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• W2893859343 abstract "Genomic instability describes a state in which there is an increased tendency to acquire hereditable genetic alterations that may influence phenotype. It characteristically occurs as a consequence of deficient genome maintenance processes, such as DNA repair or cell-cycle checkpoints [[1]Lee J.K. Choi Y.L. Kwon M. Park P.J. Mechanisms and consequences of cancer genome instability: lessons from genome sequencing studies.Ann Rev Pathol. 2016; 11: 283-312Crossref PubMed Scopus (88) Google Scholar]. The genetic alterations that arise are often typified, both in terms of the mechanism of their formation and their functional consequences, by their size. At the smallest scale, the bases at individual nucleotides may be substituted. At the largest scale, entire chromosomes may be gained or lost. Cancer cells often harbour several types of genomic alteration that span the wide range of these limits [[2]Ciriello G. Miller M.L. Aksoy B.A. Senbabaoglu Y. Schultz N. Sander C. Emerging landscape of oncogenic signatures across human cancers.Nat Genet. 2013; 45: 1127-1133Crossref PubMed Scopus (905) Google Scholar] (Table 1).Table 1Genetic alterations come in different shapes and sizesGenetic alterationDescriptionExample(s) of causative genomic instabilitySingle nucleotide variantThe substitution of the base at an individual nucleotidePOLE proofreading mutation [3]Roberts S.A. Gordenin D.A. Hypermutation in human cancer genomes: footprints and mechanisms.Nat Rev Cancer. 2014; 14: 786-800Crossref PubMed Scopus (286) Google ScholarInsertion/deletionThe gain or loss, respectively, of one or a few nucleotidesBRCA1/BRCA2 deficiency [4]Venkitaraman A.R. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Science. 2014; 343: 1470-1475Crossref PubMed Scopus (174) Google ScholarCopy number variantThe gain or loss of copies of a segment of DNA, such as a geneAurora A amplification [5]Anand S. Penrhyn-Lowe S. Venkitaraman A.R. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol.Cancer Cell. 2003; 3: 51-62Abstract Full Text Full Text PDF PubMed Scopus (533) Google ScholarTransposon activity [6]Belancio V.P. LINE-1 activity as molecular basis for genomic instability associated with light exposure at night.Mob Gen Elem. 2015; 5: 1-5Crossref PubMed Scopus (10) Google ScholarTranslocationThe rearrangement of non-homologous chromosomesBRCA1/BRCA2 deficiency [4]Venkitaraman A.R. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Science. 2014; 343: 1470-1475Crossref PubMed Scopus (174) Google ScholarAID/APOBEC activity [7]Casellas R. Basu U. Yewdell W.T. Chaudhuri J. Robbiani D.F. Di Noia J.M. Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity.Nat Rev Immunol. 2016; 16: 164-176Crossref PubMed Scopus (110) Google ScholarAneuploidyThe gain or loss of entire chromosomesp53 deficiency [8]Kastenhuber E.R. Lowe S.W. Putting p53 in context.Cell. 2017; 170: 1062-1078Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar Open table in a new tab The 2011 update detailing the hallmarks of cancer identified genomic instability as an enabling characteristic of cancer [[9]Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (43037) Google Scholar]. In principle, the acquisition of genomic instability facilitates carcinogenesis by enabling a cell and its descendants to alter their genomes. As each cell in this lineage acquires new genetic alterations, a group of cells that are genetically heterogeneous is formed. This sets the stage for the selection of cells that have acquired a growth advantage. Mutations emerge that enable cells to break free of homeostatic limits such as those involving proliferation, invasion, evading cell death etc, leading to classical cancerous behaviour. Defining genomic instability as an enabling characteristic predicates that it must also occur early during tumourigenesis. In keeping with this notion, it is notable that disruption of p53, a protein notorious for its capacity to restrict several types of genomic instability, is the most common founder event in cancer [8Kastenhuber E.R. Lowe S.W. Putting p53 in context.Cell. 2017; 170: 1062-1078Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar, 10Kandoth C. McLellan M.D. Vandin F. Ye K. Niu B. Lu C. et al.Mutational landscape and significance across 12 major cancer types.Nature. 2013; 502: 333-339Crossref PubMed Scopus (2949) Google Scholar]. It is also of note that a large proportion of cancer predisposition syndromes are attributable to defects in genes involved in genome maintenance, and that carcinogenesis occurs precociously in affected individuals (reviewed in [[11]Rahman N. Realizing the promise of cancer predisposition genes.Nature. 2014; 505: 302-308Crossref PubMed Scopus (372) Google Scholar]). These findings are consistent with next-generation sequencing (NGS) data, which consistently identify patterns of genomic instability at early stages of cancer development [12Campbell P.J. Yachida S. Mudie L.J. Stephens P.J. Pleasance E.D. Stebbings L.A. et al.The patterns and dynamics of genomic instability in metastatic pancreatic cancer.Nature. 2010; 467: 1109-1113Crossref PubMed Scopus (1039) Google Scholar, 13de Bruin E.C. McGranahan N. Mitter R. Salm M. Wedge D.C. Yates L. et al.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Science. 2014; 346: 251-256Crossref PubMed Scopus (783) Google Scholar]. These NGS approaches allow us to distinguish between ongoing genomic instability and the ‘scars’ of past episodes of genomic instability that may be detected by sequencing. Thus, technically, genomic instability defines the rate of mutation, whereas the readout from NGS generally provides a static snapshot of its impact. However, comparative sequencing of serially acquired or spatially distinct samples can provide a better reflection of mutational rates. In sum, these studies have confirmed that practically all cancers carry several mutations in their genome, although the burden of mutations varies across tumour types. In most solid tumours, on average 33–66 genes are significantly mutated, whereas in lung cancer and melanoma this number is nearer 200 [[14]Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz Jr., L.A. Kinzler K.W. Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5228) Google Scholar]. Although the rationale for genomic instability can be explained relatively simply, its causes and consequences are far more nuanced. As described earlier, mutational burden, and by inference genomic instability, varies across different tumour types. In addition, beyond the number of mutations, genomic instability can also differ based on the type of mutation present. Indeed, various mutational signatures have been deconvoluted from mixed patterns of single nucleotide variants in cancer genomes. In 2013, a seminal paper identified 21 distinct mutational signatures on the basis of 4 938 362 mutations from 7042 cancers [[15]Alexandrov L.B. Nik-Zainal S. Wedge D.C. Campbell P.J. Stratton M.R. Deciphering signatures of mutational processes operative in human cancer.Cell Rep. 2013; 3: 246-259Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar]. Certain signatures were associated with known mechanisms of mutagenesis. For instance, Signature 7 was frequently seen in malignant melanoma and was attributed to DNA damage from ultraviolet light. A smoking-related signature was also reported in lung cancer. Further signatures were connected to DNA repair defects. Within the cell, damaged DNA is repaired through multiple processes and the choice of repair pathway is characteristically associated with the type of DNA lesion. For instance, mismatch repair (MMR) acts on base–base mismatches and insertion/deletion mispairs, whereas homologous recombination repairs breaks in double-strand DNA. Defects in MMR (e.g. through MLH1 inactivation) and homologous recombination (e.g. through BRCA1 and BRCA2 inactivation) are classically associated with colorectal cancers or breast and ovarian cancers, respectively. However, the reasons behind these tissue specificities have proven far harder to decipher. They may partly be explained by the fact that genes are expressed differentially across tissue types and that each site has a unique microenvironment and exposure to exogenous agents. For instance, BRCA1 has been shown to mediate early differentiation of breast tissue and has also been implicated in the repair of double-stranded DNA breaks from oestrogen and oestrogen metabolites [4Venkitaraman A.R. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Science. 2014; 343: 1470-1475Crossref PubMed Scopus (174) Google Scholar, 16Liu S. Ginestier C. Charafe-Jauffret E. Foco H. Kleer C.G. Merajver S.D. et al.BRCA1 regulates human mammary stem/progenitor cell fate.Proc Natl Acad Sci USA. 2008; 105: 1680-1685Crossref PubMed Scopus (363) Google Scholar, 17Savage K.I. Matchett K.B. Barros E.M. Cooper K.M. Irwin G.W. Gorski J.J. et al.BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.Cancer Res. 2014; 74: 2773-2784Crossref PubMed Scopus (79) Google Scholar]. Together, these findings only reveal a limited view of the true sequence of events but reiterate that multiple mechanisms are likely to be involved. In fact, it has also become apparent that genomic instability does not continue at a steady and unrelenting rate throughout tumour evolution [[13]de Bruin E.C. McGranahan N. Mitter R. Salm M. Wedge D.C. Yates L. et al.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Science. 2014; 346: 251-256Crossref PubMed Scopus (783) Google Scholar]. This is important because such complexity amplifies the challenge of translating our scientific understanding into improvements to clinical care (Figure 1). Indeed, as yet there are no reliable clinical biomarkers for genomic instability and this is in large part due to its temporal dynamics (reviewed in [[18]Sansregret L. Vanhaesebroeck B. Swanton C. Determinants and clinical implications of chromosomal instability in cancer.Nat Rev Clin Oncol. 2018; 15: 139-150Crossref PubMed Scopus (184) Google Scholar]). This is because, as already discussed, current techniques used to measure features associated with genomic instability, e.g. aneuploidy, provide static snapshots that do not robustly correlate with the true nature of instability present. Identifying individuals who are predisposed to cancer due to inherited changes in genome maintenance processes is of significant clinical value. This is because these patients can then be targeted for cancer prevention strategies and/or screened in order to diagnose cancers at an early and potentially curable stage. In this cohort of patients one could hypothesise that relatively simple interventions, such as smoking cessation, could have profound effects on cancer risk reduction. If we were better able to understand the mechanisms behind cancer predisposition in these men and women, more specific interventions could also be developed. These principles are already being applied in the management of individuals carrying germline mutations in the BRCA1 or BRCA2 gene. Cancer predisposition in these cases is associated with increased genomic instability (reviewed in [[4]Venkitaraman A.R. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Science. 2014; 343: 1470-1475Crossref PubMed Scopus (174) Google Scholar]). These individuals may benefit from cancer detection and prevention strategies. Women with BRCA1 and BRCA2 mutations are currently offered the choice between more intensive screening or bilateral mastectomy and oophorectomy. Recent clinical evidence also supports the use of tamoxifen in these cases as a cancer prevention strategy. A pooled observational cohort study of almost 1600 BRCA mutation carriers showed that tamoxifen use after a diagnosis of breast cancer reduced the risk of cancer by around a half in the contralateral breast [[19]Phillips K.A. Milne R.L. Rookus M.A. Daly M.B. Antoniou A.C. Peock S. et al.Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.J Clin Oncol. 2013; 31: 3091-3099Crossref PubMed Scopus (146) Google Scholar]. One can argue that the genomic instability of cancer has long been a target of cancer therapy, based on the relative sensitivity of cancer cells to cytotoxic drugs and radiotherapy when compared with normal tissue. This notion is exemplified by the effectiveness of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA-deficient cells. This, alongside other advances in using DNA repair inhibitors for cancer treatment, is reviewed elsewhere [20Chalmers A.J. Science in Focus: combining Radiotherapy with inhibitors of the DNA damage response.Clin Oncol. 2016; 28: 279-282Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 21O'Connor M.J. Targeting the DNA damage response in cancer.Mol Cell. 2015; 60: 547-560Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar]. Our review focuses on the implications of genomic instability as a whole on anticancer therapy. How may we appraise the impact that genomic instability has upon cancer therapy? A study aimed at addressing this question used sequencing data from a broad range of tumour types and associated copy number variants (CNVs) with clinical outcome. The results showed that tumours with either the lowest or highest rate of CNVs carried the most favourable outcomes [[22]Andor N. Graham T.A. Jansen M. Xia L.C. Aktipis C.A. Petritsch C. et al.Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.Nat Med. 2016; 22: 105-113Crossref PubMed Scopus (469) Google Scholar]. This suggests that either too little or too much genomic instability can be detrimental to a cancer's survival. There are a number of possible explanations for these intriguing findings. Cancers require a minimum level of instability so that they are more easily able to evolve resistance mechanisms to the therapeutic agent. However in those cancers with excessively high levels of genomic instability (>75% CNVs), genome maintenance is impaired to the extent that the chances of producing viable daughter cells is significantly lowered. Moreover, cells with high levels of instability may be exquisitely sensitive to DNA-damaging agents due to massively impaired DNA repair and may also be more susceptible to destruction by the immune system (discussed later). These results suggest that we can stratify patients based on their profiles of genomic instability. However, as already discussed, an accurate biomarker of genomic instability remains to be discovered. In 2017, the TracerX study published preliminary data from 100 lung cancer patients who had multiple spatially distinct surgical samples sent for sequencing [[23]Jamal-Hanjani M. Wilson G.A. McGranahan N. Birkbak N.J. Watkins T.B.K. Veeriah S. et al.Tracking the evolution of non-small-cell lung cancer.New Engl J Med. 2017; 376: 2109-2121Crossref PubMed Scopus (1327) Google Scholar]. The investigators were able to derive a measure of chromosomal instability by measuring ‘mirrored subclonal allelic imbalance’. In simple terms, this relies on comparing evolving genomic changes within the tumour specimens on the basis of subclonal changes in maternal and paternal alleles. The data confirmed that increased levels of chromosomal instability correlated with intratumoral heterogeneity as well as increased risk of recurrence or death. These results suggest that genomic instability can therefore inform prognosis, and patients at higher risk may benefit from more regular follow-up. Measuring circulating tumour DNA in these individuals may be particularly advantageous as it may allow the diagnosis of relapse or residual disease prior to clinically evident metastases [[24]O'Leary B. Turner N.C. Science in focus: circulating tumour DNA as a liquid biopsy.Clin Oncol. 2016; 28: 735-738Abstract Full Text Full Text PDF Scopus (10) Google Scholar]. The extent to which these patients would benefit from more intensive adjuvant therapy is open to debate. However, based on the study described above, one could argue that a proportion of these patients will be relatively sensitive to anticancer therapy. Beyond informing clinicians as to which patients require treatment and their likely prognosis, our understanding of genomic instability may also guide the choice of therapeutic agent. PARP1 inhibitors have an established role in 1–5% of women with breast cancer who have inherited mutations in BRCA1 or 2. However, a recent study identified six distinct mutational signatures predictive of BRCA deficiency, which potentially increases the proportion of patients who may benefit from PARP1 inhibition to 22% [[25]Davies H. Glodzik D. Morganella S. Yates L.R. Staaf J. Zou X. et al.HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.Nat Med. 2017; 23: 517-525Crossref PubMed Scopus (521) Google Scholar]. These findings remain to be validated in clinical cohorts but form the basis for tangible and exciting translational clinical trials. A greater understanding of the interaction of genomic instability and the immune response has also led to important clinical observations. Cancer cells deficient in MMR acquire a large number of somatic mutations. This can lead to an increase in ‘non-self’ immunogenic antigens, which renders these cells more sensitive to immune-mediated therapies. Accordingly, in a phase II study, patients with MMR-deficient colorectal (and non-colorectal) tumours had significantly better clinical outcomes after treatment with an anti-programmed death 1 (PD-1) immune checkpoint inhibitor, pembrolizumab [[26]Le D.T. Uram J.N. Wang H. Bartlett B.R. Kemberling H. Eyring A.D. et al.PD-1 blockade in tumors with mismatch-repair deficiency.New Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6157) Google Scholar]. There may, however, be a more complex relationship between mutational load and response to immunotherapy. For example, a recent study highlighted that mutations that occur early in evolution, and are therefore present in a greater proportion of subclones, improve immune recognition, as opposed to mutations that occur late and increase tumour diversity [[27]McGranahan N. Furness A.J. Rosenthal R. Ramskov S. Lyngaa R. Saini S.K. et al.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469Crossref PubMed Scopus (1962) Google Scholar]. Moreover, aneuploidy has been associated with markers of immune evasion and poor clinical responses to immunotherapy [[28]Davoli T. Uno H. Wooten E.C. Elledge S.J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.Science. 2017; 355https://doi.org/10.1126/science.aaf8399Crossref PubMed Scopus (687) Google Scholar]. A number of other treatment strategies leveraging the effects of genomic instability are also actively being pursued. For instance, aneuploid cells have been shown to be more sensitive to agents that increase metabolic stress [[29]Tang Y.C. Williams B.R. Siegel J.J. Amon A. Identification of aneuploidy-selective antiproliferation compounds.Cell. 2011; 144: 499-512Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. Therapies that may reduce tolerance of genomic instability, such as reactivation of wildtype p53 function, have also been investigated, but as yet remain clinically unproven (reviewed in [[30]Bykov V.J.N. Eriksson S.E. Bianchi J. Wiman K.G. Targeting mutant p53 for efficient cancer therapy.Nat Rev Cancer. 2018; 18: 89-102Crossref PubMed Scopus (494) Google Scholar]). But what are the costs of targeting genomic instability in terms of toxicity? The most important consideration in this regard relates to the risk of secondary malignancy. One might hypothesise that interfering with genomic stability in normal cells might greatly increase second cancer risk, particularly if DNA repair drugs are used in combination with DNA-damaging agents. Most of our current data are in patients receiving the PARP inhibitor olaparib. There have been initial concerns that the drug might lead to myelodysplastic syndrome and therapy-related acute myeloid leukaemia (MDS/t-AML). However, most of these patients had been heavily pre-treated with platinum agents and were therefore already at significant risk of a second cancer. A proportion of olaparib-based studies have follow-up data beyond 5 years and pooled data from all studies suggest a cumulative incidence for MDS/t-AML of 0.5% [[31]Matulonis U.A. Penson R.T. Domchek S.M. Kaufman B. Shapira-Frommer R. Audeh M.W. et al.Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.Ann Oncol. 2016; 27: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Presently no causative association with the drug has been established. The data on newer anti-DDR drugs have yet to mature and importantly many cases of second cancers associated with cytotoxic drugs and radiotherapy did not emerge until decades after treatment. This is therefore an area that requires close monitoring. To conclude, genomic instability is a key enabler of tumour evolution. In recent years it has become clear that its presence contributes to the complexity and heterogeneity of human cancer. Moreover, early strategies to leverage genomic instability in order to improve clinical outcomes have proved successful. It is likely that as our understanding of the phenomenon increases, our opportunities to exploit it will also increase. The authors declare no conflict of interest." @default.
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• W2893859343 title "Science in Focus: Genomic Instability and its Implications for Clinical Cancer Care" @default.
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