SignificanceProgrammed death-ligand 1 (PD-L1) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity, and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer.
Hydraulic fracturing (HF) has emerged as a major method of unconventional oil and gas recovery. The toxicity of hydraulic fracturing flowback and produced water (HF-FPW) has not been previously reported and is complicated by the combined complexity of organic and inorganic constituents in HF fluids and deep formation water. In this study, we characterized the solids, salts, and organic signatures in an HF-FPW sample from the Duvernay Formation, Alberta, Canada. Untargeted HPLC-Orbitrap revealed numerous unknown dissolved polar organics. Among the most prominent peaks, a substituted tri-phenyl phosphate was identified which is likely an oxidation product of a common polymer antioxidant. Acute toxicity of zebrafish embryo was attributable to high salinity and organic contaminants in HF-FPW with LC50 values ranging from 0.6% to 3.9%, depending on the HF-FPW fractions and embryo developmental stages. Induction of ethoxyresorufin-O-deethylase (EROD) activity was detected, due in part to polycyclic aromatic hydrocarbons (PAHs), and suspended solids might have a synergistic effect on EROD induction. This study demonstrates that toxicological profiling of real HF-FPW sample presents great challenges for assessing the potential risks and impacts posed by HF-FPW spills.
Background: Epidermal growth factor receptor (EGFR) gene mutation is a robust prognostic factor in patients with advanced lung adenocarcinomas. Recently, on the other hand, there are some reports proposing the difference of survival due to the type of EGFR mutation. In this study, we analyzed the difference of postoperative survivals between two most common mutations, that is, exon 19 deletions (DEL) and exon21 L858R (PM), using multi-institutional data of patients with surgically resected lung adenocarcinomas. Methods: We retrospectively collected 1,063 consecutive patients who underwent surgical resections for lung adenocarcinoma between 2005 and 2012 in five institutions, and who were examined their EGFR mutation status. The patients with minor EGFR mutations were excluded. We compared their clinicopathological characteristics among DEL, PM, and wild type (WT) group. We also analyzed postoperative recurrence-free survival (RFS) and overall survival (OS) according to the type of EGFR mutation. Results: The number of patients with DEL, PM, and WT was 218 (20.5%), 301 (28.3%), and 544 (51.2%) respectively, and their median follow-up period was 47.6 months. The patients of PM were older and earlier pathological staged than those with DEL, whereas no significant difference was observed among other clinicopathological factors. Five-year RFS and OS of DEL, PM, and WT were 67.3/85.9%, 76.4/88.6%, 59.2/71.5%, respectively, and both survivals of each mutant were significantly better than those of WT. Regarding the difference between DEL and PM, RFS curve of DEL was significantly worse than that of PM (p ¼ 0.027), but OS curves of both mutant weren't significantly different. (p ¼ 0.16). In multivariate analysis, the type of EGFR mutation (DEL vs PM) was not an independent factor both in RFS and OS. Conclusion: Exon 21 L858R might be a more favorable recurrence-risk factor than exon 19 deletions in patients with surgically resected lung adenocarcinomas.
BackgroundThere is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities.MethodsPeripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular ‘barcoding’, to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples.ResultsNo significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease.ConclusionThis study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade.Trial registrationPOPLAR trial NCT01903993.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0695-9) contains supplementary material, which is available to authorized users.
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