8 research outputs found

    Is a Cumulative Exposure to a Background Aerosol of Nanoparticles Part of the Causal Mechanism of Aerotoxic Syndrome?

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    We present strong evidence for the presence of aerosols of Nano-particles (also termed Ultrafine Particles (UFPs) in aerosol science) in the breathing air of commercial aircraft using engine bleed air architecture. The physical and chemical nature of engine oils and the high temperatures attained in aircraft jet engines (up to 1700°C in the oil circulation and up to 30,000°C in the bearings) explain why UFPs are to be expected. A discussion of oil seals used in gas turbine engines concludes that they will permit UFPs to cross them and enter the breathing air supply, in conjunction with a complex mixture of chemicals such triaryl phosphates which are neurotoxic. A consideration of the toxicology of Nano-particles concludes that their continual presence over a typical working lifetime of up to 20,000 hours in aircrew will predispose them to chronic respiratory problems and will exacerbate the translocation of neurotoxic substances across the blood brain barrier

    Is a Cumulative Exposure to a Background Aerosol of Nanoparticles Part of the Causal Mechanism of Aerotoxic Syndrome?

    Get PDF
    We present strong evidence for the presence of aerosols of Nano-particles (also termed Ultrafine Particles (UFPs) in aerosol science) in the breathing air of commercial aircraft using engine bleed air architecture. The physical and chemical nature of engine oils and the high temperatures attained in aircraft jet engines (up to 1700°C in the oil circulation and up to 30,000°C in the bearings) explain why UFPs are to be expected. A discussion of oil seals used in gas turbine engines concludes that they will permit UFPs to cross them and enter the breathing air supply, in conjunction with a complex mixture of chemicals such triaryl phosphates which are neurotoxic. A consideration of the toxicology of Nano-particles concludes that their continual presence over a typical working lifetime of up to 20,000 hours in aircrew will predispose them to chronic respiratory problems and will exacerbate the translocation of neurotoxic substances across the blood brain barrier

    Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC

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    Background Blood-based biomarkers of anti-solid tumor immune checkpoint blockade (ICB) response are lacking. We hypothesized that changes in systemic cytokine levels with the initial doses of programmed cell death protein 1 (PD-1) pathway inhibitors would correlate with clinical responses. New ultrasensitive ELISA technology enables quantitation of plasma proteins in sub-picogram-per-milliliter concentrations.Methods We measured plasma cytokines by ultrasensitive single-molecule array assays in patients with non-small-cell lung carcinoma before and during treatment with anti-PD-1 therapy. Association with best overall response and progression-free survival (PFS) was assessed by Kruskall-Wallis test and Kaplan-Meier plots with log-rank test, respectively.Results A decrease in interleukin 6 (IL-6) levels was associated with improved PFS (n=47 patients, median PFS: 11 vs 4 months, HR 0.45 (95% CI 0.23 to 0.89), p=0.04). The extent of change in IL-6 differed between best overall response categories (p=0.01) and correlated with changes in C reactive protein levels. We also explored plasma cytokine levels in relation to immune-related adverse effects and observed some correlation.Conclusions This study suggests the presence of a systemic, proteomic reflection of successful ICB outside the tumor microenvironment with plasma decreases in IL-6 and CRP

    Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions.

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    Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.All SEQC2 participants freely donated their time, reagents, and computing resources for the completion and analysis of this project. Part of this work was carried out with the support of the Intramural Research Program of the National Institutes of Health (to Mehdi Pirooznia), National Institute of Environmental Health Sciences (to Pierre Bushel), and National Library of Medicine (to Danielle Thierry-Mieg, Jean Thierry-Mieg, and Chunlin Xiao). Leming Shi and Yuanting Zheng were supported by the National Key R&D Project of China (2018YFE0201600), the National Natural Science Foundation of China (31720103909), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). Donald J. Johann, Jr. acknowledges the support by FDA BAA grant HHSF223201510172C. Timothy Mercer and Ira Deveson were supported by the National Health and Medical Research Council (NHMRC) of Australia grants APP1108254, APP1114016, and APP1173594 and Cancer Institute NSW Early Career Fellowship 2018/ECF013. This research has also been, in part, financially supported by the MEYS of the CR under the project CEITEC 2020 (LQ1601), by MH CR, grant No. (NV19-03-00091). Part of this work was carried out with the support of research infrastructure EATRIS-CZ, ID number LM2015064, funded by MEYS CR. Boris Tichy and Nikola Tom were supported by research infrastructure EATRIS-CZ, ID number LM2018133 funded by MEYS CR and MEYS CR project CEITEC 2020 (LQ1601).S
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