740 research outputs found

    Comparison of the Use of a Physiologically Based Pharmacokinetic Model and a Classical Pharmacokinetic Model for Dioxin Exposure Assessments

    Get PDF
    In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden–dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD

    The relationship between smoking exposure and p53 overexpression in colorectal cancer.

    Get PDF
    Although epidemiological studies of the relationship between cigarette smoking and colorectal cancer risk have been equivocal, a positive association is consistently found for colorectal adenoma development. We performed an epidemiological study to determine whether p53 protein overexpression, in tumours obtained at the time of resection, is associated with cigarette exposure in colorectal cancer. A total of 163 colorectal cancer cases and 326 healthy controls responded to a standardised questionnaire on colorectal cancer risk factors including detailed information on their history of cigarette smoking. All patients' tumours were analysed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Comparison of colorectal cases with controls revealed an elevated risk for ex-smokers (OR = 1.34, 95% CI 0.85-2.12) and current smokers (OR = 1.13, 95% CI 0.63-2.02) when compared with non-smokers. No dose-response relationship was found for total pack-years of smoking (trend test: P = 0.19). However, a trend for total pack-years of smoking was found when p53-positive cases were compared with p53-negative cases suggesting aetiological, heterogeneity (trend test: P = 0.06). Estimating the individual relative risk of developing a p53-positive tumour relative to controls showed no associations for smoking status or total pack-years of smoking. However, when p53-negative cases were compared with controls, an elevated risk was found for ex-smokers (OR = 1.84, 95% CI 1.00-3.37) and current years of smoking (trend test: P = 0.03). Colorectal tumours developing through p53-positive dependent pathways were not associated with smoking exposure. A significant increase in risk was observed for the p53-negative independent pathway with smoking. p53 overexpression appears to be associated with smoking exposure in colorectal cancer

    Choice at the pump: measuring preferences for lower-carbon combustion fuels

    Get PDF
    A decarbonized future will require a transition to lower carbon fuels for personal transportation. We study consumer preferences for combustion fuels including gasoline, diesel, natural gas, and E85 (85% ethanol and 15% gasoline) using consumer choice survey data from two settings: online (n = 331) and in-person at refueling stations (n = 127). Light-duty vehicle owners were asked in a series of choice tasks to choose among fuels that varied in type, price, CO2 emissions, and location of origin for a hypothetical vehicle that could accept all fuels. We find that the majority of gasoline and E85 users are willing to substitute towards other fuels at today's prices and attributes, while diesel users have a strong preference for diesel fuel. We also find that respondents are willing to pay on average $150/ton CO2 avoided from fuel consumption—more than most estimates of the social cost of carbon. Thus, communicating the climate benefits from alternative fuels may be an important strategy for decarbonizing the transportation sector

    Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

    Get PDF
    Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma

    Deep Functional and Molecular Characterization of a High-Risk Undifferentiated Pleomorphic Sarcoma.

    Get PDF
    Nonrhabdomyosarcoma soft-tissue sarcomas (STSs) are a class of 50+ cancers arising in muscle and soft tissues of children, adolescents, and adults. Rarity of each subtype often precludes subtype-specific preclinical research, leaving many STS patients with limited treatment options should frontline therapy be insufficient. When clinical options are exhausted, personalized therapy assignment approaches may help direct patient care. Here, we report the results of an adult female STS patient with relapsed undifferentiated pleomorphic sarcoma (UPS) who self-drove exploration of a wide array of personalized Clinical Laboratory Improvement Amendments (CLIAs) level and research-level diagnostics, including state of the art genomic, proteomic

    Peroxiredoxin II Regulates Effector and Secondary Memory CD8+ T cell Responses

    Get PDF
    Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2on an antigen-specific CD8+ T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8+ T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death during in vitro division. During primary acute viral and bacterial infection, the number of effector CD8+ T cells in PrdxII-deficient mice was increased, while the number of memory cells were similar to those of the wild-type cells. Adoptive transfer of P14 TCR transgenic cells demonstrated that the increased expansion of effector cells was T cell autonomous. After rechallenge, effector CD8+ T cells in mutant animals were more skewed to memory phenotype than cells from wild-type mice, resulting in a larger secondary memory CD8+ T cell pool. During chronic viral infection, increased antigen-specific CD8+ T cells accumulated in the spleens of PrdxII mutant mice, causing mortality. These results demonstrate that PrdxII controls effector CD8+ T cell expansion, secondary memory generation, and immunopathology

    Interstellar Turbulence II: Implications and Effects

    Full text link
    Interstellar turbulence has implications for the dispersal and mixing of the elements, cloud chemistry, cosmic ray scattering, and radio wave propagation through the ionized medium. This review discusses the observations and theory of these effects. Metallicity fluctuations are summarized, and the theory of turbulent transport of passive tracers is reviewed. Modeling methods, turbulent concentration of dust grains, and the turbulent washout of radial abundance gradients are discussed. Interstellar chemistry is affected by turbulent transport of various species between environments with different physical properties and by turbulent heating in shocks, vortical dissipation regions, and local regions of enhanced ambipolar diffusion. Cosmic rays are scattered and accelerated in turbulent magnetic waves and shocks, and they generate turbulence on the scale of their gyroradii. Radio wave scintillation is an important diagnostic for small scale turbulence in the ionized medium, giving information about the power spectrum and amplitude of fluctuations. The theory of diffraction and refraction is reviewed, as are the main observations and scintillation regions.Comment: 46 pages, 2 figures, submitted to Annual Reviews of Astronomy and Astrophysic

    A Standard Platform for Testing and Comparison of MDAO Architectures

    Get PDF
    The Multidisciplinary Design Analysis and Optimization (MDAO) community has developed a multitude of algorithms and techniques, called architectures, for performing optimizations on complex engineering systems which involve coupling between multiple discipline analyses. These architectures seek to efficiently handle optimizations with computationally expensive analyses including multiple disciplines. We propose a new testing procedure that can provide a quantitative and qualitative means of comparison among architectures. The proposed test procedure is implemented within the open source framework, OpenMDAO, and comparative results are presented for five well-known architectures: MDF, IDF, CO, BLISS, and BLISS-2000. We also demonstrate how using open source soft- ware development methods can allow the MDAO community to submit new problems and architectures to keep the test suite relevant
    corecore