be applied across a wide range of settings.

Cerebrovascular Disorders↗
PubMed1994

Effect of tamoxifen on mammary preneoplasia: relevance to chemopreventive intervention.

The nonsteroidal antiestrogen tamoxifen (TAM) is used to treat receptor-positive breast cancer and is now being evaluated for prophylaxis of "high-risk" population. The present study seeks to examine mechanisms that may be critical for prophylactic effects of TAM on transformation-sensitive mammary tissue. The experimental systems utilized included: in vivo rodent models for mammary tumorigenesis and in vitro cell culture models for preneoplastic transformation. In the in vivo models TAM suppressed constitutive, as well as carcinogen-induced proliferation, expression of mammary tumor virus-associated reverse transcriptase activity and decreased the incidence and frequency of mammary hyperplastic alveolar nodules. In the in vitro models TAM suppressed carcinogen-induced DNA damage, altered cellular metabolism of estradiol favoring the formation of less estrogenic catechols, and down-regulated anchorage-independent growth that is induced by ras oncogene and chemical carcinogen. Effective down-regulation of specific proliferative and metabolic biomarkers that are perturbed in mammary cell prior to tumorigenesis provides evidence that altered cellular metabolism of E2 may, in part, be responsible for antiproliferative and prophylactic properties of TAM against mammary tumorigenesis.

Animals↗
PubMed2005

Mammary epithelial cell transformation: insights from cell culture and mouse models.

Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely -- a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.

Animals↗
PubMed2004

Modeling liver motion and deformation during the respiratory cycle using intensity-based nonrigid registration of gated MR images.

We present a technique for modeling liver motion during the respiratory cycle using intensity-based nonrigid registration of gated magnetic resonance (MR) images. Three-dimensional MR images of the abdomens of four volunteers were acquired at end-inspiration, end-expiration, and eight time points in between using respiratory gating. The deformation fields between the images were computed using intensity-based rigid and nonrigid registration algorithms. Global motion is modeled by a rigid transformation while local motion is modeled by a free-form deformation based on B-splines. Much of the liver motion was cranial-caudal translation, which was captured by the rigid transformation. However, there was still substantial residual deformation (approximately 10 mm averaged over the entire liver in four volunteers, and 34 mm at one place in the liver of one volunteer). The computed organ motion model can potentially be used to determine an appropriate respiratory-gated radiotherapy window during which the position of the target is known within a specified excursion.

Adult↗
PubMed1999

Growth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assays.

The expression of the BCR-ABL fusion oncoprotein in primitive hematopoietic cells results in chronic myeloid leukemia. Over the past decade studies of several in vitro and in vivo cell systems revealed multiple signal transduction pathways activated by BCR-ABL. However, the precise function of BCR-ABL in the pathogenesis of CML is still unclear. The goal of this review is to synthesize data on intracellular signaling in the context of the diverse murine assay systems employed. We emphasize the importance of in vivo assays and assays using primary cells in understanding the biology of CML and the molecular mechanisms by which BCR-ABL exerts its effects.

Animals↗
PubMed1979

Transformation and relational-structure schemes for visual pattern recognition. Two models tested experimentally with rotated random-dot patterns.

Two models for visual pattern recognition are described; the one based on application of internal compensatory transformations to pattern representations, the other based on encoding of patterns in terms of local features and spatial relations between these local features. These transformations and relational-structure models are each endowed with the same experimentally observed invariance properties, which include independence to pattern translation and pattern jitter, and, depending on the particular versions of the models, independence to pattern reflection and inversion (180 degrees rotation). Each model is tested by comparing the predicted recognition performance with experimentally determined recognition performance using as stimuli random-dot patterns that were variously rotated in the plane. The level of visual recognition of such patterns is known to depend strongly on rotation angle. It is shown that the relational-structure model equipped with an invariance to pattern inversion gives responses which are in close agreement with the experimental data over all pattern rotation angles. In contrast, the transformation model equipped with the same invariances gives poor agreement to the experimental data. Some implications of these results are considered.

Field Dependence-Independence↗
PubMed2005

Piecewise affine registration of biological images for volume reconstruction.

This manuscript tackles the reconstruction of 3-D volumes via mono-modal registration of series of 2-D biological images (histological sections, autoradiographs, cryosections, etc.). The process of acquiring these images typically induces composite transformations that we model as a number of rigid or affine local transformations embedded in an elastic one. We propose a registration approach closely derived from this model. Given a pair of input images, we first compute a dense similarity field between them with a block matching algorithm. We use as a similarity measure an extension of the classical correlation coefficient that improves the consistency of the field. A hierarchical clustering algorithm then automatically partitions the field into a number of classes from which we extract independent pairs of sub-images. Our clustering algorithm relies on the Earth mover's distribution metric and is additionally guided by robust least-square estimation of the transformations associated with each cluster. Finally, the pairs of sub-images are, independently, affinely registered and a hybrid affine/non-linear interpolation scheme is used to compose the output registered image. We investigate the behavior of our approach on several batches of histological data and discuss its sensitivity to parameters and noise.

Algorithms↗
PubMed2000

Prediction of transdermal flux of prodrugs of 5-fluorouracil, theophylline, and 6-mercaptopurine with a series/parallel model.

Multiple regression analysis of fluxes from suspensions in isopropyl myristate (J(M)) as a function of molecular weights (MW) and solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) were performed on a data set of 41 compounds (n = 41) comprising 39 prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP), in addition to 5-FU and Th, using four models. Two series/parallel models have been developed that allow an aqueous-only path in parallel with a lipid-only path and with a lipid-aqueous series path for the permeation of solutes through skin: log J(M) = log ¿1/[1/(aS(LIPID) 10(PhiMW)) + 1/(bS(AQ)/MW(1/2))] + cS(LIPID)10(PhiMW) + dS(AQ)/MW(1/2)¿ where a, b, c, and d are coefficients for flux through the lipid and aqueous portions of the series path, the lipid-only path, and the aqueous-only path, respectively, and Phi is the dependence of diffusivity in lipid on MW. In the first series/parallel model, S(LIPID) was predicted by S(IPM), and in the second, solvatochromic series/parallel model, S(LIPID) was predicted by S(IPM)(k MW + Omegai) where Omega(i) is the sum of the solvatochromic terms alpha, beta, pi, and R(2), and k is the coefficient for the dependence of partitioning on MW. Using the n = 41 solutions, the coefficients for the aqueous-only path were very small or not different from zero in the two series/parallel models, so only two-path series/parallel models were compared with the solvatochromic and transformed Potts-Guy models where a homogeneous barrier to permeation was assumed. For each model, one compound at a time was omitted from the data set and new parameter estimates were obtained for these 41-1 solutions and used to predict log J(M) for the omitted compound. The average errors of prediction of log J(M) (experimental log J(M) - predicted log J(M)) for the four models were 0.134 for the series/parallel (r(2) = 0.937), 0.127 for the solvatochromic series/parallel (r(2) = 0.967), 0.150 for the solvatochromic (r(2) = 0.950), and 0.134 log units for the transformed Potts-Guy model (r(2) = 0.944). Thus, the solvatochromic series/parallel model provides fit and predictive ability comparable to or slightly superior to previous models that assumed homogeneity of the diffusional barrier to flux in the rate-determining step, provides further theoretical support against the existence of a high capacity aqueous-only path, and provides further insight into the physicochemical properties that should be incorporated into solutes to optimize their flux. Using the solvatochromic series/parallel model, the parameter estimates for the n = 41 solution were used to calculate the flux of each compound through the two paths. For compounds with log partition coefficients (K(IPM:AQ)) of <0.8, permeation was mostly by the lipid-aqueous series path; for compounds with log K(IPM:AQ) >1.0, permeation was mostly by the lipid-only path; the lipid-aqueous series path exhibited the higher carrying capacity. (c) 2000 Wiley-Liss, Inc.

Fluorouracil↗
PubMed1996

Implication of involvement of rat chromosome #2 in spontaneous transformation of the rat-2 cell line.

Using an in vitro model for cell transformation, the relationship between specific chromosomal aberration and phenotypic changes was studied at different passages of Rat-2 cell line. A marker chromosome resulting from a translocation [t(2;7)] was found to be associated with focus formation in soft agar. Conversely, the loss of this marker chromosome was found to be associated with phenotypic reversion. These results suggest an association of this marker chromosome with phenotypic transformation for the Rat-cell line.

Animals↗
PubMed1986

An interlaboratory comparison of transformation in Syrian hamster embryo cells with model and coded chemicals.

Three independent laboratories tested eight "model" and five coded chemicals in the Syrian hamster embryo clonal transformation assay system to establish the intra- and interlaboratory reproducibility of the system and to identify sources of variability. When a common cell pool and the same lot of fetal calf serum were used, the three laboratories obtained consensus on the activity of eight model chemicals: five chemicals (benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, N-methyl-N'-nitro-N-nitrosoguanidine, nitroquinoline-N-oxide, and lead chromate) induced morphological transformation without exogenous metabolic activation and three (N-2-fluorenylacetamide, pyrene, and anthracene) produced no transformation response. Five coded chemicals (2,6-dichloro p-phenylenediamine, 4,4'-oxydianiline, cinnamyl anthranilate, dichlorvos, and reserpine), representative of environmental chemical classes, but not necessarily strong carcinogens, produced more equivocal responses in this interlaboratory study. Thus, while the assay can be used to distinguish between transforming and nontransforming chemicals in some cases, the intrinsic limitations in low transformation frequency and in achieving any dose-response results are major constraints to the use of this system in a routine testing program at the present time. Efforts to increase the transformation frequency or to amplify the expression of the transformed phenotype constitute some of the approaches which should be explored in order to overcome these limitations.

Animals↗
PubMed1995

Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders.

Approximately 40% of transforming growth factor-beta 1 null (knockout) mice generated in our laboratory develop normally to term, but 60% die in utero. The animals appear normal during the first 2 weeks of life but develop a rapid wasting syndrome and die by 3 to 4 weeks of age. All of the knockout mice have a multifocal inflammatory disease in many tissues. The heart and lungs are most severely affected. Increased adhesion of leukocytes to the endothelium of pulmonary veins is the initial lesion seen at day 8 postnatally and is soon followed by perivascular cuffing as well as inflammatory infiltrates in lung parenchyma. The lesions in the heart begin as endocarditis and then progress to myocarditis and pericarditis. Within the lung, chronic inflammatory infiltrates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Increased expression of major histocompatibility complex class I and II proteins is seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymph nodes and spleen is also seen. In the absence of any pathogens, this massive inflammatory disease, together with overexpression of major histocompatibility complex class I and II proteins and overproduction of immunoglobulins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.

Animals↗
PubMed2005

A highly efficient transformation protocol for Micro-Tom, a model cultivar for tomato functional genomics.

We report a highly efficient protocol for the Agrobacterium-mediated genetic transformation of a miniature dwarf tomato (Lycopersicon esculentum), Micro-Tom, a model cultivar for tomato functional genomics. Cotyledon explants of tomato inoculated with Agrobacterium tumefaciens (Rhizobium radiobacter) C58C1Rif(R) harboring the binary vector pIG121Hm generated a mass of chimeric non-transgenic and transgenic adventitious buds. Repeated shoot elongation from the mass of adventitious buds on selection media resulted in the production of multiple transgenic plants that originated from independent transformation events. The transformation efficiency exceeded 40% of the explants. This protocol could become a powerful tool for functional genomics in tomato.

DNA, Bacterial↗
PubMed2004

An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL deamidation in T cell transformation.

A transgenic mouse model of T cell lymphoma was used to investigate the transforming events mediated by an oncogenic tyrosine kinase in pretumorigenic CD4-CD8- (DN) thymocytes. Parental CD45(-/-) and p56(lck-F505Y) mice do not develop tumors, whereas their CD45(-/-)p56(lck-F505Y) progeny develop T lymphomas. Increased but nononcogenic p56lck kinase activity in p56(lck-F505Y) mice DN thymocytes causes cell-cycle progression, survival, and Bcl-XL upregulation. Additional unique oncogenic signals occur in pretumorigenic CD45(-/-)p56(lck-F505Y) thymocytes in which p56lck kinase activity is 2- to 3-fold higher relative to p56(lck-F505Y): inhibition of DNA repair, inhibition of DNA-damage-induced Bcl-XL deamidation, Bax conformational change and mitochondrial translocation, cytochrome c release, and the apoptotic caspase execution cascade. Inhibition of Bcl-XL deamidation may be a critical switch in oncogenic kinase-induced T cell transformation.

Animals↗
PubMed1991

Autoregressive analysis of aortic input impedance: comparison with Fourier transform.

We evaluated the advantages of the autoregressive (AR) model over the conventional Fourier transform in estimating aortic input impedance. In 10 anesthetized open-chest dogs, we digitized aortic pressure and flow at 200 Hz for 51.20 s under random ventricular pacing and subdivided them into five segments. We obtained aortic input impedance over the frequency range of 0.1-20 Hz both by AR model and by Fourier transform for various lengths of data, i.e., from one to four consecutive segments. For any given data length, the impedance spectrum estimated by the AR model was smoother than that obtained by the Fourier transform. To evaluate the accuracy of the estimated impedance, we predicted instantaneous aortic pressure of the fifth segment by convolving corresponding aortic flow with the impulse response of aortic input impedance. The prediction error was less with the AR model than that resulting from Fourier transform as long as the number of the segments was less than four. We conclude that the AR model provides a more accurate estimate of aortic input impedance than does the Fourier transform when data length is limited.

Animals↗
PubMed1986

Analysis of the interlaboratory and intralaboratory reproducibility of the enhancement of simian adenovirus SA7 transformation of Syrian hamster embryo cells by model carcinogenic and noncarcinogenic compounds.

The intralaboratory and interlaboratory reproducibility of a DNA virus (SA7) transformation enhancement assay was investigated using nine carcinogenic and noncarcinogenic compounds representing a variety of chemical classes. By the use of standardized procedures designed to limit assay variables, replicate assay data were collected in two independent laboratories and analyzed for concurrence. The carcinogens, 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, and N-methyl-N'-nitro-N-nitrosoguanidine yielded reproducible dose-dependent cytotoxicity and positive transformation effects (defined as statistically significant [p less than or equal to 0.05] enhancement of virus transformation at two or more consecutive dose levels) in all experiments in both laboratories. The carcinogens lead chromate, diethylnitrosamine, 4-nitroquinoline-N-oxide, and 2-acetylaminofluorene demonstrated enhancement of SA7 transformation at two or more dose levels in 40-50% of the assays. The noncarcinogenic structural analogs anthracene and pyrene consistently did not produce positive assay responses when tested at dose levels up to the limits of solubility. Good interlaboratory concurrence was demonstrated for these model compounds in the Syrian hamster embryo cell-SA7 assay.

2-Acetylaminofluorene↗