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nicotine-derived nitrosamine ketone nnk tobacco-specific nitrosamine nicotine carcinogenesis n-nitrosonornicotine pyrrolidine ring organic synthesis tobacco cigarette e-cigarettes e-cigarette liquid metabolism signaling pathway tumorigenesis cellular proliferation metastasis toxicity mutagen polymorphisms point mutations gene silencing 3d carcinogen cancer carcinogenicity carcinogenic tumor promotion malignancy angiogenesis poison venom toxicant toxic toxin toxicology poisoning danger hazard harmful kill exposure limit