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      Worldwide research trends on aristolochic acids (1957–2017): Suggestions for researchers

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          Abstract

          Aristolochic acids and their derivatives are components of many traditional medicines that have been used for thousands of years, particularly in Asian countries. To study the trends of research into aristolochic acids and provide suggestions for future study, we performed the following work. In this paper, we performed a bibliometric analysis using CiteSpace and HistCite software. We reviewed the three phases of the development of aristolochic acids by using bibliometrics. In addition, we performed a longitudinal review of published review articles over 60 years: 1,217 articles and 189 review articles on the history of aristolochic acid research published between 1957 and 2017 were analyzed. The performances of relevant countries, institutions, and authors are presented; the evolutionary trends of different categories are revealed; the history of research into aristolochic acids is divided into three phases, each of which has unique characteristics; and a roadmap of the historical overview of aristolochic acid research is finally established. Finally, five pertinent suggestions for future research into aristolochic acid are offered: (1) The study of the antitumor efficacy of aristolochic acids is of value; (2) The immune activity of aristolochic acids should be explored further; (3) Researchers should perform a thorough overview of the discovery of naturally occurring aristolochic acids; (4) More efforts should be directed toward exploring the correlation between aristolochic acid mutational signature and various cancers; (5) Further efforts should be devoted to the research and review work related to analytical chemistry. Our study is expected to benefit researchers in shaping future research directions.

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          Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

          Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.
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            Mutational landscape of intrahepatic cholangiocarcinoma.

            Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer (PLC) that affects 5-10% of all PLCs. Here we sequence tumour and matching control sample pairs of a large cohort of 103 ICC patients in China, resulting in the identification of an ICC-specific somatic mutational signature that is associated with liver inflammation, fibrosis and cirrhosis. We further uncover 25 significantly mutated genes including eight potential driver genes (TP53, KRAS, IDH1, PTEN, ARID1A, EPPK1, ECE2 and FYN). We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive, whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients. Three pathways (Ras/phosphatidylinositol-4,5-bisphosphate 3-kinase signalling, p53/cell cycle signalling and transforming growth factor-β/Smad signalling), genes important for epigenetic regulation and oxidative phosphorylation are substantially affected in ICC. We reveal mutations in this study that may be valuable for designing further studies, better diagnosis and effective therapies.
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              Aristolochic acid-associated urothelial cancer in Taiwan.

              Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draft
                Role: Validation
                Role: Validation
                Role: Validation
                Role: Validation
                Role: Validation
                Role: ConceptualizationRole: Project administration
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 May 2019
                2019
                : 14
                : 5
                : e0216135
                Affiliations
                [1 ] Engineering Research Center of Chinese Medicine Resource, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
                [2 ] College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
                [3 ] School of Information Technologies, The University of Sydney, Sydney, Australia
                [4 ] Analytic and Clinical Cooperative Laboratory of Integrative Medicine, Chinese University of Hong Kong and The University of Sydney, Sydney, Australia
                [5 ] Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
                [6 ] College of Science, Sichuan Agricultural University, Yaan, Sichuan, China
                [7 ] College of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
                University of Toronto, CANADA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9977-2945
                Article
                PONE-D-18-33729
                10.1371/journal.pone.0216135
                6497264
                31048858
                d94b1feb-2390-455a-a1d7-e146b7c6aaa4
                © 2019 Zhou 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
                : 28 November 2018
                : 15 April 2019
                Page count
                Figures: 9, Tables: 2, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81473315
                Award Recipient :
                Funded by: Public Welfare Scientific Research Project of State Administration of Traditional Chinese Medicine
                Award ID: 201507004-2-1
                Award Recipient :
                Funded by: CAMS Innovation Fund for Medical Sciences
                Award ID: 2016-I2M-3-015
                Award Recipient :
                This study was supported by the National Natural Science Foundation of China (No. 81473315), Public Welfare Scientific Research Project of State Administration of Traditional Chinese Medicine (201507004-2-1) and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2016-I2M-3-015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Research and Analysis Methods
                Research Assessment
                Bibliometrics
                Research and Analysis Methods
                Research Assessment
                Citation Analysis
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Biology and Life Sciences
                Organisms
                Eukaryota
                Plants
                Herbs
                Biology and Life Sciences
                Toxicology
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Physical Sciences
                Chemistry
                Analytical Chemistry
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
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                All relevant data are within the manuscript and its Supporting Information files.

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