{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T18:04:41Z","timestamp":1773252281956,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,6]],"date-time":"2018-01-06T00:00:00Z","timestamp":1515196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5 R01 CA148818"],"award-info":[{"award-number":["5 R01 CA148818"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-13-138-01\u2014CNE to L.-S. Wang"],"award-info":[{"award-number":["RSG-13-138-01\u2014CNE to L.-S. Wang"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Early inhibition of inflammation suppresses the carcinogenic process. Aspirin is the most commonly used non-steroid anti-inflammatory drugs (NSAIDs), and it irreversibly inhibits cyclooxygenase-1 and -2 (COX1, COX2). Multiple randomized clinical trials have demonstrated that aspirin offers substantial protection from colon cancer mortality. The lower aspirin doses causing only minimal gastrointestinal disturbance, ideal for long-term use, can achieve only partial and transitory inhibition of COX2. Aspirin\u2019s principal metabolite, salicylic acid, is also found in fruits and vegetables that inhibit COX2. Other phytochemicals such as curcumin, resveratrol, and anthocyanins also inhibit COX2. Such dietary components are good candidates for combination with aspirin because they have little or no toxicity. However, obstacles to using phytochemicals for chemoprevention, including bioavailability and translational potential, must be resolved. The bell\/U-shaped dose\u2013response curves seen with vitamin D and resveratrol might apply to other phytochemicals, shedding doubt on \u2018more is better\u2019. Solutions include: (1) using special delivery systems (e.g., nanoparticles) to retain phytochemicals; (2) developing robust pharmacodynamic biomarkers to determine efficacy in humans; and (3) selecting pharmacokinetic doses relevant to humans when performing preclinical experiments. The combination of aspirin and phytochemicals is an attractive low-cost and low-toxicity approach to colon cancer prevention that warrants testing, particularly in high-risk individuals.<\/jats:p>","DOI":"10.3390\/ijms19010166","type":"journal-article","created":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T12:26:02Z","timestamp":1515414362000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans?"],"prefix":"10.3390","volume":"19","author":[{"given":"Pan","family":"Pan","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoko","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Pathology, John Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha","family":"Yearsley","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, College of Medicine, Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Shu","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(10)62110-1","article-title":"Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials","volume":"377","author":"Rothwell","year":"2011","journal-title":"The Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/S0140-6736(10)61543-7","article-title":"Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials","volume":"376","author":"Rothwell","year":"2010","journal-title":"The Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/qjmed\/94.8.445","article-title":"Salicylic acid: A link between aspirin, diet and the prevention of colorectal cancer","volume":"94","author":"Paterson","year":"2001","journal-title":"QJM Int. J. Med."},{"key":"ref_4","first-page":"422","article-title":"Cyclooxygenase inhibitors: From pharmacology to clinical read-outs","volume":"1851","author":"Patrignani","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1079\/PNS2005477","article-title":"Is there a role for dietary salicylates in health?","volume":"65","author":"Paterson","year":"2006","journal-title":"Proc. Nutr. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1136\/jcp.56.9.651","article-title":"Urinary excretion of salicyluric and salicylic acids by non-vegetarians, vegetarians, and patients taking low dose aspirin","volume":"56","author":"Lawrence","year":"2003","journal-title":"J. Clin. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1136\/jcp.54.7.553","article-title":"Salicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirin","volume":"54","author":"Blacklock","year":"2001","journal-title":"J. Clin. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S0002-8223(21)03743-3","article-title":"Salicylates in foods","volume":"85","author":"Swain","year":"1985","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S151","DOI":"10.1016\/j.semcancer.2015.03.006","article-title":"A multi-targeted approach to suppress tumor-promoting inflammation","volume":"35","author":"Samadi","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"542","DOI":"10.2174\/15680096113139990036","article-title":"Anti-inflammatory phytochemicals for chemoprevention of colon cancer","volume":"13","author":"Madka","year":"2013","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"G59","DOI":"10.1152\/ajpgi.00101.2014","article-title":"Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention","volume":"309","author":"Fajardo","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17279","DOI":"10.3390\/ijms140917279","article-title":"Potential Targets for Colorectal Cancer Prevention","volume":"14","author":"Temraz","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_13","first-page":"387","article-title":"The Ambidextrous Cyclooxygenase: An Enduring Target","volume":"13","author":"Mayank","year":"2014","journal-title":"Inflamm. Allergy Drug Targets (Discontinued)"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7908","DOI":"10.1038\/sj.onc.1203286","article-title":"The role of cyclooxygenases in inflammation, cancer, and development","volume":"18","author":"Williams","year":"1999","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/jjco\/hyt053","article-title":"Prevention and Intervention Trials for Colorectal Cancer","volume":"43","author":"Komiya","year":"2013","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1136\/gutjnl-2011-300817","article-title":"\u03b2-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells","volume":"61","author":"Smartt","year":"2012","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1056\/NEJM200006293422603","article-title":"The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis","volume":"342","author":"Steinbach","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1158\/1940-6207.CAPR-11-0391","article-title":"Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview","volume":"5","author":"Chan","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/jnci\/djn485","article-title":"Aspirin for the Chemoprevention of Colorectal Adenomas: Meta-analysis of the Randomized Trials","volume":"101","author":"Cole","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1158\/1541-7786.MCR-15-0360","article-title":"Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention","volume":"14","author":"Dachineni","year":"2016","journal-title":"Mol. Cancer Res. (MCR)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1056\/NEJMoa1207756","article-title":"Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival","volume":"367","author":"Liao","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1124\/mol.115.098616","article-title":"Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells","volume":"88","author":"Jung","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jacc.2015.05.012","article-title":"The Multifaceted Clinical Readouts of Platelet Inhibition by Low-Dose Aspirin","volume":"66","author":"Patrono","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/23948","article-title":"The anti-inflammatory agents aspirin and salicylate inhibit the activity of I\u03baB kinase-\u03b2","volume":"396","author":"Yin","year":"1998","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1053\/j.gastro.2012.02.050","article-title":"Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells","volume":"142","author":"Din","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_26","first-page":"383","article-title":"A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells","volume":"9","author":"Goel","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/nrclinonc.2012.216","article-title":"Potential biomarker for aspirin use in colorectal cancer therapy","volume":"10","author":"Langley","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.critrevonc.2016.05.011","article-title":"The role of aspirin in colorectal cancer chemoprevention","volume":"104","year":"2016","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_29","first-page":"254","article-title":"Chemopreventive effects of aspirin at a glance","volume":"1855","author":"Usman","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mehy.2011.09.039","article-title":"Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention","volume":"78","author":"McCarty","year":"2012","journal-title":"Med. Hypotheses"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Afrin, S., Giampieri, F., Gasparrini, M., Forbes-Hernandez, T.Y., Varela-Lopez, A., Quiles, J.L., Mezzetti, B., and Battino, M. (2016). Chemopreventive and Therapeutic Effects of Edible Berries: A Focus on Colon Cancer Prevention and Treatment. Molecules (Basel, Switz.), 21.","DOI":"10.3390\/molecules21020169"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1021\/mp700113r","article-title":"Bioavailability of curcumin: Problems and promises","volume":"4","author":"Anand","year":"2007","journal-title":"Mol. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1055\/s-2006-957450","article-title":"Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers","volume":"64","author":"Shoba","year":"1998","journal-title":"Planta Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1158\/1078-0432.CCR-08-0024","article-title":"Phase II trial of curcumin in patients with advanced pancreatic cancer","volume":"14","author":"Dhillon","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00280-010-1470-2","article-title":"A phase I\/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer","volume":"68","author":"Kanai","year":"2011","journal-title":"Cancer Chemother Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/1055-9965.120.14.1","article-title":"Consumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and their Pharmacodynamic Consequences","volume":"14","author":"Garcea","year":"2005","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_37","first-page":"1894","article-title":"Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer","volume":"7","author":"Sharma","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s11095-011-0375-z","article-title":"Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin","volume":"28","author":"Bansal","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ejps.2009.02.019","article-title":"Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer","volume":"37","author":"Shaikh","year":"2009","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00280-006-0355-x","article-title":"Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine","volume":"60","author":"Marczylo","year":"2007","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1055\/s-2005-864130","article-title":"Selective COX-2 Inhibition by a Pterocarpus marsupium Extract Characterized by Pterostilbene, and its Activity in Healthy Human Volunteers","volume":"71","author":"Hougee","year":"2005","journal-title":"Planta Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"601","DOI":"10.3332\/ecancer.2015.601","article-title":"New concepts and challenges in the clinical translation of cancer preventive therapies: The role of pharmacodynamic biomarkers","volume":"9","author":"Brown","year":"2015","journal-title":"Ecancermedicalscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1001\/archinte.168.15.1629","article-title":"25-hydroxyl Vitamin D Levels and the Risk of Mortality in the General Population","volume":"168","author":"Melamed","year":"2008","journal-title":"Arch. Int. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1016\/S0960-9776(11)70292-2","article-title":"The science behind vitamins and natural compounds for breast cancer prevention. Getting the most prevention out of it","volume":"20","author":"Lazzeroni","year":"2011","journal-title":"The Breast"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/S0140-6736(89)91789-3","article-title":"Serum 25-Hydroxyvitamin D and Colon Cancer: Eight-Year Prospective Study","volume":"334","author":"Garland","year":"1989","journal-title":"The Lancet"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/ijc.11375","article-title":"Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case-control study in the Nordic countries","volume":"108","author":"Tuohimaa","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"djt456","DOI":"10.1093\/jnci\/djt456","article-title":"Baseline Selenium Status and Effects of Selenium and Vitamin E Supplementation on Prostate Cancer Risk","volume":"106","author":"Kristal","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_48","first-page":"298ra117","article-title":"Less is more for cancer chemoprevention: Evidence of a non-linear dose response for the protective effects of resveratrol in humans and mice","volume":"7","author":"Scott","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1158\/1055-9965.EPI-05-0333","article-title":"Does Nonsteroidal Anti-inflammatory Drug Use Modify the Effect of a Low-Fat, High-Fiber Diet on Recurrence of Colorectal Adenomas?","volume":"14","author":"Hartman","year":"2005","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1023\/A:1024990617158","article-title":"Non-steroidal anti-inflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States)","volume":"14","author":"Tangrea","year":"2003","journal-title":"Cancer Causes Control"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1093\/jnci\/94.6.437","article-title":"Calcium Intake and Risk of Colon Cancer in Women and Men","volume":"94","author":"Wu","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1056\/NEJM199901143400204","article-title":"Calcium Supplements for the Prevention of Colorectal Adenomas","volume":"340","author":"Baron","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/aje\/kwh130","article-title":"Physical Activity and Reduced Risk of Incident Sporadic Colorectal Adenomas: Observational Support for Mechanisms Involving Energy Balance and Inflammation Modulation","volume":"159","author":"Hauret","year":"2004","journal-title":"Am. J. Epidemiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1001\/jama.295.6.643","article-title":"Low-fat dietary pattern and risk of colorectal cancer: The women\u2019s health initiative randomized controlled dietary modification trial","volume":"295","author":"Beresford","year":"2006","journal-title":"JAMA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1080\/07315724.2017.1321505","article-title":"Interaction between Nonsteroidal Anti-inflammatory Drugs and Low-fat Dietary Intervention on Colorectal Cancer Incidence; the Women\u2019s Health Initiative (WHI) Dietary Modification Trial","volume":"36","author":"Kato","year":"2017","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1158\/1940-6207.CAPR-11-0106","article-title":"A Randomized Placebo-controlled Prevention Trial of Aspirin and\/or Resistant Starch in Young People with Familial Adenomatous Polyposis","volume":"4","author":"Burn","year":"2011","journal-title":"Cancer Prev. Res. (Philadelphia, Pa.)"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1158\/1940-6207.CAPR-14-0052","article-title":"A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis","volume":"7","author":"Wang","year":"2014","journal-title":"Cancer Prev. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:50:20Z","timestamp":1760194220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,6]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["ijms19010166"],"URL":"https:\/\/doi.org\/10.3390\/ijms19010166","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,6]]}}}