{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:39:58Z","timestamp":1790739598334,"version":"4.1.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,5,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tumor heterogeneity complicates biomarker development and fosters drug resistance in solid malignancies. In lymphoma, our knowledge of site-to-site heterogeneity and its clinical implications is still limited. Here, we profiled 2 nodal, synchronously acquired tumor samples from 10 patients with follicular lymphoma (FL) using single-cell RNA, B-cell receptor (BCR) and T-cell receptor sequencing, and flow cytometry. By following the rapidly mutating tumor immunoglobulin genes, we discovered that BCR subclones were shared between the 2 tumor sites in some patients, but in many patients, the disease had evolved separately with limited tumor cell migration between the sites. Patients exhibiting divergent BCR evolution also exhibited divergent tumor gene-expression and cell-surface protein profiles. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper (Tfh) cell abundance. We further observed enrichment of particular ligand-receptor pairs between tumor and Tfh cells, including CD40 and CD40LG, and a significant correlation between tumor CD40 expression and Tfh proliferation. Our study may explain discordant responses to systemic therapies, underscores the difficulty of capturing a patient\u2019s disease with a single biopsy, and furthers our understanding of tumor-immune networks in FL.<\/jats:p>","DOI":"10.1182\/blood.2020009855","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T23:55:46Z","timestamp":1615938946000},"page":"2869-2880","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":93,"title":["Single-cell analysis can define distinct evolution of tumor sites in follicular lymphoma"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6813-5476","authenticated-orcid":false,"given":"Sarah","family":"Haebe","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-3512","authenticated-orcid":false,"given":"Tanaya","family":"Shree","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2100-0013","authenticated-orcid":false,"given":"Anuja","family":"Sathe","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9150-1182","authenticated-orcid":false,"given":"Grady","family":"Day","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra K.","family":"Czerwinski","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Grimes","sequence":"additional","affiliation":[{"name":"Stanford Genome Technology Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0973-9544","authenticated-orcid":false,"given":"HoJoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2640-5255","authenticated-orcid":false,"given":"Michael S.","family":"Binkley","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8539-9556","authenticated-orcid":false,"given":"Brock","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-3424","authenticated-orcid":false,"given":"Hanlee P.","family":"Ji","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"},{"name":"Stanford Genome Technology Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-0650","authenticated-orcid":false,"given":"Ronald","family":"Levy","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"7467","key":"2021052721431250200_B1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature12624","article-title":"Tumour heterogeneity and cancer cell plasticity","volume":"501","author":"Meacham","year":"2013","journal-title":"Nature"},{"issue":"1","key":"2021052721431250200_B2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nm.3984","article-title":"Pan-cancer analysis of the extent and consequences of intratumor heterogeneity","volume":"22","author":"Andor","year":"2016","journal-title":"Nat Med"},{"issue":"7319","key":"2021052721431250200_B3","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nature09515","article-title":"Distant metastasis occurs late during the genetic evolution of pancreatic cancer","volume":"467","author":"Yachida","year":"2010","journal-title":"Nature"},{"issue":"10","key":"2021052721431250200_B4","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1113205","article-title":"Intratumor heterogeneity and branched evolution revealed by multiregion sequencing","volume":"366","author":"Gerlinger","year":"2012","journal-title":"N Engl J Med"},{"issue":"6","key":"2021052721431250200_B5","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1182\/blood-2013-03-491514","article-title":"Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience","volume":"122","author":"Tan","year":"2013","journal-title":"Blood"},{"issue":"3","key":"2021052721431250200_B6","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/leu.2014.251","article-title":"Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry Study","volume":"29","author":"Junl\u00e9n","year":"2015","journal-title":"Leukemia"},{"issue":"23","key":"2021052721431250200_B7","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1200\/JCO.2014.59.7534","article-title":"Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study [published correction appears in J Clin Oncol. 2016;34(12):1430]","volume":"33","author":"Casulo","year":"2015","journal-title":"J Clin Oncol"},{"issue":"11","key":"2021052721431250200_B8","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1002\/ajh.24492","article-title":"Early event status informs subsequent outcome in newly diagnosed follicular lymphoma","volume":"91","author":"Maurer","year":"2016","journal-title":"Am J Hematol"},{"issue":"7","key":"2021052721431250200_B9","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/annonc\/mdx097","article-title":"International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017)","volume":"28","author":"Younes","year":"2017","journal-title":"Ann Oncol"},{"issue":"32","key":"2021052721431250200_B10","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1200\/JCO.2008.16.0283","article-title":"Population-based analysis of incidence and outcome of transformed non-Hodgkin\u2019s lymphoma","volume":"26","author":"Al-Tourah","year":"2008","journal-title":"J Clin Oncol"},{"issue":"6","key":"2021052721431250200_B11","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1182\/blood.V99.6.2192","article-title":"Tumor cell dissemination in follicular lymphoma","volume":"99","author":"Oeschger","year":"2002","journal-title":"Blood"},{"issue":"9","key":"2021052721431250200_B12","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.3324\/haematol.2012.074252","article-title":"Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse","volume":"98","author":"Wartenberg","year":"2013","journal-title":"Haematologica"},{"issue":"5","key":"2021052721431250200_B13","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/s41375-018-0043-y","article-title":"Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma [published correction appears in Leukemia. 2019;33(6):1540]","volume":"32","author":"Araf","year":"2018","journal-title":"Leukemia"},{"issue":"10","key":"2021052721431250200_B14","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1158\/2159-8290.CD-18-0743","article-title":"In situ vaccination with a TLR9 agonist and local low-dose radiation induces systemic responses in untreated indolent lymphoma","volume":"8","author":"Frank","year":"2018","journal-title":"Cancer Discov"},{"issue":"5","key":"2021052721431250200_B15","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat Biotechnol"},{"issue":"7","key":"2021052721431250200_B16","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2021052721431250200_B17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF01908075","article-title":"Comparing partitions","volume":"2","author":"Hubert","year":"1985","journal-title":"J Classif"},{"issue":"20","key":"2021052721431250200_B18","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1093\/bioinformatics\/btv359","article-title":"Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data","volume":"31","author":"Gupta","year":"2015","journal-title":"Bioinformatics"},{"key":"2021052721431250200_B19","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/msb.2011.75","article-title":"Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol Syst Biol"},{"issue":"22","key":"2021052721431250200_B20","doi-asserted-by":"crossref","first-page":"3718","DOI":"10.1093\/bioinformatics\/btv428","article-title":"dendextend: an R package for visualizing, adjusting and comparing trees of hierarchical clustering","volume":"31","author":"Galili","year":"2015","journal-title":"Bioinformatics"},{"issue":"20","key":"2021052721431250200_B21","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJM199911113412007","article-title":"Cellular origin of human B-cell lymphomas","volume":"341","author":"K\u00fcppers","year":"1999","journal-title":"N Engl J Med"},{"key":"2021052721431250200_B22","first-page":"1","article-title":"Statistisch-\u00f6kologische Untersuchungen \u00fcber die terrestrische K\u00e4ferwelt der finnischen Bruchmoore","volume":"6","author":"Renkonen","year":"1938","journal-title":"Annales Zoologici Societatis Zoologicae-Botanicae Fennicae Vanamo"},{"issue":"4","key":"2021052721431250200_B23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat Biotechnol"},{"issue":"10","key":"2021052721431250200_B24","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1182\/blood-2018-08-862292","article-title":"Single-cell RNA-Seq of follicular lymphoma reveals malignant B-cell types and coexpression of T-cell immune checkpoints","volume":"133","author":"Andor","year":"2019","journal-title":"Blood"},{"issue":"9","key":"2021052721431250200_B25","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/s41590-018-0181-4","article-title":"Human germinal center transcriptional programs are de-synchronized in B cell lymphoma","volume":"19","author":"Milpied","year":"2018","journal-title":"Nat Immunol"},{"issue":"7","key":"2021052721431250200_B26","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/s41556-020-0532-x","article-title":"Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels","volume":"22","author":"Roider","year":"2020","journal-title":"Nat Cell Biol"},{"issue":"9","key":"2021052721431250200_B27","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1200\/JCO.2010.32.1398","article-title":"Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin\u2019s lymphoma and mantle cell lymphoma","volume":"29","author":"Kirschbaum","year":"2011","journal-title":"J Clin Oncol"},{"issue":"26","key":"2021052721431250200_B28","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1200\/JCO.2008.21.3017","article-title":"Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin\u2019s lymphoma","volume":"27","author":"Advani","year":"2009","journal-title":"J Clin Oncol"},{"issue":"5","key":"2021052721431250200_B29","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1016\/S2352-3026(19)30026-2","article-title":"Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS)","volume":"6","author":"Morschhauser","year":"2019","journal-title":"Lancet Haematol"},{"issue":"3","key":"2021052721431250200_B30","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/2159-8290.CD-19-0680","article-title":"Single-cell transcriptome analysis reveals disease-defining T-cell subsets in the tumor microenvironment of classic Hodgkin lymphoma","volume":"10","author":"Aoki","year":"2020","journal-title":"Cancer Discov"},{"issue":"15","key":"2021052721431250200_B31","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1182\/blood-2015-02-625152","article-title":"CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells","volume":"125","author":"Am\u00e9-Thomas","year":"2015","journal-title":"Blood"},{"issue":"5","key":"2021052721431250200_B32","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.immuni.2018.09.009","article-title":"High-dimensional single-cell analysis identifies organ-specific signatures and conserved NK cell subsets in humans and mice","volume":"49","author":"Crinier","year":"2018","journal-title":"Immunity"},{"issue":"6335","key":"2021052721431250200_B33","doi-asserted-by":"crossref","first-page":"eaah4573","DOI":"10.1126\/science.aah4573","article-title":"Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors","volume":"356","author":"Villani","year":"2017","journal-title":"Science"},{"issue":"4","key":"2021052721431250200_B34","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes","volume":"15","author":"Efremova","year":"2020","journal-title":"Nat Protoc"},{"issue":"1","key":"2021052721431250200_B35","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1182\/blood.V91.1.244","article-title":"Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival","volume":"91","author":"Ghia","year":"1998","journal-title":"Blood"},{"issue":"2","key":"2021052721431250200_B36","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.4049\/jimmunol.181.2.1001","article-title":"CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL","volume":"181","author":"Travert","year":"2008","journal-title":"J Immunol"},{"issue":"5","key":"2021052721431250200_B37","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/leu.2011.301","article-title":"Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells","volume":"26","author":"Am\u00e9-Thomas","year":"2012","journal-title":"Leukemia"},{"issue":"4","key":"2021052721431250200_B38","first-page":"912","article-title":"CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin\u2019s disease","volume":"147","author":"Carbone","year":"1995","journal-title":"Am J Pathol"},{"issue":"1","key":"2021052721431250200_B39","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/imr.12860","article-title":"T follicular helper cells in germinal center B cell selection and lymphomagenesis","volume":"296","author":"Mintz","year":"2020","journal-title":"Immunol Rev"},{"issue":"2","key":"2021052721431250200_B40","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.immuni.2019.05.022","article-title":"The HVEM-BTLA axis restrains T cell help to germinal center B cells and functions as a cell-extrinsic suppressor in lymphomagenesis","volume":"51","author":"Mintz","year":"2019","journal-title":"Immunity"},{"issue":"2","key":"2021052721431250200_B41","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cell.2016.08.032","article-title":"Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells","volume":"167","author":"Boice","year":"2016","journal-title":"Cell"},{"issue":"5","key":"2021052721431250200_B42","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.exphem.2010.02.008","article-title":"Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma cells","volume":"38","author":"de Totero","year":"2010","journal-title":"Exp Hematol"},{"issue":"1","key":"2021052721431250200_B43","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.coi.2010.10.007","article-title":"Regulation of T follicular helper cell formation and function by antigen presenting cells","volume":"23","author":"Deenick","year":"2011","journal-title":"Curr Opin Immunol"},{"issue":"4","key":"2021052721431250200_B44","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1365-2567.2011.03487.x","article-title":"The regulation and role of T follicular helper cells in immunity","volume":"134","author":"Deenick","year":"2011","journal-title":"Immunology"},{"issue":"1","key":"2021052721431250200_B45","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41572-019-0132-x","article-title":"Follicular lymphoma","volume":"5","author":"Carbone","year":"2019","journal-title":"Nat Rev Dis Primers"},{"issue":"12","key":"2021052721431250200_B46","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1038\/leu.2010.223","article-title":"Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis","volume":"24","author":"Pangault","year":"2010","journal-title":"Leukemia"},{"issue":"4","key":"2021052721431250200_B47","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1470-2045(18)30102-5","article-title":"A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts","volume":"19","author":"Huet","year":"2018","journal-title":"Lancet Oncol"},{"issue":"2","key":"2021052721431250200_B48","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ng.2856","article-title":"Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma","volume":"46","author":"Okosun","year":"2014","journal-title":"Nat Genet"},{"issue":"1","key":"2021052721431250200_B49","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.celrep.2013.12.027","article-title":"Genetics of follicular lymphoma transformation","volume":"6","author":"Pasqualucci","year":"2014","journal-title":"Cell Rep"},{"issue":"10","key":"2021052721431250200_B50","doi-asserted-by":"crossref","first-page":"E1116","DOI":"10.1073\/pnas.1501199112","article-title":"Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation","volume":"112","author":"Green","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"4","key":"2021052721431250200_B51","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1159\/000447734","article-title":"Lymph node fine-needle cytology: beyond flow cytometry","volume":"60","author":"Peluso","year":"2016","journal-title":"Acta Cytol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/137\/21\/2869\/1808404\/bloodbld2020009855.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/137\/21\/2869\/1808404\/bloodbld2020009855.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T22:36:35Z","timestamp":1622154995000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/137\/21\/2869\/475531\/Single-cell-analysis-can-define-distinct-evolution"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,27]]},"references-count":51,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2021,5,27]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020009855","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,27]]}}}