107 research outputs found

    An evaluation of the fixed concentration procedure for assessment of acute inhalation toxicity

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    Acute inhalation studies are conducted in animals as part of chemical hazard identification and for classification and labelling. Current methods employ death as an endpoint (OECD TG403 and TG436) while the recently approved fixed concentration procedure (FCP) (OECD TG433) uses fewer animals and replaces lethality as an endpoint with evident toxicity. Evident toxicity is the presence of clinical signs that predict that exposure to the next highest concentration will cause severe toxicity or death in most animals. Approval of TG433 was the result of an international initiative, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), which collected data from six laboratories on clinical signs recorded for inhalation studies on 172 substances. This paper summarises previously published data and describes the additional analyses of the dataset that were essential for approval of the TG

    Characterization and modelling of electromagnetic interactions in aircraft

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    This article describes the development of modelling techniques and simulation tools for the electromagnetic (EM) analysis of aircraft. It is shown that hybrid solvers and multi-scale techniques can be used effectively to analyse the EM response of aircraft. The importance of supplementing models with appropriate measurement and characterization techniques for parameter extraction and for validation is also demonstrated

    Consensus recommendations for the safe handling of cytotoxic agents in Cytotoxic Academic Research Laboratories (CARL)

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    Cytotoxic agents, also called antineoplastic agents, are used in cancer treatment due to their inherent activity to inhibit cell growth or proliferation, or DNA, RNA and protein synthesis. They are, therefore, hazardous by nature in a non-selective manner leading to disruption of cell growth and function of both diseased and healthy cells of treated patients. While the benefits of receiving cytotoxic agents may outweigh the incurred risks for patients, the same cannot be said for exposed healthcare practitioners involved in the transport, preparation, administration, and resulting waste disposal of these agents. Consequently, many professional bodies around the world have set standards of practice to prevent occupational exposure of healthcare workers to cytotoxic agents, and hospitals have been active in defining strict policies in this concern. However, due to the variability of the practice and infrastructure in academic settings, some activities performed within the cytotoxic academic research laboratory often do not adhere to recommendations published by guidelines. The present recommendations were therefore set forward by members of a working group who are experts on the subject matter representing academic, clinical, and research backgrounds in an attempt to promote safe cytotoxic handling in academic institutions. The document maps out the trajectory of cytotoxic agents being investigated in academic research laboratories while providing recommendations on the delivery, storage, use and disposal of cytotoxic agents in university settings

    Intergenerational social mobility and mid-life status attainment: influences of childhood intelligence, childhood social factors, and education

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    We examined the influences of childhood social background, childhood cognitive ability, and education on intergenerational social mobility and social status attainment at midlife. The subjects were men born in 1921 and who participated in the Scottish Mental Survey of 1932 and thereafter in the Midspan Collaborative study in Scotland between 1970 and 1973. In logistic regression analyses, childhood cognitive ability and height were associated with upward and downward change from father's social class to participant's social class at mid-life. Education significantly influenced upward social mobility. Number of siblings had no significant effect on social mobility. These effects were also examined after adjusting for the other variables. In structural equation modelling analyses, father's social class and childhood cognitive ability influenced social status attainment at midlife, with education and occupational status in young adulthood as partially mediating factors. It was noteworthy that childhood cognitive ability related more strongly to occupation in midlife than to first occupation. These data add to the relatively few studies that track the process of status attainment in adulthood, they provide information from a new geographical setting, and they contain information from a greater proportion of the lifecourse than do most existing studies

    LILRB1 blockade enhances bispecific T cell engager antibody-induced tumor cell killing by effector CD8+ T cells

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    Elicitation of tumor cell killing by CD8+ T cells is an effective therapeutic approach for cancer. In addition to using immune checkpoint blockade to reinvigorate existing but unresponsive tumor-specific T cells, alternative therapeutic approaches have been developed, including stimulation of polyclonal T cell cytolytic activity against tumors using bispecific T cell engager (BiTE) molecules that simultaneously engage the TCR complex and a tumor-associated Ag. BiTE molecules are efficacious against hematologic tumors and are currently being explored as an immunotherapy for solid tumors. To understand mechanisms regulating BiTE molecule­–mediated CD8+ T cell activity against solid tumors, we sought to define human CD8+ T cell populations that efficiently respond to BiTE molecule stimulation and identify factors regulating their cytolytic activity. We find that human CD45RA+CCR7− CD8+ T cells are highly responsive to BiTE molecule stimulation, are enriched in genes associated with cytolytic effector function, and express multiple unique inhibitory receptors, including leukocyte Ig-like receptor B1 (LILRB1). LILRB1 and programmed cell death protein 1 (PD1) were found to be expressed by distinct CD8+ T cell populations, suggesting different roles in regulating the antitumor response. Engaging LILRB1 with its ligand HLA-G on tumor cells significantly inhibited BiTE molecule–induced CD8+ T cell activation. Blockades of LILRB1 and PD1 induced greater CD8+ T cell activation than either treatment alone. Together, our data suggest that LILRB1 functions as a negative regulator of human CD8+ effector T cells and that blocking LILRB1 represents a unique strategy to enhance BiTE molecule therapeutic activity against solid tumors

    Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection

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    Despite the pressing need for an AIDS vaccine, the determinants of protective immunity to HIV remain concealed within the complexity of adaptive immune responses. We dissected immunodominant virus-specific CD8+ T cell populations in Mamu-A*01+ rhesus macaques with primary SIV infection to elucidate the hallmarks of effective immunity at the level of individual constituent clonotypes, which were identified according to the expression of distinct T cell receptors (TCRs). The number of public clonotypes, defined as those that expressed identical TCR β-chain amino acid sequences and recurred in multiple individuals, contained within the acute phase CD8+ T cell population specific for the biologically constrained Gag CM9 (CTPYDINQM; residues 181–189) epitope correlated negatively with the virus load set point. This independent molecular signature of protection was confirmed in a prospective vaccine trial, in which clonotype engagement was governed by the nature of the antigen rather than the context of exposure and public clonotype usage was associated with enhanced recognition of epitope variants. Thus, the pattern of antigen-specific clonotype recruitment within a protective CD8+ T cell population is a prognostic indicator of vaccine efficacy and biological outcome in an AIDS virus infection
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