[Abstract] The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations. ; This article is based upon work from COST Action hCOMET CA15132, supported by COST (European Cooperation in Science and Technology www.cost.eu) - STSM fellowships for Mirta Milić (IMROH, EU 19); IMROH, Zagreb, Croatia, Institute for Medical Research and Occupational Health (IMROH), Zagreb, Croatia, and the Ministry of Science, Education and Sports of the Republic of Croatia (Grant No. 022-0222148-2125) (EU4); Cancer Plan for PestiBG; Grant number: no ENV201401(EU 8, EU9); Italian Ministry of Education, University and Research PRIN 2005, prot. 2005058197 and Cariplo Foundation (Milan, Italy), Rif. Pratica 2007-5810 and Rif. Pratica 2010.2303 (EU 18); Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 2015/17564). (EU19); European Union Integrated Projects New Generis, 6th Framework Programme, Priority 5: Food Quality and Safety; Newborns and Genotoxic Exposure Risks, FOOD-CT-2005-016320 (EU22); ACT project No. 036APy/09 and No. 005DBB/12 (EU 24); FCT-SFRH/BPD/96196/2013, SFRH/BPD/100948/2014, Portugal (EU 26); MZ 2012/8-UKBA-8; VEGA 1/0703/13, APVV 15-0063 (EU30); Xunta de Galicia (XUGA 10605B98; INCITE08PXIB106155PR; ED481B2016/190-0; Grants ED431B2019/02), Spain (EU 32); Grant 01 173034, Ministry of Education, Science and Technological Development of the Republic of Serbia (EU 42); The Centre for Industrial and Technological Development within National Strategic Consortia for Techical Research (Industrial Research diets and food with specific characteristics for elderly, SENIFOOD); University of Navarra LE/97; Physiopathology of Obesity and Nutrition (CIBER Obn); Carlos III Health Research Institute (CB12/03/30002); Ministerio de Economia y Compatitividad ('Ramón y Cajal' Programme, RYC-2013-14370) of the Spanish Government for personal support (EU 45); the Ministry of Education, Youth and Sports of the Czech Republic project Healthy Aging in Industrial Environment HAIE (CZ.02.1.01/0.0/0.0/16_019/0000798) which is co-financed by the European Union (European Structural and Investment funds; Operation Programme Research, Development and Education); MYES LO 1508 (EU 46); MICRODIAB Study; ClinicalTrials.org (#NCT02231736) (EU 52); The study was funded by the Italian Ministry for Education, University and Scientific Research (MIUR) - Research No. 2005-062547 (EU14, EU53); Projects financed from Serbian Ministry of Education, Science and Technological Development #11146002, #175035, #173034 (EU 54); Mehr foundation organisation, UK (EU 55); MCTI/CNPQ No. 01/2016-Universal; FAPESC No. 09/2015; MEC/MCTI/CAPES/CNPQ/FAPS/ No. 09/2014, Brazil (CSA 6); the National Nuclear Energy Agency of Indonesia (Badan Tenaga Nuklir Nasional) with contract number 080.01.06 3447.001 001.052.A (AS4); Slovak Grant Agency (APVT-21 013202, APVT-21- 017704); Ministry of Health, Slovak Republic (2005/43-SZU-21, 2006/07- SZU-02 MZ SR, 2005/42-SZU-20
Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd. ; Funding Agencies|Terry Fox Foundation Grant [TF-13-20]; UAEU Program for Advanced Research (UPAR) [31S118]; NIH [AR47901, R21CA188818, R15 CA137499-01, F32CA177139, P20RR016477, P20GM103434, R01CA170378, U54CA149145, U54CA143907, R01-HL107652, R01CA166348, R01GM071725, R01 CA109335-04A1, 109511R01CA151304CA168997 A11106131R03CA1711326 1P01AT003961RO1 CA100816P01AG034906 R01AG020642P01AG034906-01A1R01HL108006]; NIH NRSA Grant [F31CA154080]; NIH (NIAID) R01: Combination therapies for chronic HBV, liver disease, and cancer [AI076535]; Sky Foundation Inc. Michigan; University of Glasgow; Beatson Oncology Centre Fund; Spanish Ministry of Economy and Competitivity, ISCIII [PI12/00137, RTICC: RD12/0036/0028]; FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion [CTS-6844, CTS-1848]; Consejeria de Salud of the Junta de Andalucia [PI-0135-2010, PI-0306-2012]; ISCIII [PIE13/0004]; FEDER funds; United Soybean Board; NIH NCCAM Grant [K01AT007324]; NIH NCI Grant [R33 CA161873-02]; Michael Cuccione Childhood Cancer Foundation Graduate Studentship; Ovarian and Prostate Cancer Research Trust, UK; West Virginia Higher Education Policy Commission/Division of Science Research; National Institutes of Health; Italian Association for Cancer Research (AIRC) [IG10636, 15403]; GRACE Charity, UK; Breast Cancer Campaign, UK; Michael Cuccione Childhood Cancer Foundation Postdoctoral Fellowship; Connecticut State University; Swedish Research Council; Swedish Research Society; University of Texas Health Science Centre at Tyler, Elsa U. Pardee Foundation; CPRIT; Cancer Prevention and Research Institute of Texas; NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA); Gilead and Shire Pharmaceuticals; NIH/NCI [1R01CA20009, 5R01CAl27258-05, R21CA184788, NIH P30 CA22453, NCI RO1 28704]; Scottish Governments Rural and Environment Science and Analytical Services Division; National Research Foundation; United Arab Emirates University; Terry Fox Foundation; Novartis Pharmaceutical; Aveo Pharmaceutical; Roche; Bristol Myers Squibb; Bayer Pharmaceutical; Pfizer; Kyowa Kirin; NIH/NIAID Grant [A1076535]; Auckland Cancer Society; Cancer Society of New Zealand; NIH Public Service Grant from the National Cancer Institute [CA164095]; Medical Research Council CCU-Program Grant on cancer metabolism; EU Marie Curie Reintegration Grant [MC-CIG-303514]; Greek National funds through the Operational Program Educational and Lifelong Learning of the National Strategic Reference Framework (NSRF)-Research Funding Program THALES [MIS 379346]; COST Action CM1201 `Biomimetic Radical Chemistry; Duke University Molecular Cancer Biology T32 Training Grant; National Sciences Engineering and Research Council Undergraduate Student Research Award in Canada; Charles University in Prague projects [UNCE 204015, PRVOUK P31/2012]; Czech Science Foundation projects [15-03834Y, P301/12/1686]; Czech Health Research Council AZV project [15-32432A]; Internal Grant Agency of the Ministry of Health of the Czech Republic project [NT13663-3/2012]; National Institute of Aging [P30AG028716-01]; NIH/NCI training grants to Duke University [T32-CA059365-19, 5T32-CA059365]; Ministry of Education, Culture, Sports, Science and Technology, Japan [24590493]; Ministry of Health and Welfare [CCMP101-RD-031, CCMP102-RD-112]; Tzu-Chi University of Taiwan [61040055-10]; Svenska Sallskapet for Medicinsk Forskning; Cancer Research Wales; Albert Hung Foundation; Fong Family Foundation; Welsh Government A4B scheme; NIH NCI; University of Glasgow, Beatson Oncology Centre Fund, CRUK [C301/A14762]; NIH Intramural Research Program; National Science Foundation; American Cancer Society; National Cancer Center [NCC-1310430-2]; National Research Foundation [NRF-2005-0093837]; Sol Goldman Pancreatic Cancer Research Fund Grant [80028595]; Lustgarten Fund Grant [90049125, NIHR21CA169757]; Alma Toorock Memorial for Cancer Research; National Research Foundation of Korea (NRF); Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea [2011-0017639, 2011-0030001]; Ministry of Education of Taiwan [TMUTOP103005-4]; International Life Sciences Institute; United States Public Health Services Grants [NIH R01CA156776]; VA-BLR&D Merit Review Grant [5101-BX001517-02]; V Foundation; Pancreatic Cancer Action Network; Damon Runyon Cancer Research Foundation; Childrens Cancer Institute Australia; University Roma Tre; Italian Association for Cancer Research (AIRC-Grant) [IG15221]; Carlos III Health Institute; Feder funds [AM: CP10/00539, PI13/02277]; Basque Foundation for Science (IKERBASQUE); Marie Curie CIG Grant [2012/712404]; Canadian Institutes of Health Research; Avon Foundation for Women [OBC-134038]; Canadian Institutes of Health [MSH-136647, MOP 64308]; Bayer Healthcare System G4T (Grants4Targets); NIH NIDDK; NIH NIAAA; Shire Pharmaceuticals; Harvard-MIT Health Sciences and Technology Research Assistantship Award; Italian Ministry of University; University of Italy; Auckland Cancer Society Research Centre (ACSRC); German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF) [16SV5536K]; European Commission [FP7 259679 "IDEAL"]; Cinque per Mille dellIRPEF-Finanziamento della Ricerca Sanitaria; European Union Seventh Framework Programme (FP7) [278570]; AIRC [10216, 13837]; European Communitys Seventh Framework Program FP7 [311876]; Canadian Institute for Health Research [MOP114962, MOP125857]; Fonds de Recherche Quebec Sante [22624]; Terry Fox Research Institute [1030]; FEDER; MICINN [SAF2012-32810]; Junta de Castilla y Leon [BIO/SA06/13]; ARIMMORA project [FP7-ENV-2011]; European Union; NIH NIDDK [K01DK077137, R03DK089130]; NIH NCI grants [R01CA131294, R21 CA155686]; Avon Foundation; Breast Cancer Research Foundation Grant [90047965]; National Institute of Health, NINDS Grant [K08NS083732]; AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research [13-20-23-SIEG]; Department of Science and Technology, New Delhi, India [SR/FT/LS-063/2008]; Yorkshire Cancer Research; Wellcome Trust, UK; Italian Ministry of Economy and Finance Project CAMPUS-QUARC, within program FESR Campania Region; National Cancer Institute [5P01CA073992]; IDEA Award from the Department of Defense [W81XWH-12-1-0515]; Huntsman Cancer Foundation; University of Miami Clinical and Translational Science Institute (CTSI) Pilot Research Grant [CTSI-2013-P03]; SEEDS You Choose Awards; DoD [W81XVVH-11-1-0272, W81XWH-13-1-0182]; Kimmel Translational Science Award [SKF-13-021]; ACS Scholar award [122688-RSG-12-196-01-TBG]; National Cancer Institute, Pancreatic Cancer Action Network, Pew Charitable Trusts; American Diabetes Association; Elsa U. Pardee Foundation; Scientific Research Foundation for the Returned Oversea Scholars, State Education Ministry and Scientific and Technological Innovation Project, Harbin [2012RFLX5011]; United States National Institutes of Health [ES019458]; California Breast Cancer Research Program [17UB-8708]; National Institutes of Health through the RCMI-Center for Environmental Health [G1200MD007581]; NIH/National Heart, Lung, and Blood Institute Training Grant [T32HL098062]; European FP7-TuMIC [HEALTH-F2-2008-201662]; Italian Association for Cancer research (AIRC) Grant IG [11963]; Regione Campania L.R:N.5; European National Funds [PON01-02388/1 2007-2013]
