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      Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer

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          Abstract

          Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease.

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          Periodontitis: a polymicrobial disruption of host homeostasis.

          Periodontitis, or gum disease, affects millions of people each year. Although it is associated with a defined microbial composition found on the surface of the tooth and tooth root, the contribution of bacteria to disease progression is poorly understood. Commensal bacteria probably induce a protective response that prevents the host from developing disease. However, several bacterial species found in plaque (the 'red-complex' bacteria: Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) use various mechanisms to interfere with host defence mechanisms. Furthermore, disease may result from 'community-based' attack on the host. Here, I describe the interaction of the host immune system with the oral bacteria in healthy states and in diseased states.
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            Smoking and drinking in relation to oral and pharyngeal cancer.

            A case-control study of oral and pharyngeal cancer conducted in four areas of the United States provided information on the tobacco and alcohol use of 1114 patients and 1268 population-based controls. Because of the large study size, it could be shown that the risks of these cancers among nondrinkers increased with amount smoked, and conversely that the risks among nonsmokers increased with the level of alcohol intake. Among consumers of both products, risks of oropharyngeal cancer tended to combine more in a multiplicative than additive fashion and were increased more than 35-fold among those who consumed two or more packs of cigarettes and more than four alcoholic drinks/day. Cigarette, cigar, and pipe smoking were separately implicated, although it was shown for the first time that risk was not as high among male lifelong filter cigarette smokers. Cessation of smoking was associated with a sharply reduced risk of this cancer, with no excess detected among those having quit for 10 or more years, suggesting that smoking affects primarily a late stage in the process of oropharyngeal carcinogenesis. The risks varied by type of alcoholic beverage, being higher among those consuming hard liquor or beer than wine. The relative risk patterns were generally similar among whites and blacks, and among males and females, and showed little difference when oral and pharyngeal cancers were analyzed separately. From calculations of attributable risk, we estimate that tobacco smoking and alcohol drinking combine to account for approximately three-fourths of all oral and pharyngeal cancers in the United States.
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              Hydrogen sulfide and cell signaling.

              Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.
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                Author and article information

                Contributors
                maura.gillison@osumc.edu
                chuttenh@hsph.harvard.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                15 December 2017
                15 December 2017
                2017
                : 7
                : 17686
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Biostatistics, , Harvard T.H. Chan School of Public Health, Harvard University, ; Boston, MA 02115 USA
                [2 ]GRID grid.66859.34, The Broad Institute of MIT and Harvard, ; Cambridge, MA 02115 USA
                [3 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, The Ohio State University Comprehensive Cancer Center, ; Columbus, OH 43202 USA
                [4 ]ISNI 0000 0004 1936 8008, GRID grid.170202.6, Biology and the Built Environment Center and Institute of Ecology and Evolution, , University of Oregon, ; Eugene, OR 97403 USA
                [5 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Present Address: Department of Civil and Environmental Engineering, , Northwestern University, ; Evanston, IL 60208 USA
                [6 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, , Harvard T.H. Chan School of Public Health, Harvard University, ; Boston, MA 02115 USA
                [7 ]ISNI 0000 0004 1936 8091, GRID grid.15276.37, Department of Oral Biology, , College of Dentistry, University of Florida, ; Gainesville, FL 32610 USA
                [8 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Present Address: University Heart Center Hamburg-Eppendorf, Clinic for General and Interventional Cardiology, ; Hamburg, Germany
                [9 ]ISNI 0000 0004 5937 5237, GRID grid.452396.f, German Center for Cardiovascular Research (DZHK), Hamburg/Lübeck/Kiel Partner Site, ; Hamburg, Germany
                Author information
                http://orcid.org/0000-0002-0966-2014
                http://orcid.org/0000-0002-8798-7068
                http://orcid.org/0000-0002-1110-0096
                Article
                17795
                10.1038/s41598-017-17795-z
                5732161
                29247187
                466788f9-067f-4f86-bd0c-6118566923a0
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 August 2017
                : 30 November 2017
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