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      Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation

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          Abstract

          Second-hand smoke (SHS) is associated with 20–30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL ( p < 0.001), lung ( p < 0.05), and bladder mucosa ( p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair ( p < 0.01) and base excision repair ( p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly ( p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers.

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          Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

          The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.
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            Alcohol and public health.

            Alcoholic beverages, and the problems they engender, have been familiar fixtures in human societies since the beginning of recorded history. We review advances in alcohol science in terms of three topics: the epidemiology of alcohol's role in health and illness; the treatment of alcohol use disorders in a public health perspective; and policy research and options. Research has contributed substantially to our understanding of the relation of drinking to specific disorders, and has shown that the relation between alcohol consumption and health outcomes is complex and multidimensional. Alcohol is causally related to more than 60 different medical conditions. Overall, 4% of the global burden of disease is attributable to alcohol, which accounts for about as much death and disability globally as tobacco and hypertension. Treatment research shows that early intervention in primary care is feasible and effective, and a variety of behavioural and pharmacological interventions are available to treat alcohol dependence. This evidence suggests that treatment of alcohol-related problems should be incorporated into a public health response to alcohol problems. Additionally, evidence-based preventive measures are available at both the individual and population levels, with alcohol taxes, restrictions on alcohol availability, and drinking-driving countermeasures among the most effective policy options. Despite the scientific advances, alcohol problems continue to present a major challenge to medicine and public health, in part because population-based public health approaches have been neglected in favour of approaches oriented to the individual that tend to be more palliative than preventative.
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              Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers.

              It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobacco-related cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers' lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpG-methylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                20 October 2015
                28 September 2015
                : 6
                : 32
                : 33226-33236
                Affiliations
                1 Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA
                2 Department of Urology, New York University School of Medicine, New York, NY, USA
                3 Department of Medicine, New York University School of Medicine, New York, NY, USA
                4 Department of Pathology, New York University School of Medicine, New York, NY, USA
                Author notes
                Correspondence to: Moon-shong Tang, moon-shong.tang@ 123456nyumc.org
                Article
                10.18632/oncotarget.5429
                4741761
                26431382
                b3903b3e-8148-453e-84f2-5b5aa6cb03d0
                Copyright: © 2015 Lee et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 July 2015
                : 16 September 2015
                Categories
                Research Paper

                Oncology & Radiotherapy
                second-hand and side-stream smoke,acrolein and bpde,dna damage and repair,lung and bladder cancer,anchorage independent growth

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