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At least 1,045 records · Page 58Linked to original sources
PubMed2000

A physiologically based pharmacodynamic analysis of hepatic foci within a medium-term liver bioassay using pentachlorobenzene as a promoter and diethylnitrosamine as an initiator.

A stochastic clonal growth model for describing quantitative changes in size and number of putative preneoplastic lesions was modified to analyze the time-course information of cell proliferation and glutathione S-transferase pi (GST-P) foci within a medium-term bioassay. The study used F344 rats and a single initiating event using diethylnitrosamine (200 mg/kg ip) at Week 0. After a 2-week recovery period, chemical treatment began by gavage administration of pentachlorobenzene (PeCB; 100 micromol/kg/day, 7 days/week) in a corn oil vehicle and continued for 6 weeks. One week after beginning gavage dosing, a two-thirds partial hepatectomy was performed and the animals were serially euthanized at 48, 120, 168, 624, and 840 h postsurgery, which corresponds to 216, 288, 336, 792, and 1008 h following the beginning of PeCB treatment, respectively. For analysis, two types of models were evaluated for describing the time-course changes in GST-P foci. First, a sequential model describing the transformation of normal cells into a homogenous initiated cell population (i.e., one-cell model). Second, a two-cell model that describes a heterogeneous foci population by splitting the initiated cell population into two distinct types. In our study, the one-cell model was unable to adequately represent the time-course data for changes in both size and number of foci. In contrast, the two-cell model, which was parameterized to describe a negative selection mechanism, produced adequate simulations of both the size and number of foci. This model-based analysis suggested that the differences between PeCB-treated and untreated animals were primarily in parameters involving the rates of cell death.

Administration, Oral↗
PubMed2005

Phenomenological and molecular-level Petri net modeling and simulation of long-term potentiation.

Petri net-based modeling methods have been used in many research projects to represent biological systems. Among these, the hybrid functional Petri net (HFPN) was developed especially for biological modeling in order to provide biologists with a more intuitive Petri net-based method. In the literature, HFPNs are used to represent kinetic models at the molecular level. We present two models of long-term potentiation previously represented by differential equations which we have transformed into HFPN models: a phenomenological synapse model and a molecular-level model of the CaMKII regulation pathway. Through simulation, we obtained results similar to those of previous studies using these models. Our results open the way to a new type of modeling for systems biology where HFPNs are used to combine different levels of abstraction within one model. This approach can be useful in fully modeling a system at the molecular level when kinetic data is missing or when a full study of a system at the molecular level it is not within the scope of the research.

Animals↗
PubMed2003

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1.

Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS/FLI-1. To elucidate the mechanisms by which EWS/FLI-1 mediates transformation in mouse models, we have generated a murine Ews/Fli-1 fusion protein. We demonstrate that this protein transforms fibroblast cells in vitro similar to human EWS/FLI-1 as demonstrated by serum and anchorage-independent growth, the formation of tumours in nude mice and elevation of the oncogenic marker c-myc. Furthermore, transformation of these cells was inhibited by a specific repressor, KRAB/FLI-1. The KRAB/FLI-1 repressor also suppressed the tumorigenic phenotype of a human Ewing's sarcoma cell line. These findings suggest that the transformed phenotype of Ewing's sarcoma cells can be reversed by using the sequence-specific FLI-1-DNA-binding domain to target a gene repressor domain. The inhibition of EWS/FLI-1 is the first demonstration of the KRAB domain suppressing the action of an ETS factor. This approach provides potential avenues for the elucidation of the biological mechanisms of EWS/FLI-1 oncogenesis and the development of novel therapeutic strategies.

3T3 Cells↗
PubMed2004

Metastatic cancer DNA phenotype identified in normal tissues surrounding metastasizing prostate carcinomas.

Fourier transform-infrared statistical models have the proven ability to identify subtle structural changes in DNA at various stages of tumor development. Using these models, we show evidence for a metastatic cancer DNA phenotype in histologically normal prostate tissues surrounding metastasizing tumors. Strikingly, the DNA base and backbone structures of the metastatic phenotype are indistinguishable from those of the metastasizing prostate tumors but distinctly different from the structure recently reported for the primary cancer DNA phenotype. These findings suggest that the DNA structure linked to the development of metastasis is preordained in progenitor cells relatively early in multistep tumorigenesis. The substantial structural differences found between the primary and metastatic cancer DNA phenotypes suggest that each evolves through a separate pathway. The metastatic phenotype is potentially an early predictor of metastatic disease. Interventions that inhibit its formation would be expected to also inhibit the development of metastatic tumors.

Aged↗
PubMed2005

Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers.

OBJECTIVE: To evaluate the effects of antiretroviral treatment (ART) for mother-to-child transmission of HIV and infant/maternal characteristics on total lymphocytes (TLC) and lymphocyte subsets in uninfected children of HIV-1-infected mothers. DESIGN: The European Collaborative Study followed 1663 uninfected children from birth until at least 8 years of age using a standard protocol. METHODS: Smoothers (running medians) illustrated patterns of immune markers over age by ART exposure and race. Associations between lymphocyte parameters and maternal/infant characteristics were quantified in linear regression analyses using z-scores obtained after modelling log10-transformed TLC, CD4 and CD8 cell counts using the LMS method. Cox proportional hazard models assessed time to TLC, CD4 and CD8 cell counts below the defined cut-off. Covariates included prematurity, gender, race, drug withdrawal and ART exposure. RESULTS: Overall, black children had lower TLC, CD4 and CD8 cell counts than white children, and an increased risk of TLC, CD4 and CD8 cell counts below the cut-off. ART exposure was associated with TLC levels (but not with TLC below the cut-off for lymphopenia), with reduced CD4 cell counts in the first year of life, and with reduced CD8 cell counts until at least 8 years of age. Duration and intensity of ART exposure was associated with TLC levels. CONCLUSION: The effect of ART exposure in fetal and early life on TLC and CD8 cell counts was prolonged until at least 8 years. These results add to the growing list of adverse effects associated with ART used as prevention of mother-to-child transmission of HIV.

Antiretroviral Therapy, Highly Active↗
PubMed1999

Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors.

Farnesyltransferase inhibitors (FTIs) are in clinical trials, but their mechanism of action is not fully understood. We have shown that FTI treatment rapidly elevates the level of geranylgeranylated RhoB in cells and that this event is sufficient to inhibit cell cycle transit and reverse malignant transformation without affecting normal cells. However, because these observations were made in rodent fibroblast models in which transformation was driven by defined genetic alterations, it remained to be established whether RhoB-GG was relevant to the antineoplastic effects of FTIs in human epithelial tumor cells with diverse genetic backgrounds. In this study, we show that elevated levels of RhoB-GG are sufficient to block the proliferation of FTI-sensitive but not FTI-resistant human carcinoma cells. RhoB-GG induced the cell cycle kinase inhibitor p21(WAF1) in a p53-dependent manner, similar to FTI treatment, but this event was dispensable because RhoB-GG could still inhibit the growth of p53-null cells that lacked p21WAF1 activation. Consistent with actions beyond G1-phase arrest, certain cell lines exhibited accumulation in G2-M phase or an increased apoptotic index in response to RhoB-GG. We concluded that RhoB-GG suppressed human tumor cell proliferation by more than one mechanism and that it promoted apoptosis as well as inhibited cell cycle transit in malignant epithelial cells. These findings suggest how FTIs suppress the growth of human tumor cells that lack Ras mutations.

Alkyl and Aryl Transferases↗
PubMed1980

Ordinal properties of subjective ratios and differences: Comment on Veit.

Because nonmetric analyses of judged ratios and differences in sensory magnitude have yielded similar scales, some investigators have concluded that a single perceived relation underlies both judgment tasks. Issues rasied by this interpretation are considered in this article. Simulated data based on the assumption that subjects evaluate both perceived relations were computed for stimulus values used by Veit to investigate judgments of ratios and differences in grayness. A nonmetric analysis of both sets of simulated data in terms of a difference model yielded a solution such that each set of data was a weak monotonic transformation of the model's values, and the scale values were approximately linear with those obtained by Veit from empirical data. This result leaves open the question of whether one or two perceived relations underly the data. Ordinal properties of ratios and differences for a finite set are discussed together with their relation to systematic biases in psychophysical judgment tasks.

Color Perception↗
PubMedDate not supplied

Effect of transforming growth factor-beta neutralization on survival and bacterial clearance in a murine model of Pseudomonas aeruginosa burn wound infection.

Transforming growth factor-beta (TGF-beta), a cytokine with anti-inflammatory properties, may contribute to postburn immunosuppression. This study was designed to determine whether neutralizing TGF-beta in burned mice could improve resistance to infection. C57BL/6J mice received a 35% TBSA flame burn under isoflurane anesthesia. Four days after injury, mice were treated with TGF-beta antibody or nonspecific IgG. On day 5 after burn injury, mice were inoculated with Pseudomonas aeruginosa at the burn wound site or received intraperitoneal injection with P. aeruginosa. Mice treated with anti-TGF-beta exhibited significantly improved survival compared with mice treated with nonspecific IgG after challenge with P. aeruginosa at the burn wound site or after intraperitoneal injection of P. aeruginosa. In mice with burn wound infections, bacterial counts in burn wounds, blood, and lung were decreased in mice treated with anti-TGF-beta compared with mice treated with control IgG. Bacterial counts in lung and blood after intraperitoneal challenge with P. aeruginosa also were significantly lower in burned mice treated with anti-TGF-beta compared with those treated with nonspecific IgG. Our data suggest that neutralization of TGF-beta at 4 days after burn injury in mice improves local and systemic clearance of P. aeruginosa and enhances survival after P. aeruginosa challenge.

Animals↗
PubMed2001

Mathematical models of tumour invasion mediated by transformation-induced alteration of microenvironmental pH.

The invasive phenotype, characteristic of malignancy, is found in multiple transformed populations with widely varying genotypes. The authors hypothesize that this genetic heterogeneity and instability precludes mechanisms of tumour invasion requiring consistent, coordinated production of one or more proteins or other macromolecules. Instead, this model assumes that the genetically disordered, unstable populations found in tumours must employ a simple mechanism of invasion that arises from one common trait of all transformed cells--reversion to a phenotype more primitive (less differentiated) than the tissue of origin. Specifically, this approach focuses on primitive metabolic pathways with preferential use of glycolysis for energy production. Mathematical models of invasive cancer based on tumour-induced acidification of the microenvironment are presented. Using population ecology and diffusion-reaction models, it is shown that normal tissue adjacent to the tumour edge is subjected to an extracellular pH that is significantly lower than normal. This leads to degradation of the interstitial matrix, loss of intercellular gap junctions and cell necrosis. Tumour cells have an optimal extracellular pH less than that of normal cells and are thus able to thrive in the acidic microenvironment expanding into the space of the dying normal tissue. The model is consistent with extant data on the tumour microenvironment as well as clinical data relating increasing tumour invasiveness with elevated glucose utilization and lactate content. It predicts well-established phenomena in tumorigenesis such as the adenoma-carcinoma sequence and the critical role of angiogenesis in the invasive phenotype. An acellular gap at the tumour host interface is also predicted and can be demonstrated in pathologic specimens. Novel treatment approaches based on this model are discussed.

Extracellular Space↗
PubMed1992

A model system for tumor angiogenesis: involvement of transforming growth factor-alpha in tube formation of human microvascular endothelial cells induced by esophageal cancer cells.

Tumor growth is dependent on angiogenesis, which is thought to be mediated through growth factors, such as transforming growth factor-alpha (TGF-alpha) and -beta (TGF-beta), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), produced by tumor cells. We have developed a model system for tumor angiogenesis in vitro: tube formation of human omentum microvascular endothelial (HOME) cells in type I collagen gels when these cells are co-cultured with tumor cells. Exogenously added TGF-alpha induced tube formation of HOME cells in collagen gel. In contrast, TGF-beta inhibited the TGF-alpha-induced tube formation of endothelial cells. We investigated whether tube formation could be induced in HOME cells in collagen gel when the HOME cells were co-cultured with three esophageal cancer cell lines, TE1, TE2, and TE5. TE1 and TE2 cells expressed both TGF-alpha and TGF-beta mRNA, but the level of TGF-alpha mRNA in TE2 was found to be much lower than in TE1 cells. TE5 did not express either TGF-alpha or TGF-beta. The tube formation of HOME cell was induced when they were co-cultured with TE1 cells, while both TE2 and TE5 cell lines induced tube formation at much lower rates than TE1. TE1-induced tube formation of HOME cells was specifically blocked by co-administration of anti-TGF-alpha-antibody, but not by anti-bFGF-antibody. The present study suggests that, in our model system, esophageal tumor angiogenesis is partly controlled by TGF-alpha, possibly through a paracrine pathway.

Blotting, Northern↗
PubMed2000

Choice of scale for cubic smoothing spline models in medical applications.

The determination of the functional form of the relationship between an outcome variable and one or more continuous covariates is an important aspect of the modelling of medical data. For correct interpretation of the data it is essential that the functional form be specified at least approximately correctly. I show that for given model complexity, logarithmic transformation of a covariate can greatly improve the fit of one of the most useful and convenient non-parametric regression models, the cubic smoothing spline. A mathematical rationale for the idea is given. I propose a diagnostic for deciding initially whether a log transformation is needed. The method is illustrated using several medical data sets. No special software other than that used for fitting the spline models is needed.

Adult↗
PubMed1992

Wound healing in aged animals--effects of locally applied transforming growth factor beta 2 in different model systems.

Local application of a growth factor which could stimulate cell turnover, extracellular matrix synthesis and blood vessel formation in the skin should improve and accelerate wound healing processes which are often impaired in old age. We demonstrate the effects of TGF-beta 2 in promoting wound repair in old animals where normal healing responses are shown to be naturally slower. The potential use of TGF-beta s for the treatment of wound injuries, including chronic non-healing ulcers in the elderly, is discussed.

Allantois↗
PubMed1998

Satiety splits feeding behaviour into bouts

Animal behaviour is frequently displayed in bouts. Bout analysis aims at finding a bout criterion, i.e. that time between events that separates intervals within, from intervals between, bouts. Methods used for quantitative bout analysis are log-supervivorship and log-frequency analysis. Both models assume that the probability of the start of an event (or a bout) is independent of the time since the last event (or bout) and that, therefore, events as well as bouts occur according to Poisson processes, i.e. purely at random. The frequencies of intervals within, as well as between, bouts are then distributed as negative exponentials. These models are also widely applied in feeding behaviour analysis, where bouts can be meals. However, the satiety concept predicts that after terminating a meal, the animal's feeding motivation will be low. The probability of the animal initiating the next meal is expected to increase with time since the last meal and, therefore, meals will not likely be randomly distributed. A negative exponential is then not the most appropriate model to describe the frequency distribution of intervals between meals. Results of an experiment in which feeding behaviour of 16 cows was recorded continuously for 30 days were used to test the suitability of existing bout analysis techniques. It is concluded that these techniques are inadequate for the description of the observed interval distributions. A new model is proposed that takes account of the observed "shortage" of short intervals between meals. In contrast to existing models, that describe log-transformed frequency distributions of interval lengths, the proposed model describes frequency distributions of log-transformed interval lengths. Compared with existing models, this log-normal model is in better agreement with the biological phenomenon of satiety, it gave a better fit to the observed interval distribution and led to a more meaningful meal criterion.Copyright 1998 Academic Press Limited

Journal Article↗
PubMed1998

Neural control of rotational kinematics within realistic vestibuloocular coordinate systems.

Previous theoretical investigations of the three-dimensional (3-D) angular vestibuloocular reflex (VOR) have separately modeled realistic coordinate transformations in the direct velocity path or the nontrivial problems of converting angular velocity into a 3-D orientation command. We investigated the physiological and behavioral implications of combining both approaches. An ideal VOR was simulated using both a plant model with head-fixed eye muscle actions (standard plant) and one with muscular position dependencies that facilitate Listing's law (linear plant). In contrast to saccade generation, stabilization of the eye in space required a 3-D multiplicative (tensor) interaction between the various components of velocity and position in both models: in the indirect path of the standard plant version, but also in the direct path of the linear plant version. We then incorporated realistic nonorthogonal coordinate transformations (with the use of matrices) into both models. Each now malfunctioned, predicting ocular drift/retinal destabilization during and/or after the head movement, depending on the plant version. The problem was traced to the standard multiplication tensor, which was only defined for right-handed, orthonormal coordinates. We derived two solutions to this problem: 1) separating the brain stem coordinate transformation into two (sensory and motor) transformations that reordered and "undid" the nonorthogonalities of canals and muscle transformations, thus ensuring orthogonal brain stem coordinates, or 2) computing the correct tensor components for velocity-orientation multiplication in arbitrary coordinates. Both solutions provided an ideal VOR. A similar problem occurred with partial canal or muscle damage. Altering a single brain stem transformation was insufficient because the resulting coordinate changes rendered the multiplication tensor inappropriate. This was solved by either recomputing the multiplication tensor, or recomputing the appropriate internal sensory or motor matrix to normalize and reorthogonalize the brain stem. In either case, the multiplication tensor had to be correctly matched to its coordinate system. This illustrates that neural coordinate transformations affect not only serial/parallel projections in the brain, but also lateral projections associated with computations within networks/nuclei. Consequently, a simple progression from sensory to motor coordinates may not be optimal. We hypothesize that the VOR uses a dual coordinate transformation (i.e., both sensory and motor) to optimize intermediate brain stem coordinates, and then sets the appropriate internal tensor for these coordinates. We further hypothesize that each of these processes should optimally be capable of specific, experimentally identifiable adjustments for motor learning and recovery from damage.

Brain Stem↗
PubMed1994

Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis.

We examined the contribution of the cytokine transforming growth factor beta 1 (TGF-beta 1) in the inflammatory response and fibrotic reaction in a mouse model of immune-induced lung fibrosis caused by repeated intranasal exposure to heat-killed bacillus Calmette-Guérin (BCG). Mice received 200 micrograms of BCG 3 days/week for 4 weeks, and simultaneous intraperitoneal injections of a monospecific rabbit antiserum against mouse TGF-beta 1 or a preimmune serum (normal rabbit globulin). BCG instillations generated a copious release of antigenic TGF-beta 1 in the lungs at 1, 2, 3 and 4 weeks (up to 15 ng/lungs/mouse). Treatment with anti-TGF-beta 1 antiserum significantly diminished the number of free lung cells recovered by bronchoalveolar lavage (BAL), although the BAL cellular profile was not affected. Moreover, anti-TGF-beta 1 treatment of challenged mice diminished very significantly the total levels of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) in the lungs of animals challenged with BCG. Histological examination and morphometric analysis of Masson's Trichrome-stained sections and measurements of total lung hydroxyproline levels showed a substantial decrease in lung fibrosis and granulomatous response of challenged mice given anti-TGF-beta 1. These data argue for a role for TGF-beta 1 in inducing inflammation and lung fibrosis in response to an immune stimulus.

Animals↗
PubMed2002

Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable.

Recent studies in mouse models deficient in transforming growth factor beta (TGF-beta) signaling have documented TGF-beta as one of the major regulators of immune function. TGF-beta1-null animals demonstrated massive autoimmune inflammation affecting multiple organs, but attempts to transfer the phenotype to normal animals by bone marrow transplantation only resulted in minor inflammatory lesions. We wanted to ask whether a lethal inflammatory phenotype would develop following transplantation of bone marrow deficient for the TGF-beta type II receptor (TbetaRII) gene to normal recipient animals. The TbetaRII-null mutation would generate a cell autonomous phenotype that cannot be reverted by the influence of endocrine or paracrine TGF-beta derived from the recipient animal. We have generated conditional knockout mice in which the TbetaRII gene is disrupted upon induction with interferon-alphabeta or polyI:polyC. We show that induction of TbetaRII gene disruption in these mice by polyI:polyC results in a lethal inflammatory disease. Importantly, bone marrow from conditional knockout mice transferred to normal recipent mice caused a similar lethal inflammation, regardless of whether induction of TGF-beta receptor deficiency occurred in donor animals before, or in recipient animals after transplantation. These results show that TGF-beta signaling deficiency within cells of hematopoietic origin is sufficient to cause a lethal inflammatory disorder in mice. This animal model provides an important tool to further clarify the pathogenic mechanisms in animals deficient for TGF-beta signaling and the importance of TGF-beta to regulate immune functions.

Animals↗
PubMedDate not supplied

[Odds ratio or prevalence ratio? Their use in cross-sectional studies].

BACKGROUND: The most commonly used measures of association in cross-sectional studies are the odds ratio (OR) and the prevalence ratio (PR). Some cross-sectional epidemiologic studies describe their results as OR but use the definition of PR. The main aim of this study was to describe and compare different calculation methods for PR described in literature using two situations (prevalence < 20% and prevalence > 20%). MATERIAL AND METHODS: A literature search was carried out to determine the most commonly used techniques for estimating the PR. The four most frequent methods were: 1) obtaining the OR using non-conditional logistic regression but using the correct definition; 2) using Breslow-Cox regression; 3) using a generalized linear model with logarithmic transformation and binomial family, and 4) using the conversion formula from OR into PR. The models found were replicated for both situations (prevalence less than 20% and greater than 20%) using real data from the 1994 Catalan Health Interview Survey. RESULTS: When prevalence was low, no substantial differences were observed in either the estimators or standard errors obtained using the four procedures. When prevalence was high, differences were found between estimators and confidence intervals although all the measures maintained statistical significance. CONCLUSION: All the methods have advantages and disadvantages. Individual researchers should decide which technique is the most appropriate for their data and should be consistent when using an estimator and interpreting it.

Cross-Sectional Studies↗
PubMed2003

[Screening of natural immunosuppressors by their ability to modify steroid synthesis in hepatocytes].

In the programme for screening sterol synthesis inhibitors with the use of actinomycetes and fungi 702 strains were tested. The effect of alcohol extracts of the mycelium of fungi and actinomycetes at a dilution of 1/10(3) on sterol synthesis by the Hep G2 hepatome cells was determined by incorporation of 3H acetate into sterols and proteins. Lovastatin (200 pg/ml) was used as the control: the sterol synthesis was decreased by 49 +/- 4% without inhibiting the protein synthesis. A number of the cultures produced compounds inhibiting under the experimental conditions the synthesis of sterols by 70 to 80% with simultaneous inhibition of the protein synthesis at least by 60 to 70%. Three compounds from that group produced by streptomycetes were subjected to a more detailed investigation. The compounds were demonstrated to be active antifungal antibiotics (MIC 0.1-1 mcg/ml). In a dose of 0.1-1 mcg/ml they showed high immunosuppressive activity in models of lymphocyte transformation in mice, whereas cyclosporin was active in a dose of 1 mcg/ml. Therefore, the model for screening hypolipidemic compounds could be considered useful for screening promising natural immunosuppressors.

Actinobacteria↗