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Temporal subtraction of thorax CR images using a statistical deformation model.

We propose a voxel-based nonrigid registration algorithm for temporal subtraction of two-dimensional thorax X-ray computed radiography images of the same subject. The deformation field is represented by a B-spline with a limited number of degrees of freedom, that allows global rib alignment to minimize subtraction artifacts within the lung field without obliterating interval changes of clinically relevant soft-tissue abnormalities. The spline parameters are constrained by a statistical deformation model that is learned from a training set of manually aligned image pairs using principal component analysis. Optimization proceeds along the transformation components rather then along the individual spline coefficients, using pattern intensity of the subtraction image within the automatically segmented lung field region as the criterion to be minimized and applying a simulated annealing strategy for global optimization in the presence of multiple local optima. The impact of different transformation models with varying number of deformation modes is evaluated on a training set of 26 images using a leave-one-out strategy and compared to the manual registration result in terms of criterion value and deformation error. Registration quality is assessed on a second set of validation images by a human expert rating each subtraction image on screen. In 85% of the cases, the registration is subjectively rated to be adequate for clinical use.

Algorithms↗

Sources and remediation for mercury contamination in aquatic systems--a literature review.

Sources of mercury contamination in aquatic systems were studied in a comprehensive literature review. The results show that the most important anthropogenic sources of mercury pollution in aquatic systems are: (1) atmospheric deposition, (2) erosion, (3) urban discharges, (4) agricultural materials, (5) mining, and (6) combustion and industrial discharges. Capping and dredging are two possible remedial approaches to mercury contamination in aquatic systems, and natural attenuation is a passive decontamination alternative. Capping seems to be an economical and effective remedial approach to mercury-contaminated aquatic systems. Dredging is an expensive remedial approach. However, for heavily polluted systems, dredging may be more effective. Natural attenuation, involving little or no cost, is a possible and very economical choice for less contaminated sites. Proper risk assessment is necessary to evaluate the effectiveness of remedial and passive decontamination methods as well as their potential adverse environmental effects. Modeling tools have a bright future in the remediation and passive decontamination of mercury contamination in aquatic systems. Existing mercury transport and transformation models were reviewed and compared.

Decontamination↗

Differential stromal regulation of MMP-1 expression in benign and malignant keratinocytes.

There is accumulating evidence of the critical role of tumor stroma in carcinoma development and progression. We have studied the significance of stromal components in regulating matrix metalloproteinases in different stages of human skin carcinogenesis using the HaCaT keratinocyte transformation model. Expression of matrix metalloproteinase 1 and matrix metalloproteinase 13 was analyzed in nontumorigenic HaCaT cells and their c-Ha-ras-transformed tumorigenic clones, benign A-5 and malignant A-5RT3, in response to different matrices and cocultured fibroblasts as well as in transplants in nude mice. When cultured on a collagen type I gel, expression of matrix metalloproteinase 1 mRNA was induced in A-5 and A-5RT3 but less in HaCaT cells, whereas matrix metalloproteinase 13 was only induced in A-5 cells. Induction of matrix metalloproteinase 1 by collagen was also observed in two other malignant HaCaT-ras clones as well as in 2/2 primary squamous cell carcinoma lines. In organotypic cocultures with skin fibroblasts, matrix metalloproteinase 1 mRNA and protein was further strongly upregulated in A-5RT3 cells but less in HaCaT and A-5 cells. Importantly, matrix metalloproteinase 1 was also upregulated in fibroblasts when cocultured with A-5RT3 cells. In vivo, A-5RT3 transplants and subcutaneous tumors expressed matrix metalloproteinase 1 mRNA consistently, preferentially at the tumor front to the mouse stroma. In contrast, matrix metalloproteinase 1 expression was absent in the transplants of A-5 cells and HaCaT cells. Thus, our results demonstrate the specific induction of matrix metalloproteinase 1 in malignant keratinocytes by fibroblasts, supposedly through paracrine-acting factors, and a reciprocally enhanced expression in fibroblasts. This further substantiates the important role of tumor stroma in regulating the expression of matrix metalloproteinase 1, a major matrix-degrading proteinase implicated in tumor invasion.

Cell Line, Transformed↗

Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.

Frizzled related proteins (FRPs) comprise a family of secreted molecules that contain an N-terminal cysteine-rich domain (CRD) highly similar to the CRDs of the frizzled family of membrane-anchored Wnt receptors. FRPs have been shown to interact with Wnt proteins and antagonize Wnt signaling in a Xenopus developmental model. We demonstrated that FRP antagonizes the Wnt-induced increase in uncomplexed beta-catenin in both transient cotransfection and stable transformation models, where Wnt-induced morphological alterations are inhibited as well. We showed further that FRP inhibits Wnt signaling in a paracrine mode using a T-cell factor luciferase reporter to measure Wnt function. Investigation of the mechanisms responsible for FRP inhibition revealed that FRP forms complexes with WNT-1 or WNT-2 through its CRD domain. Transfection analysis with FRPs containing different tags revealed that FRP itself forms complexes and that this ability is conferred by its CRD domain. Finally, we demonstrated by cotransfection that FRP forms complexes with a prototype frizzled. All of these findings are consistent with a model by which FRP inhibits Wnt signaling through interactions with Wnt and/or formation of nonfunctional complexes with the frizzled receptor.

Animals↗

Physiological function of hydrogen metabolism during growth of sulfidogenic bacteria on organic substrates.

Desulfovibrio vulgaris Madison and Thermodesulfobacterium commune contained functionally distinct hydrogenase activities, one which exchanged 3H2 into 3H2O and was inhibited by carbon monoxide and a second activity which produced H2 in the presence of CO. Cell suspensions of D. vulgaris used either lactate, pyruvate, or CO as the electron donor for H2 production in the absence of sulfate. Both sulfidogenic species produced and consumed hydrogen as a trace gas during growth on lactate or pyruvate as electron donors and on thiosulfate or sulfate as electron acceptors. Higher initial levels of hydrogen were detected during growth on lactate-sulfate than on pyruvate-sulfate. D. vulgaris but not T. commune also produced and then consumed CO during growth on organic electron donors and sulfate or thiosulfate. High partial pressures of exogenous H2 inhibited growth and substrate consumption when D. vulgaris was cultured on pyruvate alone but not when it was metabolizing pyruvate plus sulfate or lactate plus sulfate. The data are discussed in relation to supporting two different models for the physiological function of H2 metabolism during growth of sulfidogenic bacteria on organic electron donors plus sulfate. A trace H2 transformation model is proposed for control of redox processes during growth on either pyruvate or lactate plus sulfate, and an obligate H2 cycling model is proposed for chemiosmotic energy coupling during growth on CO plus sulfate.

Bacteria↗

Progressive changes in Met-dependent signaling in a human ovarian surface epithelial model of malignant transformation.

We used an experimental in vitro model of human ovarian surface epithelium (OSE), the tissue of origin of >90% of ovarian cancers, to more precisely define the contribution of hepatocyte growth factor (HGF) to various OSE phenotypes at different stages of neoplastic progression. Neoplastic transformation of OSE in cultures was achieved by multiple genetic manipulations, resulting in the nontumorigenic line IOSE-29, the tumorigenic IOSE-Ov29, and the tumor-derived, more highly malignant IOSE-Ov29/T4. We demonstrate here that, compared to IOSE-29, IOSE-Ov29 and IOSE-Ov29/T4 exhibited higher levels of the HGF receptor Met and an increasing duration of ERK1/2 activation with malignant progression, in conjunction with other neoplastic properties. HGF activated Met signaling in all lines but elicited different responses: HGF induced cell dispersion (scattering) and collagen gel invasion in IOSE-Ov29 and IOSE-Ov29/T4 but did not alter the growth pattern of IOSE-29. Inhibition with PD98059 and LY294002 independently prevented HGF-induced invasive growth. Furthermore, our results show that HGF-induced invasion can be mediated through a rapamycin-sensitive p70 S6K cascade, which demonstrates that p70S6K can regulate cell motility in addition to its well-established role in protein synthesis. Taken together, our data correlate specific responses to HGF-mediated signaling with specific signaling pathways and with progressive neoplastic changes.

Carcinoma↗

Effect of salt intake on progression of chronic kidney disease.

PURPOSE OF REVIEW: The attempt of this review is to bring into focus the potential role of dietary salt intake in progression of chronic kidney disease. RECENT FINDINGS: Ongoing work has elucidated a role for dietary salt intake in modulating intrarenal production of transforming growth factor-beta1. The mechanism is independent of angiotensin II and systemic blood pressure and involves activation of vascular endothelium by dietary salt intake with release of this growth factor. In this model, transforming growth factor-beta1 serves an autacoid function by stimulating nitric oxide production by the endothelium. In turn, endothelium-derived nitric oxide modulates production of this growth factor. The model further predicts that individuals who have lost the requisite endothelial cell flexibility to adapt to this environmental stress (a high salt diet) are potentially at increased risk of developing end-organ damage from excess salt intake. Animal and human studies are presented to support this working hypothesis. SUMMARY: Overproduction of transforming growth factor-beta1 permits excess biological activity of this important fibrogenic growth factor with subsequent development or acceleration of vascular and kidney damage. In patients with diseases whose pathogenesis is related to excess production of transforming growth factor-beta1, such as chronic allograft nephropathy and diabetic nephropathy, increased salt intake may hasten loss of function, particularly if nitric oxide production does not increase. The role that endothelial cell plasticity plays in altering vascular tone and renal function, especially in response to changes in dietary salt intake, should be examined further in chronic kidney disease.

Animals↗

Theoretical model of reticulocyte to erythrocyte shape transformation.

A theoretical model describing the kinetics of reticulocyte shape transformation was developed. The model considers the evolution of a simple cellular shape under transmembrane pressure difference, and proposes a four-parameter axisymmetric approximation of the cell surface. The mathematical analysis considers plasma membrane tension in the plane of bilayer leaflets, membrane spontaneous curvature and transmembrane transport of water. Cytoskeleton dilatational and shear rigidity, and the energetic barrier preventing the decrease of cell volume below a certain minimum are also incorporated. The set of adequate physical assumptions allowed for formulation of the equation for free energy of the investigated system. Computer simulations of cell shape changes, down to the state of free energy minimum, together with estimation of the time needed for the resulting transport of water, revealed a complex, three-phase picture of temporal alterations in cellular geometry with a wide spectrum of final results, and led to propose a standard model of reticulocyte-erythrocyte transformation. According to the model, both cell volume and surface undergo changes, and the work of the pressure, initially accumulated in the cytoskeleton, is consumed for local bending of the cell membrane. Further simulations with modified initial shape or parameters of the standard model show the trajectories of system evolution and help in better understanding the conditions for the erythro-, sphero-, ovalo-, stomato-, and leptoidal metamorphosis of maturing red blood cells. The stability of the final biconcave shape was also verified. Spherogenic modifications were discussed in the context of spherocytosis. Future development of the model was proposed.

Cell Differentiation↗

Disruption of the TGF-beta pathway and modeling human cancer in mice.

There is considerable complexity underlying the mechanisms through which the TGF-beta signaling pathway regulates the initiation and progression of cancer. Analysis of this pathway and the role that it plays in human malignancy continues to elucidate novel mechanisms through which various genetic and epigenetic events subvert the controls that TGF-beta exerts over cell growth, differentiation, and malignant transformation. Modeling these events in the mouse represents an important goal, as the relevant preclinical models are essential not only for improving our understanding of the role of the TGF-beta pathway in the molecular pathogenesis of cancer, but also as tools for evaluating the impact of novel therapeutics on TGF-beta signaling and the role they may play in the prevention and treatment of malignancies. Here, we consider highlights from a number of in vivo murine model systems and relate a few of the significant observations to what we know about TGF-beta signaling in human cancer.

Animals↗

Intracisternal A-particle (IAP)-mediated leukemogenesis: levels and stability of IAP mRNA in FDC-P1 cells exposed to the conditions of an irradiated environment.

Following injection into sublethally irradiated DBA/2 or BALB/c mice, factor-dependent FDC-P1 cells undergo leukemic transformation due to oncogene activation by insertion of intracisternal A-particle (IAP) genetic elements. Similar events are observed in vitro during coculture of FDC-P1 cells with irradiated bone marrow stroma cells. To elucidate the mechanism of IAP transposition, we studied the level of IAP expression under the growth conditions preceding cell transformation. In vitro experiments showed that the type of growth factor, FDC-P1 cell density, costimulation with steroid hormones or abrupt growth factor withdrawal had no effect on IAP mRNA levels (major transcripts of 7.4, 4.0 and 1.9 kb). By contrast, stimulation with suboptimal concentrations of GM-CSF or IL-3 induced a mean 2. 5-fold increase in the intensity of the 7.4 kb band, and induction of macrophage differentiation with retinoic acid resulted in an increased stability of the 4.0 kb band. Although suboptimal growth stimulation and incipient macrophage differentiation have previously been shown to occur in the process of FDC-P1 cell transformation, an increase in IAP expression could not convincingly be demonstrated in FDC-P1 cell populations isolated from irradiated BALB/c mice or stroma cell cocultures. Further experiments are required to define the role of suboptimal growth stimulation and/or macrophage differentiation in this transformation model.

Animals↗

A UML profile for framework modeling.

The current standard Unified Modeling Language(UML) could not model framework flexibility and extendability adequately due to lack of appropriate constructs to distinguish framework hot-spots from kernel elements. A new UML profile that may customize UML for framework modeling was presented using the extension mechanisms of UML, providing a group of UML extensions to meet the needs of framework modeling. In this profile, the extended class diagrams and sequence diagrams were defined to straightforwardly identify the hot-spots and describe their instantiation restrictions. A transformation model based on design patterns was also put forward, such that the profile based framework design diagrams could be automatically mapped to the corresponding implementation diagrams. It was proved that the presented profile makes framework modeling more straightforwardly and therefore easier to understand and instantiate.

Algorithms↗

Development of small-size tubular-flow continuous reactors for the analysis of operational stability of enzymes in low-water systems.

A very small-scale continuous flow reactor has been designed for use with enzymes in organic media, particularly for operational stability studies. It is constructed from fairly inexpensive components, and typically uses 5 mg of catalyst and flow rates of 1 to 5 mL/h, so only small quantities of feedstock need to be handled. The design allows control of the thermodynamic water activity of the feed, and works with temperatures up to at least 80 degrees C. The reactor has been operated with both nonpolar (octane) and polar (4-methyl-pentan-2-one) solvents, and with the more viscous solvent-free reactant mixture. It has been applied to studies of the operational stability of lipases from Chromobacterium viscosum (lyophilized powder or polypropylene-adsorbed) and Rhizomucor miehei (Lipozyme) in different experimental conditions. Transesterification of geraniol and ethylcaproate has been adopted as a model transformation.

Acyclic Monoterpenes↗

Differential expression of the splicing regulatory factor genes during two-step chemical transformation in a BALB/3T3-derived cell line, MT-5.

Although the alternative splicing of various genes is a common event in human tumors, the mechanisms behind it have not been characterized. We hypothesized that the expression of splicing regulatory factors would be changed during cellular transformation. Gene expression of three splicing regulatory factors, alternative splicing factor/splicing factor 2 (ASF/SF2), heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) and the 65 kDa subunit of U2 small nuclear ribonucleoprotein particles auxiliary factor (U2AF(65)), were examined by northern blotting in a two-step chemical transformation model. This in vitro model is composed of BALB/3T3 cells and a BALB/3T3-derived N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-initiated cell line (MT-5). MT-5 cells can be transformed on exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA). ASF/SF2 mRNA levels were decreased 2-fold in both MNNG-initiated cells and TPA-induced transformed cells compared with the normal parental cells, whereas hnRNP A2 mRNA expression did not significantly change between these three types of cells. U2AF(65) mRNA levels were markedly increased ( approximately 4.7-fold) associated with progression of cellular transformation. Moreover, RT-PCR analysis showed that distinct forms of ASF/SF2 mRNA were present in the MNNG-initiated cells and TPA-induced transformed cells but not in the parental cells. These findings indicate that ASF/SF2 or U2AF(65) gene expression is altered during in vitro two-step chemical transformation. The data suggest that the differential expression of splicing regulatory factors is one cause of aberrant expression of alternatively spliced mRNAs encoded by various genes in tumor cells.

3T3 Cells↗

Transforming growth factor-beta administration modifies cyclosporine A-induced bone loss.

Cyclosporine A (CsA), a potent immunosuppressant used in transplantation, induces increased formation with excess resorption in the rat with resultant osteopenia. These findings are confirmed in the human model. Transforming growth factor-beta (TGF-beta) is reported to be involved in the coupling of bone formation with resorption and in vivo and in vitro stimulates osteoblasts, and in vitro inhibits osteoclasts. CsA stimulates secretion of TGF-beta1 in humans, which, while improving immunosuppression, may also contribute to renal toxicity. This study was performed determine whether exogenously administered TGF-beta would modify the bone effects of CsA. Male Sprague-Dawley rats, 6 months of age, were randomized to receive: TGF-beta and CsA vehicle (group A); TGF-beta 5 microg/kg three times per week and CsA vehicle (group B); TGF-beta vehicle and CsA 10 mg/kg (group C); or TGF-beta 5 microg/kg three times per week and CsA 10 mg/kg (group D). These were compared with control over 28 days. CsA, but not TGF-beta, increased serum 1,25(OH)(2)D levels throughout the study. CsA increased osteocalcin (BGP), but TGF-beta negated this effect. Histomorphometry confirmed the known effects of CsA, whereas TGF-beta alone had no effect. However, in combination, TGF-beta blocked CsA's effect and increased osteoblast recruitment and activity, as reflected by increased percent mineralizing surface, percent osteoid perimeter, bone formation rate (bone volume referent), and activation frequency. Thus, it appears as if TGF-beta administration may have potential in modulating the deleterious bone effects of CsA.

Animals↗

Life-course theory of readmission of substance abusers among homeless veterans.

This study examined outcomes of 310 female and 315 male homeless veterans who were admitted to a Department of Veterans Affairs inpatient program for dual diagnoses of a substance use disorder and another mental illness. Participants were surveyed to determine gender differences for types of transforming experiences and for types of abuse as predictors of readmission within two years. Predictors were selected primarily from life-course theory and were analyzed with Cox's proportional hazards model. Transforming experiences, such as enhanced ego identity and spiritual well-being, attenuated the effects of childhood abuses, combat exposure, and depression for both genders. Transforming experiences also reduced the risk of readmission that was associated with aggression for men and abuse that occurred either in the military or recently for women.

Adult↗

Comparison of fast Fourier transformation and autoregressive modelling as a diagnostic tool in analysis of lower extremity venous signals.

In this study, we have compared the efficacy of autoregressive modelling (ARM) and fast Fourier transformation (FFT) of Doppler signals from lower extremity veins of healthy volunteers in various physiologic situations. Compared to FFT, ARM produced smooth spectra and less spectral broadening both in sonograms and power spectra. However, faulty positioning of the peaks along the time axis in FFT-derived power spectral density curves show that FFT is not a suitable method if these graphs are to be used as a diagnostic tool. Analysis of ARM-based venous sonograms and power spectral density graphs revealed that FFT should not be used in signals with high power spectral density levels and low-frequency bandwidth within limited segments of time.

Adult↗

A threshold causal model for clinical trials with departures from intended treatment.

Randomized clinical trials often are planned to study a specific intervention. However, the collection of data on treatment actually received often reveals variable levels of treatment exposure (or 'dose') across subjects, due to non-compliance or other reasons. This paper presents a new method, using such 'dose' data as well as control group responses, to assess a causal dose-response relationship. The specific model utilizes a threshold function and incorporates a random effect term to allow for heterogeneous treatment responses among subjects. Further modelling of the random effects allows for reduction of error variance and control for potential confounders. The threshold dose is estimated using a residual variance criterion based on a transformed model. Estimates of standard errors and confidence intervals are obtained using a bootstrap procedure. The method is applied to data from an AIDS clinical trial. A simulation study demonstrates the adequacy of the threshold estimates for particular sample sizes and error variances. The limitations of this essentially exploratory method, as well as some possible extensions, are discussed. Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government Work and is in the public domain in the United States.

CD4 Lymphocyte Count↗

The storage of energy as a cause of malignant transformation: a 7-phase model of carcinogenesis.

Although many theories for the development of cancer exist, a new hypothesis for carcinogenesis is suggested and a new 7-phase model of malignant transformation described. Both the hypothesis and the model are based on the principle of a critical point in local energy (entropy?) storage, at a certain level of structural organisation within the cells. This principle has been previously formulated by the author from the rules of non-equilibrium thermodynamics. The model introduces a new terminology and explores the concepts of both high work value of energy and bifurcation. The ability (A) of cells is suggested to be the most important cellular feature in respect to cell survival. This ability implies that the cells follow the requirement Kir > 1, even in dangerous situations and under harmful environmental influence. But, when the cells have lost their ability (A) and all levels of the cell defence machine have been exhausted, then the local energy storage may provoke a cascade of harmful events within the cells. The S-stage is the most unstable state of the cell cycle. If such harmful events take place during DNA synthesis within the 'premalignant' cell, in the phase 'promotion' at the 4th bifurcation, they lead ultimately to carcinogenesis (i.e. malignant transformation). The 7-phase model of carcinogenesis is consistent and offers many advantages in comparison to the previous hypotheses. This model could help the design of experiments, development of new drugs and optimization of medical treatment. The new hypothesis could contribute to a better understanding of the processes of carcinogenesis and the uncontrolled division, growth and lability of tumour cells.

Animals↗