30 research outputs found

    Uneven distribution of HPV 16 E6 prototype and variant (L83V) oncoprotein in cervical neoplastic lesions

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    A previous Swedish study revealed that both prototype and variant HPV16 E6 oncoprotein, occur in about equal numbers in high-grade cervical intraepithelial neoplasia (HCIN), whereas variant HPV16 predominates in invasive cervical squamous carcinoma. Most of the malignant HPV16 variants contain a common mutation, L83V, in the E6 oncoprotein. In the present investigation, 28 HPV16 positive, invasive cervical adenocarcinomas were collected from a total number of 131 adenocarcinomas. These HPV16-positive cases were evaluated with analysis of the E6 gene, using a recently described PCR-SSCP method for identification of the specific mutation (L83V) in the E6 gene. The results obtained were correlated to findings in 103 preinvasive, HCIN, and 31 invasive cervical squamous carcinomas also infected with HPV16. The HPV16 E6 variant L83V was present in 40% of the HCIN lesions, in 54% of the invasive adenocarcinomas, in comparison to 81% of the invasive squamous carcinomas. The difference between HCIN and squamous carcinomas was statistically significant, P< 0.001, whereas the difference between HCIN and invasive adenocarcinomas was not statistically significant, P = 0.604. Prototype HPV16 and its E6 variant L83V are both prevalent in preinvasive and invasive cervical lesions in Swedish women. However, the obvious predominance of HPV16 variant in squamous carcinomas was not seen in adenocarcinomas. A single amino-acid shift in the HPV16 E6 gene appears to result in a different transforming potential in squamous and glandular cervical lesions. © 2000 Cancer Research Campaig

    A Flexible Nonlinear Feedback System That Captures Diverse Patterns of Adaptation and Rebound

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    An important approach to modeling tolerance and adaptation employs feedback mechanisms in which the response to the drug generates a counter-regulating action which affects the response. In this paper we analyze a family of nonlinear feedback models which has recently proved effective in modeling tolerance phenomena such as have been observed with SSRI’s. We use dynamical systems methods to exhibit typical properties of the response-time course of these nonlinear models, such as overshoot and rebound, establish quantitive bounds and explore how these properties depend on the system and drug parameters. Our analysis is anchored in three specific in vivo data sets which involve different levels of pharmacokinetic complexity. Initial estimates for system (kin, kout, ktol ) and drug (EC50/IC50, Emax/Imax, n ) parameters are obtained on the basis of specific properties of the response-time course, identified in the context of exploratory (graphical) data analysis. Our analysis and the application of its results to the three concrete examples demonstrates the flexibility and potential of this family of feedback models

    Loss of Genetic Redundancy in Reductive Genome Evolution

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    Biological systems evolved to be functionally robust in uncertain environments, but also highly adaptable. Such robustness is partly achieved by genetic redundancy, where the failure of a specific component through mutation or environmental challenge can be compensated by duplicate components capable of performing, to a limited extent, the same function. Highly variable environments require very robust systems. Conversely, predictable environments should not place a high selective value on robustness. Here we test this hypothesis by investigating the evolutionary dynamics of genetic redundancy in extremely reduced genomes, found mostly in intracellular parasites and endosymbionts. By combining data analysis with simulations of genome evolution we show that in the extensive gene loss suffered by reduced genomes there is a selective drive to keep the diversity of protein families while sacrificing paralogy. We show that this is not a by-product of the known drivers of genome reduction and that there is very limited convergence to a common core of families, indicating that the repertoire of protein families in reduced genomes is the result of historical contingency and niche-specific adaptations. We propose that our observations reflect a loss of genetic redundancy due to a decreased selection for robustness in a predictable environment

    Busulphan-Cyclophosphamide Cause Endothelial Injury, Remodeling of Resistance Arteries and Enhanced Expression of Endothelial Nitric Oxide Synthase

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    Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late effects on vascular system

    A Multidisciplinary Experimental Study of Flapping Wing Aeroelasticity in Thrust Production

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