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PubMed2006

Bub1 up-regulation and hyperphosphorylation promote malignant transformation in SV40 tag-induced transgenic mouse models.

Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by > or = 10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA-mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America.

Animals↗
PubMed1995

Survival and histopathologic characteristics of human melanocytic nevi transplanted to athymic (nude) mice.

Melanocytic nevi (n = 406) covering a range of sizes and gross morphologic features were excised from human donors, sampled for histologic diagnosis, and transplanted to athymic (nude) mice. Ninety percent of these xenografts survived transplantation, of which a subset was irradiated daily with ultraviolet light to promote neoplastic transformation. Over 16 weeks of observation, nearly all grafts histologically showed focal inflammatory cell infiltration and fibrosis, progressing in approximately 30% of grafts to complete regression at final observation. During the inflammatory phase, the nevi often had junctional intraepidermal melanocytic hyperplasia in a lentiginous pattern, with cytologic hypertrophy, dendritic morphology, and hypermelaninization. These changes were evident in approximately 20-30% of nevi where they were absent before transplantation, suggesting that host factors, such as those related to the immune response, had stimulated growth. Graft survival was independent of nevus size and initial histologic diagnosis. No melanomas developed in any of the grafts, either spontaneously or with ultraviolet irradiation. These results indicate that successful transplantation can be achieved in a high proportion of human nevus xenografts and that the majority survive for a period of time that would be sufficient for experimental studies. The host response, however, has effects on intraepidermal melanocytic growth that lead to progressive fibrous replacement of the nevus, introducing significant artifacts that compromise the model. Furthermore, malignant transformation of engrafted melanocytes seems to be a rare event, which would limit studies of neoplastic progression in the transplanted melanocytes. Nonetheless, the intraepidermal melanocytic pattern described here evidently constitutes one pattern of melanocyte growth that could be exploited experimentally for studies of growth and differentiation control in melanocytes.

Animals↗
PubMedDate not supplied

The Smads: transcriptional regulation and mouse models.

The field of transforming growth factor-beta (TGF-beta) signaling sees periodic discoveries that revolutionize our thinking, redirect our experiments, and peak our excitement. One of the first such discoveries was less than a decade ago: the molecular cloning of the type I and type II TGF-beta receptors. This breakthrough defined a novel family of serine/threonine kinase receptors, which led to the description of an ever-expanding superfamily. The discovery of how these receptors are grouped on the cell surface, bind TGF-beta and are activated by specific phosphorylation events further defined the uniqueness of this system in comparison to other families of growth factor receptors. Now, once again, the TGF-beta field has been revolutionized. This time, the discovery is the Smad family of proteins. Although one can hardly imagine TGF-beta without the Smads, the cloning of the Smads and their implication in TGF-beta signaling was only four years ago. Since that time, great advances have been made in our understanding of the Smads as transcription factors, which are activated by receptor mediated phosphorylation. In addition, animal models for a loss of Smad function have provided insight into the role of specific Smads in a variety of physiologic systems. The Smad field has been growing exponentially. A comprehensive review of all aspects of the Smads, therefore, would be beyond the scope of a single review. Instead, this review highlights some of the general aspects of Smad function, and then focuses on the role of specific Smad family members in transcriptional regulation, animal physiology, and disease processes.

Animals↗
PubMed1996

Localization and treatment of transformed tissues using the photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a.

BACKGROUND AND OBJECTIVE: Photofrin is the photosensitizer currently used in most clinical trials examining the efficacy of photodynamic therapy (PDT) for the treatment and/or palliation of neoplasia. Although this drug has been shown to be efficacious in many of these trials, it possesses less than ideal qualities for use in a systemically administered photosensitizer. A new photosensitizer, 2-[l-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), was developed for PDT. HPPH possesses more rapid clearance from skin and greater cytotoxicity per drug dose than Photofrin. The aims of this study were to: (1) examine the uptake and retention of HPPH in tissues undergoing malignant transformation using laser-induced fluorescence, and (2) evaluate the efficacy of HPPH and 665 nm light in treating carcinogen-induced tumors of the hamster buccal cheek pouch. STUDY DESIGN/MATERIALS AND METHODS: The model of tissue transformation was the carcinogen (9,10-dimethyl-1, 2-benzanthracene)-induced premalignant and malignant lesions of the hamster buccal cheek pouch. Following induction of the specific transformation stages, hamsters were injected intraperitoneally with 0.5 mg/kg HPPH. Subsequently, the buccal mucosa was examined for fluorescence at various times up to 72 hours after photosensitizer injection. RESULTS: Uptake studies of HPPH showed highest fluorescence levels in tissues 48 hours after HPPH injection. Fluorescence levels of tissues increased significantly as follows. Normal < dysplasia < papillomas < squamous cell carcinomas. Carcinogen-induced tumors in 14 hamsters were treated with surface illuminations of red light (665 nm) via fiber optics coupled to an argon-ion pumped dye laser 48 hours after intraperitoneal injection with either 0.5 or 1.0 mg/kg HPPH. Complete necrosis of tumor tissues 7 days following PDT was observed in 57% (4/7) with 0.5 mg/kg and 86% (6/7) with 1.0 mg/kg HPPH.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Role of lipid transfer particle in transformation of lipophorin in insect oocytes.

Oocyte development in Manduca sexta involves the deposition of large amounts of lipoprotein-derived lipid. One source of this lipid is hemolymph high-density lipophorin-adult (HDLp-A) which, upon entry into the oocyte, is transformed into a lipid and apolipophorin III deficient product particle, egg very-high- density lipophorin (VHDLp-E; density = 1.24 g/ml; Kawooya et al. (1988) J. Biol. Chem. 263, 8740-8747). An in vitro model of this transformation has been established using human low-density lipoprotein (LDL) as acceptor of HDLp-A associated lipid in a reaction catalyzed by isolated M. sexta hemolymph lipid transfer particle (LTP). Facilitated vectorial net transfer of lipid from HDLp-A to LDL resulted in formation of a very-high-density lipophorin (VHDLp) product with a density and apolipoprotein content similar to that of VHDLp-E. Lipid was found to comprise 25% of the VHDLp particle mass, whereas over 50% of HDLp-A mass is lipid. Based on these observations it was hypothesized that a lipid transfer factor may be present in M. sexta oocytes and function in the transformation of HDLp-A to VHDLp-E in vivo. Transfer activity was present in the buffer soluble fraction of oocyte homogenates and purification of the active material revealed a catalyst with electrophoretic and immunological properties identical to hemolymph LTP. Incubation of 125I-HDLp-A with an M. sexta oocyte homogenate resulted in transformation of the radiolabeled lipoprotein to a density corresponding to that of VHDLp-E. When the incubation media was preincubated with anti-LTP IgG this conversion was inhibited to a large extent. Inhibition was relieved, however, by addition of exogenous LTP. The results provide the first demonstration of M. sexta LTP in a tissue other than hemolymph and support the concept that LTP-catalyzed lipid transfer plays an integral role in the conversion of HDLp-A to VHDLp-E in vivo.

Animals↗
PubMed2006

Anthropometry profiles of elite rugby players: quantifying changes in lean mass.

OBJECTIVE: To demonstrate the utility of a practical measure of lean mass for monitoring changes in the body composition of athletes. METHODS: Between 1999 and 2003 body mass and sum of seven skinfolds were recorded for 40 forwards and 32 backs from one Super 12 rugby union franchise. Players were assessed on 13 (7) occasions (mean (SD)) over 1.9 (1.3) years. Mixed modelling of log transformed variables provided a lean mass index (LMI) of the form mass/skinfolds(x), for monitoring changes in mass controlled for changes in skinfold thickness. Mean effects of phase of season and time in programme were modelled as percentage changes. Effects were standardised for interpretation of magnitudes. RESULTS: The exponent x was 0.13 for forwards and 0.14 for backs (90% confidence limits +/-0.03). The forwards had a small decrease in skinfolds (5.3%, 90% confidence limits +/-2.2%) between preseason and competition phases, and a small increase (7.8%, 90% confidence limits +/-3.1%) during the club season. A small decrease in LMI (approximately 1.5%) occurred after one year in the programme for forwards and backs, whereas increases in skinfolds for forwards became substantial (4.3%, 90% confidence limits +/-2.2%) after three years. Individual variation in body composition was small within a season (within subject SD: body mass, 1.6%; skinfolds, 6.8%; LMI, 1.1%) and somewhat greater for body mass (2.1%) and LMI (1.7%) between seasons. CONCLUSIONS: Despite a lack of substantial mean changes, there was substantial individual variation in lean mass within and between seasons. An index of lean mass based on body mass and skinfolds is a potentially useful tool for assessing body composition of athletes.

Adult↗
PubMed1995

A model of scarless human fetal wound repair is deficient in transforming growth factor beta.

Human fetal skin heals via scarless regeneration, whereas adult skin heals with scar. Scarless repair may reflect a distinct cytokine milieu. We studied the role of the cytokine transforming growth factor beta (TGF beta) using an established model of scarless human fetal skin repair in which human fetal skin is transplanted into a subcutaneous pocket on the flank of an adult nude mouse. In this model, wounded 16-week-gestation human fetal skin heals without scar, whereas wounded adult skin heals with scar. Seven days after transplantation, incisional wounds were made in the skin grafts. In the first phase of the study, wounds were harvested from 1 hour to 4 weeks postwounding, and immunohistochemistry was performed for TGF beta (isoform nonspecific), TGF beta 1, and TGF beta 2. Scarfree wounds in the fetal skin grafts did not show TGF beta staining. In contrast, wounds in adult grafts that heal with scar demonstrated isoform nonspecific TGF beta staining from 6 hours through 21 days, TGF beta 1 from 6 hours through 21 days, and TGF beta 2 from 12 hours through 7 days. In the second phase of the study, a slow-release disk with 0.01, 0.1, 1.0, or 10 micrograms of TGF beta 1 was placed beneath the fetal skin graft at the time of wounding. Fourteen days postwounding, there was marked scarring in the fetal grafts treated with TGF beta 1, and the size of the scar was proportional to the amount of TGF beta 1 applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Altered expression of wild-type p53 tumor suppressor gene during murine epithelial cell transformation.

An epidermal cell model in which initiated, benign tumor-producing and carcinoma stages were derived from a cloned parental cell strain was used to examine p53 expression during multistage epithelial carcinogenesis. Increased steady-state levels of p53 RNA were detected in squamous cell carcinomas compared to papilloma and normal epidermal cells. Nontumorigenic initiated cell precursors of the carcinomas exhibited normal p53 expression, localizing altered p53 regulation to the malignant conversion stage. Immunoprecipitation and Western immunoblot analyses demonstrated elevated levels of p53 protein in the moderately differentiated carcinoma compared to normal cells, and negligible levels of p53 in the poorly differentiated carcinoma cells. Sequence analysis of p53 complementary DNA from normal and carcinoma cells revealed no mutations in the coding or 5'- and 3'-untranslated regions, suggesting a novel mechanism of p53 inactivation.

Animals↗
PubMed2006

Modeling mercury in power plant plumes.

Measurements of speciated mercury (Hg) downwind of coal-fired power plants suggest that the Hg(II)/(Hg0 + HgII) ratio (where HgII is divalent gaseous Hg and Hg0 is elemental Hg) decreases significantly between the point of emission and the downwind ground-level measurement site, but that the SO2/(Hg0 + HgII) ratio is conserved. We simulated nine power plant plume events with the Reactive & Optics Model of Emissions (ROME), a reactive plume model that includes a comprehensive treatment of plume dispersion, transformation, and deposition. The model simulations fail to reproduce such a depletion in HgII. A sensitivity study of the impact of the HgII dry deposition velocity shows that a difference in dry deposition alone cannot explain the disparity. Similarly, a sensitivity study of the impact of cloud chemistry on results shows that the effect of clouds on Hg chemistry has only minimal impact. Possible explanations include HgII reduction to Hg0 in the plume, rapid reduction of HgII to Hg0 on ground surfaces, and/or an overestimation of the HgII fraction in the power plant emissions. We propose that a chemical reaction not included in current models of atmospheric mercury reduces HgII to Hg0 in coal-fired power plant plumes. The incorporation of two possible reduction pathways for HgII (pseudo-first-order decay and reaction with SO2) shows better agreement between the model simulations and the ambient measurements. These potential HgII to Hg0 reactions need to be studied in the laboratory to investigate this hypothesis. Because the speciation of Hg has a significant effect on Hg deposition, models of the fate and transport of atmospheric Hg may need to be modified to account for the reduction of HgII in coal-fired power plant plumes if such a reaction is confirmed in further experimental investigations.

Air Pollutants↗
PubMed1986

A finite-element model of blood flow in arteries including taper, branches, and obstructions.

A nonlinear mathematical model of arterial blood flow, which can account for tapering, branching, and the presence of stenosed segments, is presented. With the finite-element method, the model equations are transformed into a system of algebraic equations that can be solved on a high-speed digital computer to yield values of pressure and volume rate of flow as functions of time and arterial position. A model of the human femoral artery is used to compare the effects of linear and nonlinear modeling. During periods of rapid alternations in pressure or flow, the nonlinear model shows significantly different results than the linear model. The effect of a stenosis on pressure and flow waveforms is also simulated, and the results indicate that these waveforms are significantly altered by moderate and severe stenoses.

Arteries↗
PubMed2005

Design of controller using variable transformations for a nonlinear process with dead time.

In this work, a globally linearized controller (GLC) for a first-order nonlinear system with dead time is proposed. This is similar to the GLC proposed by Ogunnalke [Ind. Eng. Chem. Process. Des. Dev. 25, 241-248 (1986)] for nonlinear systems without dead time. Two methods are proposed. One is based on the Smith prediction from the model in the transformed domain and the other is based on Newton's extrapolation method. The simulation study is made on the conical tank level process and the results are compared with those obtained using a conventional PI controller and the Smith PI controller based on the transfer function model about the operating point 39%. Finally, experimental results on the laboratory conical tank level process are also given.

Journal Article↗
PubMed1978

Evidence for the progressive nature of neoplastic transformation in vitro.

The temporal acquisition of in vitro phenotypes associated with neoplasia were examined after exposure of Syrian hamster embryo cells to a chemical carcinogen. Quantitative assays measuring morphological changes, enhanced fibrinolytic activity, and anchorage independent growth were used to detect the development of transformed cells within a population of normal hamster embryo cells. Morphological transformation and enhanced fibrinolytic activity were early changes observed after treatment with benzo[alpha]-pyrene, whereas the ability to grow in semisolid agar was delayed 32-75 population doublings after carcinogen exposure. This delay was not due to selection of a small number of cells that were present early after treatment but at a level below detection, because a large percentage of the cells isolated at early passage (10(3)-fold above the level of detection) developed the potential for anchorage independent growth at later passages. This development of the anchorage independent growth phenotype was induced by the carcinogen treatment, because spontaneous transformation was rare. These observation suggest that multiple cellular changes are required for the acquisition of the capacity for anchorage independent growth and that neoplastic transformation in vitro is a progressive process through qualitatively different stages. Thus, an analogy can be drawn to the progressive nature of in vivo carcinogenesis. These results strongly justify the study of oncogenesis in cell culture as a model for neoplastic transformation in vivo.

Animals↗
PubMed1983

The 3 A resolution structure of a D-galactose-binding protein for transport and chemotaxis in Escherichia coli.

X-ray diffraction studies of a D-galactose-binding protein essential for transport and chemotaxis in Escherichia coli have yielded a model of the polypeptide chain backbone. An initial polyalanine backbone trace was obtained at 3.2 A resolution by the molecular replacement technique, using a polyalanine search model derived from the refined structure of the L-arabinose-binding protein. Concurrently, a 3 A resolution electron-density map of the D-galactose receptor was determined from multiple isomorphous replacement (MIR) phases. The properly transformed initial polyalanine model superimposed on the MIR electron-density map proved to be an excellent guide in obtaining a final trace. The few changes made in the polyalanine model to improve the fit to the density were confined primarily to the COOH-terminal peptide and some loops connecting the elements of the secondary structure. Despite the lack of significant sequence homology, the overall course of the polypeptide backbone of the D-galactose-binding protein is remarkably similar to that of the L-arabinose-binding protein, the first structure in a series to be solved from this family of binding proteins. Both structures are elongated (axial ratios of 2:1) and composed of two globular domains. For both proteins, the arrangements of the elements of the secondary structure in both domains are identical; both lobes contain a core of beta-pleated sheet with a pair of helices on either side of the plane of the sheet. The four major hydrophobic clusters that stabilize the structure of the L-arabinose-binding protein are also present in the D-galactose-binding protein.

Bacterial Proteins↗
PubMed1989

Continuous maintenance of transformed fibroblasts under reduced serum conditions: utility as a model system for investigating growth factor-specific effects in nonquiescent cells.

We report the continuous growth maintenance of untransformed and chemically transformed fibroblasts (AKR-2B, AKR-MCA cells) in low concentrations of serum (0.1% FBS). The cell lines established (AKR-0.1F, MCA-0.1F) proliferated at rates comparable to cells maintained under high serum conditions (10% FBS). Complete removal of serum from the cells did not induce quiescence. The MCA-0.1F cells were more similar to the untransformed AKR-2B fibroblasts in their morphology, saturation density, inability to form colonies under anchorage-independent conditions, steady-state level of c-myc expression, and kinetics of induction of c-myc in response to specific growth factors. This report demonstrates the utility of this cell line as a nonquiescent model system for investigating growth factor-specific effects in serum-free, cycling cells. Addition of transforming growth factor-beta (TGF-beta) (5 ng/ml) to proliferating MCA-0.1F cells, in the absence of any serum, induced a multilayered growth pattern at confluency, similar to that of AKR-MCA cells maintained in 10% FBS. Other growth factors tested did not elicit this effect. The induction of this growth pattern by TGF-beta was associated with a sustained induction of the c-myc proto-oncogene at confluency, but not with a restoration of anchorage-independent growth. The data suggest that TGF-beta may play a role in the up-regulation of c-myc at confluency previously described for AKR-MCA cells maintained in 10% serum.

Animals↗
PubMedDate not supplied

[The calculation of the dose from a 60Co source using 3-dimensional Fourier transform].

The distribution of a dose in tissue-equivalent phantoms was calculated through convolution of scattered photon flux by using three-dimensional Fourier transform. A simplified model of a scattering kernel is presented, wherein multiple scattering radiation is taken into account by a water point source accumulation factor. A 64 x 64 x 64 grid calculation lasts about 2 sec on a routine personal computer (three-dimensional Fourier transform and convolution). The dose were calculated in the cube, 32 x 32 x 32 cm in size and in the cylinder, 12 cm in diameter for 4 x 4-to-20 x 20-cm radiation fields. The results are in good agreement with the reference data and Monte Carlo simulation results.

Cobalt Radioisotopes↗
PubMed2001

Association of c-myc overexpression and hyperproliferation with arsenite-induced malignant transformation.

Numerous studies link arsenic exposure to human cancers in a variety of tissues, including the liver. However, inorganic arsenic has never been unequivocally shown to be an animal carcinogen, and its carcinogenic mechanism remains undefined. Our previous studies indicate that chronic (> or =18 weeks), low-level (125 to 500 nM) exposure to arsenite induces malignant transformation in the normally nontumorigenic rat liver epithelial cell line (TRL 1215), and these chronic arsenic-exposed (CAsE) cells produce invasive and metastatic tumors upon inoculation into nude mice. In addition, a prior microarray screening analysis of aberrant gene expression showed several oncogenes were overexpressed in CAsE cells exposed to 500 nM arsenite, including a prominent overexpression of the protooncogene c-myc, as well as genes related to cell proliferation. Thus, to better understand the mechanism of arsenic carcinogenesis, we studied the role of c-myc overexpression in arsenite-induced cell transformation. The upregulation of c-myc was confirmed by RT-PCR at the transcription level and by Western blot analysis for the translation product. Further analysis showed that arsenite produced significant increases in the steady-state expression of c-myc in a time- and concentration-dependent manner during the malignant transformation process. The level of c-myc expression was highly correlated (r = 0.988) with tumor formation after inoculation of CAsE cells into nude mice and was also highly correlated (r = 0.997) with genomic DNA hypomethylation. CAsE cells showed a high cell proliferation rate in a fashion related to the level of arsenic exposure. The expression of c-myc was highly correlated with cellular hyperproliferation (r = 0.961). Consistent with the enhanced proliferation both proliferating cell nuclear antigen and cyclin D1 were overexpressed in CAsE cells. In summary, a prominent overexpression of c-myc, a gene frequently activated during hepatocarcinogenesis, is strongly correlated with several events possibly associated with arsenic-induced malignant transformation, including hyperproliferation, DNA hypomethylation and tumor formation upon inoculation into nude mice. These correlations provide convincing evidence c-myc overexpression is mechanistically important in arsenic-induced malignant transformation in this model system.

Animals↗
PubMed1995

DNA index and S phase fraction in uveal malignant melanomas.

AIMS: To predict 5 year survival in patients with uveal malignant melanomas DNA indices were studied. METHODS: Using 45 paraffin embedded uveal malignant melanomas, the DNA index and S phase fraction of each tumour were the predictor variables recorded. RESULTS: Using the Cox proportional hazards model, aneuploid tumours and tumours which had an S phase fraction greater than 4% were significant predictors of early death. In order to demonstrate a biological gradient between a larger DNA index and shorter survival time, linear regression and transformed linear regression models were used. However, no such gradient could be demonstrated. CONCLUSION: Although this study shows promise for the use of DNA studies in the prognosis of uveal malignant melanoma, the exact role of these techniques remains to be determined.

Adult↗
PubMed2003

Challenges to masculine transformation among urban low-income African American males.

In this article we describe and analyze the challenges faced by an intervention program that addresses the fatherhood needs of low-income urban African American males. We used life history as the primary research strategy for a qualitative evaluation of a program we refer to as the Healthy Men in Healthy Families Program to better understand the circumstances and trajectory of men's lives, including how involvement in the program might have benefited them in the pursuit of their fatherhood goals. A model of masculine transformation, developed by Whitehead, was used to interpret changes in manhood/fatherhood attitudes and behaviors that might be associated with the intervention. We combined Whitehead's model with a social ecology framework to further interpret challenges at intrapersonal, interpersonal, community, and broader societal levels.

Adult↗