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      Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis

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          Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pathways associated with 11 hallmarks of cancer (HOCs) reported by the Halifax Project. To demonstrate the usefulness of the curated HOC data, the interacting HOC genes and affected HOC pathways of chemicals of the three carcinogen lists from IARC, NTP and EPA were analyzed using the in silico toxicogenomics ChemDIS system. Results showed that a higher number of affected HOCs were observed for known carcinogens than the other chemicals. The curated HOC data is expected to be useful for prioritizing chemicals of carcinogenic concern.

          Database URL: The HOC database is available at and the website of Database journal as Supplementary Data.

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          Most cited references 29

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          The Hallmarks of Cancer

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            Aristolochic acid as a probable human cancer hazard in herbal remedies: a review.

            The old herbal drug aristolochic acid (AA), derived from Aristolochia spp., has been associated with the development of a novel nephropathy, designated aristolochic acid nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence that the major components of the plant extract AA, aristolochic acid I (AAI) and aristolochic acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. Several mammalian enzymes have been shown to be capable of activating both AAI and AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent with the formation of a cyclic nitrenium ion with delocalized charge leading to the preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N(6)-yl)aristolactam I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic lesion leading to AT-->TA transversions in vitro. This transversion mutation is found at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process in rodents. DNA-binding studies confirmed that both AAs bind to the adenines of codon 61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic administration of AA remains to be explored. However, preliminary findings suggest that DNA damage by AA is not only responsible for the tumour development but also for the destructive fibrotic process in the kidney. It is concluded that there is significant evidence that AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans. In particular, the highly similar metabolic pathway of activation and resultant DNA adducts of AA allows the extrapolation of carcinogenesis data from laboratory animals to the human situation. Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide.
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              Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

              Summary Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

                Author and article information

                Database (Oxford)
                Database (Oxford)
                Database: The Journal of Biological Databases and Curation
                Oxford University Press
                15 June 2020
                15 June 2020
                : 2020
                [1 ]Phd Program in Toxicology, Kaohsiung Medical University , 100 Shiquan 1st Road, Kaohsiung 80706, Taiwan
                [2 ]Department of Pathology, Kaohsiung Medical University Hospital , Kaohsiung Medical University, 100 Ziyou 1st Road, Kaohsiung 80706, Taiwan
                [3 ]Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University , 1 Section 4 Roosevelt Rd, Taipei 10617, Taiwan
                [4 ] National Institute of Environmental Health Sciences , National Health Research Institutes, 35 Keyan Road, Miaoli County 35053, Taiwan
                [5 ]Graduate Institute of Data Science, College of Management, Taipei Medical University , 250 Wuxing Street, Taipei 10675, Taiwan
                [6 ]School of Pharmacy, Kaohsiung Medical University , 100 Shiquan 1st Road, Kaohsiung 80706, Taiwan
                Author notes
                Corresponding author: Chun-Wei Tung, Tel: +886-2-66382736 ext. 1185; Fax: +886-2-27358254; Email: cwtung@ ; Pinpin Lin, Tel: +885-37-246166 ext. 36508; Fax: +886-37-587406; Email: pplin@
                © The Author(s) 2020. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9
                Funded by: Ministry of Science and Technology of Taiwan 10.13039/501100004663
                Award ID: MOST107-2221-E-038-020-MY3
                Funded by: National Health Research Institutes 10.13039/501100004737
                Award ID: NHRI-109A1-EMCO-0319204
                Funded by: Taipei Medical University 10.13039/501100004700
                Award ID: TMU108-AE1-B36
                Funded by: Kaohsiung Medical University Hospital, Kaohsiung Medical University
                Award ID: KMUH104-4R69
                Funded by: National Health Research Institutes 10.13039/501100004737
                Award ID: NHRI-109-EMGP-01
                Original Article

                Bioinformatics & Computational biology

                cancer hallmark, curation, the halifax project


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