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      Differential Effect of Smoking on Gene Expression in Head and Neck Cancer Patients

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          Abstract

          Smoking is a well-known behavior that has an important negative impact on human health, and is considered to be a significant factor related to the development and progression of head and neck squamous cell carcinomas (HNSCCs). Use of high-dimensional datasets to discern novel HNSCC driver genes related to smoking represents an important challenge. The Cancer Genome Atlas (TCGA) analysis was performed in three co-existing groups of HNSCC in order to assess whether gene expression landscape is affected by tobacco smoking, having quit, or non-smoking status. We identified a set of differentially expressed genes that discriminate between smokers and non-smokers or based on human papilloma virus (HPV)16 status, or the co-occurrence of these two exposome components in HNSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways classification shows that most of the genes are specific to cellular metabolism, emphasizing metabolic detoxification pathways, metabolism of chemical carcinogenesis, or drug metabolism. In the case of HPV16-positive patients it has been demonstrated that the altered genes are related to cellular adhesion and inflammation. The correlation between smoking and the survival rate was not statistically significant. This emphasizes the importance of the complex environmental exposure and genetic factors in order to establish prevention assays and personalized care system for HNSCC, with the potential for being extended to other cancer types.

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          The head and neck cancer immune landscape and its immunotherapeutic implications.

          Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV(+) and HPV(-) HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8(+) T cell ratio and the highest levels of CD56(dim) NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8(+) T cell infiltration and CD56(dim) NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV(+) and HPV(-) HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti-PD-1 in the treatment of advanced HNSCC.
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            Cigarette smoking and variations in systemic immune and inflammation markers.

            A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.
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              The exposome in practice: Design of the EXPOsOMICS project

              EXPOsOMICS is a European Union funded project that aims to develop a novel approach to the assessment of exposure to high priority environmental pollutants, by characterizing the external and the internal components of the exposome. It focuses on air and water contaminants during critical periods of life. To this end, the project centres on 1) exposure assessment at the personal and population levels within existing European short and long-term population studies, exploiting available tools and methods which have been developed for personal exposure monitoring (PEM); and 2) multiple “omic” technologies for the analysis of biological samples (internal markers of external exposures). The search for the relationships between external exposures and global profiles of molecular features in the same individuals constitutes a novel advancement towards the development of “next generation exposure assessment” for environmental chemicals and their mixtures. The linkage with disease risks opens the way to what are defined here as ‘exposome-wide association studies’ (EWAS).
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                Author and article information

                Journal
                Int J Environ Res Public Health
                Int J Environ Res Public Health
                ijerph
                International Journal of Environmental Research and Public Health
                MDPI
                1661-7827
                1660-4601
                23 July 2018
                July 2018
                : 15
                : 7
                : 1558
                Affiliations
                [1 ]Department of Prosthetic Dentistry and Dental Materials, Division Dental Propaedeutics, Aesthetic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 23 Marinescu Street, Cluj-Napoca 40015, Romania; irimie.alexandra@ 123456umfcluj.ro (A.I.I.); ddudea@ 123456umfcluj.ro (D.D.)
                [2 ]Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, Cluj-Napoca 40015, Romania; cornelia.braicu@ 123456umfcluj.ro (C.B.); roxana.petric@ 123456umfcluj.ro (R.C.); lorand.magdo@ 123456gmail.com (L.M.); ioana.neagoe@ 123456umfcluj.ro (I.B.-N.)
                [3 ]MEDFUTURE-Research Center for Advanced Medicine, University of Medicine and Pharmacy Iuliu Hatieganu, 23 Marinescu Street, Cluj-Napoca 40015, Romania; anca.onaciu@ 123456umfcluj.ro (A.O.); cristina.ciocan@ 123456umfcluj.ro (C.C.)
                [4 ]Department of Medical Biology, Faculty of Medicine, Medical University-Plovdiv, 15-А Vassil Aprilov Blvd., Plovdiv 4000, Bulgaria; ni_ki82@ 123456abv.bg
                [5 ]Technological Center for Emergency Medicine, 15-А Vassil Aprilov Blvd., Plovdiv 4000, Bulgaria
                [6 ]Prosthetics and Dental Materials, Faculty of Dental Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 32 Clinicilor Street, Cluj-Napoca 400006, Romania
                [7 ]Department of Functional Genomics and Experimental Pathology, The Oncology Institute Ion Chiricuta, Republicii 34th Street, Cluj-Napoca 400015, Romania
                Author notes
                [* ]Correspondence: dana.buduru@ 123456umfcluj.ro ; Tel.: +40-264-597256
                Author information
                https://orcid.org/0000-0002-0625-4445
                Article
                ijerph-15-01558
                10.3390/ijerph15071558
                6069101
                30041465
                8a8594f4-110c-4009-8dc4-9d78de23c4f7
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 April 2018
                : 17 July 2018
                Categories
                Article

                Public health
                head and neck squamous cell carcinomas,smoking,tgca data,gene expression data,survival rate

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