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PubMed2001

Mechanisms of radiation-induced neoplastic transformation of human bronchial epithelial cells.

Carcinogenesis is a multistage process with sequences of genetic events that govern the phenotypic expression of a series of transformation steps that lead to the development of metastatic cancer. To better understand the mechanisms involved in human bronchial carcinogenesis induced by alpha particles from radon, we have developed a model of neoplastic transformation based on human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells. Cells exposed to alpha particles become tumorigenic after progressing through a series of sequential stages including altered growth pattern, resistance to serum-induced terminal differentiation, agar-positive growth, tumorigenicity, and metastasis, with each step representing a necessary yet insufficient step toward the later, more malignant phase. Cell fusion studies indicated that the radiation-induced tumorigenic phenotype in BEP2D cells can be completely suppressed by fusion with nontumorigenic BEP2D cells. Several cellular differentiation and growth regulation genes such as DCC (deleted in colorectal cancer), CDKN1A (also known as p21(C1P1)) and the gene that encodes DNA-PK were frequently found to be modulated in tumorigenic BEP2D cells and may be related to the process of carcinogenesis.

Animals↗
PubMed1990

Transformation of rabbit vascular smooth muscle cells by transfection with the early region of SV40 DNA.

Rabbit aortic smooth muscle cells (SMC) and Rb-1 cells, a continuous line of the same origin, were transformed by transfection with pSV3-neo DNA, a plasmid containing the SV40 early region linked to the neoR resistance gene. Transformed clones were selected in G418-containing medium at a rate of 10(-4) per cell. All transformed clones were immortalized and contained in the early passages two free recombined plasmids derived from pSV3-neo. At advanced passages pSV3-neo sequences were found integrated in the cellular genome. Transformed cells had an altered morphology and growth pattern that differed among clones. Some clones reached high density in low-serum medium. All the clones stained positively for the intranuclear T antigen. Some clones had distinct transcripts for the large T and small t antigens, while in others only larger or truncated transcripts were found. Alpha-actin filaments were visualized by immunofluorescent staining in all the clones, but Northern blot analysis revealed a significant reduction in transcripts for this actin. All the transformed clones accumulated, to a variable extent, cholesteryl esters after incubation with beta very low-density lipoprotein. Six of the eight transformed clones maintained a diploid chromosome number, but there was an increase in structural chromosome aberrations, predominantly dicentrics. Transfection of pSV3-neo into rabbit vascular SMCs is an efficient model for obtaining transformed clonal populations. These clones show some phenotypic changes that may be relevant to the study of atherogenesis.

Actins↗
PubMed1986

Hormones and multistage carcinogenesis.

Initiation, promotion and the role of hormones in carcinogenesis are viewed within the framework of a two-stage model for malignant transformation that has been shown by Moolgavkar and Knudson to be consistent with the main body of epidemiological and experimental data on carcinogenesis. It is argued that hormones influence carcinogenesis principally by clonal expansion or contraction of initiated or first-stage cells. The role of hormones in breast cancer and endometrial cancer is briefly discussed.

Adolescent↗
PubMed1996

Creating a true learning organization.

Where possible, an environment should be composed of opportunity and excitement, rather than fear of failure. New models of behavior transform fear of failure without losing the overarching commitment to the patient.

Education, Nursing, Continuing↗
PubMed1997

Morphological transformation caused by a partial sequence of U5 small nuclear RNA.

My colleagues and I have reported that a small nuclear RNA, U5, can cause transformation of and chromosomal aberrations in rat fibroblast 3Y1 cells. In the study described here, I found that a partial U5 sequence, the 3' half of the first stem structure (designated RNA3S), transformed the cells morphologically at a high frequency when expressed with a poly(A) tail (RNA3S+). The transformation critically depended upon a polypurine sequence in RNA3S+. The expressed RNA3S+ was associated with polysomes. The transformed cells did not exhibit significant frequencies of chromosome aberrations when compared with control cells, suggesting that the transformation occurs without significant induction of chromosome damage. Heterogeneous subcolonies emerged in monolayers when the morphologically transformed cells were subcultured and maintained at postconfluence. Cells from subcolonies acquired the ability to form small colonies in soft agar and tumors in nude mice, suggesting that RNA3S+ can drive the cells into the neoplastic stage. RNA3S+ also conferred morphological alterations and a growth advantage and decreased levels of fibronectin protein synthesis in human HeLa cells, confirming the transforming potential of the RNA. RNA3S+ transformation may therefore be a useful model system for studying a transformation process.

Animals↗
PubMed1998

Endogenous expression of transforming growth factor beta1 inhibits growth and tumorigenicity and enhances Fas-mediated apoptosis in a murine high-grade glioma model.

It has been hypothesized that transforming growth factor beta (TGF-beta) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-beta may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-beta in the progression of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that resulted in over- or underproduction of active TGF-beta1. Using these cell lines, we have shown that (a) TGF-beta1 inhibits induction of antitumor cytotoxicity when the tumor cells are given s.c. but not when they are given intracranially; (b) Fas/APO-1 is expressed on SMA 560 cells in vitro and in vivo, SMA 560 cells are susceptible to TGF-beta1- and Fas-induced apoptosis in vitro, and TGF-beta1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-beta1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-beta1 reduces the rate of s.c. SMA 560 tumor growth and also reduces the tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-beta1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-beta1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-beta1 on the growth of the SMA 560 murine high-grade glioma in vivo is growth inhibition. This contrasts with results seen with non-central nervous system malignant tumors in immunocompetent animals, in which TGF-beta1 production provides a major growth advantage.

Animals↗
PubMed1979

Cellular regulation of mammalian sarcoma virus expression: a gene regulation model for oncogenesis.

Investigations aimed at defining cellular functions required for expression of transformation by mammalian sarcoma viruses have led to the isolation of a class of revertants that contain biologically active feline sarcoma virus, yet possess in vitro and in vivo properties of normal cells. The block to expression of the transformed state in these cellular revertants was spontaneously reversible at low frequency. Moreover, infection with certain helper viruses reversed the block at very high efficiency. Helper virus complementation was shown not to be a direct effect of helper virus functions expressed in the initially infected revertant cell. Rather, the helper virus acted indirectly by rescuing sarcoma virus and allowing it to infect and transform another cell within the revertant population. Using biochemical and immunologic techniques, it was possible to demonstrate a specific and very marked reduction in transcriptional and translational products of the sarcoma viral genome in the revertant cells. Findings that the reversal of this block was associated with reacquisition of the transformed phenotype, together with other evidence, suggest that reversion results from cellular transcriptional regulation of the integrated sarcoma virus genome. Reversion in this virus transformation system provides a model for oncogenesis resulting from derepression of cellular genes that possess malignant potential.

Animals↗
PubMed1998

Experimental tumour induction by SV40 transformed cells.

Although SV40 transforms cells from many species, transformed cells from species other than the Syrian hamster are rarely tumorigenic in immunocompetent animals. However, secondary manipulations of SV40-transformed cells can result in increased tumorigenicity. Some early observations on tumour induction by SV40 and transformed cells will be followed by a selected review of evidence suggesting that tumorigenicity of SV40-transformed cells involves serial mutations. An SV40-transformed rat cell model will be described to illustrate the changes in tumorigenic phenotype that can occur during tumour progression. This information will be used to propose that SV40 immortalization of cells (other than hamster cells) is only the first in a series of steps in the pathway toward tumorigenicity and that a complete understanding of the oncogenicity of SV40 will require definition of the secondary genetic events which complement SV40 immortalization to create the fully tumorigenic phenotype.

Animals↗
PubMed2004

Activation of the Smad pathway in glomeruli from a spontaneously diabetic rat model, OLETF rats.

BACKGROUND/AIMS: Transforming growth factor-beta (TGF-beta) mediates the excess accumulation of extracellular matrix in the diabetic kidney. Smad family proteins have been identified as signal transducers for the TGF-beta superfamily. We sought to characterize the role of Smad proteins in mediating TGF-beta responses in the development of diabetic nephropathy. METHODS: We evaluated the time course of TGF-beta1 fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli from spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using immunohistochemistry and Western blot analysis. RESULTS: The glomeruli of diabetic OLETF rats showed not only accelerated activation of Smad3, but also enhanced protein expression of Smad2 and Smad3, which occurred in parallel to the increased expression of TGF-beta and fibronectin compared with glomeruli of control, Long-Evans Tokushima Otsuka (LETO) rats at 30 weeks of age. No differences were found in TGF-beta1 fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli between the two strains at 12 weeks of age when OLETF rats were not diabetic. CONCLUSIONS: The enhancement of Smad protein expression and activation may be involved in the TGF-beta signaling cascade that plays an important role in the development of diabetic nephropathy through progressive expansion of the mesangial matrix.

Animals↗
PubMed1996

Studies on the mechanisms of tumorigenesis induced by polyetherurethanes in rats: leachable and biodegradable oligomers involving the diphenyl carbamate structure acted as an initiator on the transformation of Balb 3T3 cells.

The tumor-initiating activities of the methanol extracts of polyetherurethanes (PEUs) were first detected in the presence of 12-0-tetradecanyl-phorbol-13-acetate (TPA) using Balb 3T3 transformation assay. A model hard segment of PEUs, 4,4'-di(ethoxycarboamide) diphenylmethane (MDU), showed initiating activity, while chemical moieties other than the hard segment were shown to be negative in the test. The transformation assay was carried out using glass dishes half coated with two different PEUs, PU4 and PU8. In the presence of TPA, the transforming activities correlated with the tumorigenic potential in the rat implantation study on the coated surface of PEUs, but not on the uncoated glass area. From these results it was concluded that initiation was caused by the hard-segment moiety such as MDU structure derived not only from the leachable extracts but also from the biodegradable substances by the direct interaction of cells with the coated materials.

3T3 Cells↗
PubMed2006

Alterations in CDK1 expression and nuclear/nucleolar localization following induction in a spontaneous canine mammary cancer model.

Transcription of CDK1 is induced as cells re-enter the cell cycle from quiescence and these early cell cycle re-entry events have been modeled by okadaic acid treatment due to its activity on specific enhancer sequences in the human CDK1 promoter. To investigate heterogeneity of control of this mechanism in the context of neoplastic transformation, a cellular model derived from spontaneous canine mammary cancer (CMT) was developed that includes six cell lines derived from different animals. Notable heterogeneity in response to okadaic acid was observed in expression of CDK1 mRNA and protein. In response to okadaic acid treatment, two CMT cell lines exhibited a CDK1 mRNA induction while one cell line exhibited CDK1 mRNA suppression, and three remained unchanged. Despite this variability, three CMT cell lines arrested in S or G2/M phase and five exhibited marked increases in apoptosis. Moderation of some of these differences were observed at the level of CDK1 protein as three of six CMT cell lines exhibited only moderate enhancement in CDK1 protein levels while three remained essentially unchanged. Some additional differences in distribution of CDK1 protein, favoring enhanced nuclear over cytoplasmic CDK1 localization, were observed in treated cells in the form of concentrated nuclear CDK1 labeled foci. Confocal microscopy revealed the presence of brightly labeled punctate foci containing CDK1 protein within nuclei as well as nucleoli in okadaic acid treated non-mitotic cells suggesting a role for this kinase outside the normal G2/mitotic phase of the cell cycle and suggesting a possible new function within the nucleolus.

Animals↗
PubMed1996

Effects of cardiac output on disposition kinetics of sorbitol: recirculatory modelling.

1. The purpose of this study was to determine the effects of cardiac output on distribution and elimination kinetics of the marker compound sorbitol. 2. The disposition kinetics of sorbitol were investigated after rapid intravenous injection and arterial sampling in nine patients who had undergone cardiac catheterization whereby the cardiac output was measured. 3. A minimal circulatory model consisting of pulmonary and systemic subsystems, both of which were characterized by an inverse Gaussian transit time density function, fitted the data very well. The method involves numerical inverse Laplace transform of the model equations. 4. The mixing clearance introduced as a novel non-compartmental parameter of distribution dynamics was significantly correlated with cardiac output. The steady-state volume of 14 l matched the extracellular volume. The systemic extraction ratio of 23% may reflect the fractional liver blood flow. 5. This pharmacokinetic model can be applied when an independent observation of cardiac output is available. In contrast to the conventional compartmental (or sum of exponential) approach it contains fewer adjustable parameters which can be more readily interpreted in physiological terms.

Aged↗
PubMed2005

The plasticity of p19 ARF null hepatic stellate cells and the dynamics of activation.

In the healthy adult liver, quiescent hepatic stellate cells (HSCs) present the major site for vitamin A storage in cytoplasmic lipid droplets. During liver injury due to viral infection or alcohol intoxication, HSCs get activated and produce high amounts of extracellular matrix components for tissue repair and fibrogenesis. Employing p19 ARF deficiency, we established a non-transformed murine HSC model to investigate their plasticity and the dynamics of HSC activation. Primary HSCs isolated from livers of adult p19 ARF null mice underwent spontaneous activation through long-term passaging without an obvious replicative limit. The immortalized cell line, referred to as M1-4HSC, showed stellate cell characteristics including the expression of desmin, glial fibrillary acidic protein, alpha-smooth muscle actin and pro-collagen I. Treatment of these non-tumorigenic M1-4HSC with pro-fibrogenic TGF-beta1 provoked a morphological transition to a myofibroblastoid cell type which was accompanied by enhanced cellular turnover and impaired migration. In addition, M1-4HSCs expressed constituents of cell adhesion complexes such as p120(ctn) and beta-catenin at cell borders, which dislocalized in the cytoplasm during stimulation to myofibroblasts, pointing to the epitheloid characteristics of HSCs. By virtue of its non-transformed phenotype and unlimited availability of cells, the p19(ARF) deficient model of activated HSCs and corresponding myofibroblasts render this system a highly valuable tool for studying the cellular and molecular basis of hepatic fibrogenesis.

Actins↗
PubMed2000

Testing for neural responses during temporal components of trials with BOLD fMRI.

Some cognitive neuroscientific hypotheses might concern neural responses occurring during particular periods of time in a behavioral trial. Here, these particular periods of time are referred to as temporal components of the trial. A difficulty in using BOLD fMRI to test hypotheses about neural responses during temporal components is that some information is irretrievably lost when neural responses are hemodynamically transformed. As a result, one cannot in general use the fMRI signal to unambiguously specify if there was a neural response during a given temporal component. However, adoption of a linear-time invariant model for the transform from neural signal to fMRI signal and constraint of the space of underlying neural waveforms might allow one to ask such questions. Here, the basic theory relevant to this issue and a corresponding method are discussed. The application of this method to fMRI time series data collected during the performance of a delayed-response trial is provided as an illustrative example.

Brain↗
PubMed1996

The role of the fetal fibroblast and transforming growth factor-beta in a model of human fetal wound repair.

The fetus heals skin wounds without scar formation. Human fetal skin that is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded heals without scar formation, whereas the same fetal skin heals with scar formation when transplanted to a cutaneous location. To characterize the healing process of human fetal skin in these two locations, species-specific human and mouse DNA probes were constructed and used to probe graft wounds under high stringency in situ hybridization conditions. Immunostaining for species-specific fibroblasts, macrophages, and neutrophils was also performed. The cutaneous human fetal graft healed with scar and showed an influx of adult mouse fibroblasts and macrophages. In contrast, subcutaneous human fetal grafts showed exclusively human fetal fibroblasts in the wound environment, an absence of inflammatory cells, and scar-free repair. Thus, the highly organized collagen deposition in scarless human fetal wound repair appears to be intrinsic to the human fetal fibroblast and occurs in the absence of an adult-like inflammatory response. One important cytokine involved in wound repair is transforming growth factor-beta (TGF beta). TGF beta promotes inflammatory cell recruitment and collagen deposition in healing wounds. To determine the role of TGF beta 1 in fetal wound healing, in situ hybridization for TGF beta 1 mRNA expression, immunostaining for TGF beta protein, and species-specific immunohistochemistry for fibroblasts, macrophages, and neutrophils were performed in human adult wounds, fetal wounds, and fetal wounds treated with a TGF beta 1 slow release disk. TGF beta 1 RNA expression and TGF beta protein were found in wounded adult skin. Neither TGF beta 1 mRNA upregulation nor TGF beta protein was detected in human fetal skin after wounding. However, when exogenous TGF beta 1 was added to human fetal skin, induction of TGF beta 1 mRNA expression in human fetal fibroblasts occurred, an adult-like inflammatory response was detected, and the skin healed with scar formation. Thus, non-scarring fetal skin is relatively TGF beta 1 deficient when compared to scarring adult skin. Furthermore, when exogenous TGF beta is added to fetal skin, scarring occurs. TGF beta appears to be an important modulator in scar formation. With a more thorough understanding of scarless repair mechanisms, clinical induction of scarless healing in adults and children soon may be possible.

Adult↗
PubMed1990

Distributed parallel processing in the vertical vestibulo-ocular reflex: learning networks compared to tensor theory.

The vestibulo-ocular reflex (VOR) is capable of producing compensatory eye movements in three dimensions. It utilizes the head rotational velocity signals from the semicircular canals to control the contractions of the extraocular muscles. Since canal and muscle coordinate frames are not orthogonal and differ from one another, a sensorimotor transformation must be produced by the VOR neural network. Tensor theory has been used to construct a linear transformation that can model the three-dimensional behavior of the VOR. But tensor theory does not take the distributed, redundant nature of the VOR neural network into account. It suggests that the neurons subserving the VOR, such as vestibular nucleus neurons, should have specific sensitivity-vectors. Actual data, however, are not in accord. Data from the cat show that the sensitivity-vectors of vestibular nucleus neurons, rather than aligning with any specific vectors, are dispersed widely. As an alternative to tensor theory, we modeled the vertical VOR as a three-layered neural network programmed using the back-propagation learning algorithm. Units in mature networks had divergent sensitivity-vectors which resembled those of actual vestibular nucleus neurons in the cat. This similarity suggests that the VOR sensorimotor transformation may be represented redundantly rather than uniquely. The results demonstrate how vestibular nucleus neurons can encode the VOR sensorimotor transformation in a distributed manner.

Animals↗
PubMed1988

Oncogenic activation of p185neu stimulates tyrosine phosphorylation in vivo.

p185, the product of the neu/erbB2 proto-oncogene, is oncogenically activated by a point mutation that substitutes glutamic acid for valine in the transmembrane domain of the protein. We have found that the transforming form of p185 differs from its normal counterpart in inducing increased tyrosine phosphorylation of other proteins in vivo and in having a much shorter half-life. These results support the model that the transforming p185 resembles a ligand-activated receptor.

Animals↗
PubMed2006

Divergent effects of transformational and passive leadership on employee safety.

The authors concurrently examined the impact of safety-specific transformational leadership and safety-specific passive leadership on safety outcomes. First, the authors demonstrated via confirmatory factor analysis that safety-specific transformational leadership and safety-specific passive leadership are empirically distinct constructs. Second, using hierarchical regression, the authors illustrated, contrary to a stated corollary of transformational leadership theory (B. M. Bass, 1997), that passive leadership contributes incrementally to the prediction of organizationally relevant outcomes, in this case safety-related variables, beyond transformational leadership alone. Third, further analyses via structural equation modeling showed that both transformational and passive leadership have opposite effects on safety climate and safety consciousness, and these variables, in turn, predict safety events and injuries. Implications for research and application are discussed.

Administrative Personnel↗