In Silico Analysis of Cell Cycle Synchronisation Effects in Radiotherapy of Tumour Spheroids
Publication Date
November 14, 2013
Journal
PLOS Computational Biology
Authors
Harald Kempf, Haralampos Hatzikirou, Marcus Bleicher & Michael Meyer Hermann
Volume
9
Issue
11
Pages
e1003295
DOI
https://dx.plos.org/10.1371/journal.pcbi.1003295
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1003295
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24244120
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828142
Europe PMC
http://europepmc.org/abstract/MED/24244120
Web of Science
000330357200009
Scopus
84888239900
Mendeley
http://www.mendeley.com/research/silico-analysis-cell-cycle-synchronisation-effects-radiotherapy-tumour-spheroids
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Mendeley | Further Information

{"title"=>"In Silico Analysis of Cell Cycle Synchronisation Effects in Radiotherapy of Tumour Spheroids", "type"=>"journal", "authors"=>[{"first_name"=>"Harald", "last_name"=>"Kempf", "scopus_author_id"=>"36144042800"}, {"first_name"=>"Haralampos", "last_name"=>"Hatzikirou", "scopus_author_id"=>"22979835400"}, {"first_name"=>"Marcus", "last_name"=>"Bleicher", "scopus_author_id"=>"7006707245"}, {"first_name"=>"Michael", "last_name"=>"Meyer-Hermann", "scopus_author_id"=>"6602091186"}], "year"=>2013, "source"=>"PLoS Computational Biology", "identifiers"=>{"pmid"=>"24244120", "doi"=>"10.1371/journal.pcbi.1003295", "sgr"=>"84888239900", "scopus"=>"2-s2.0-84888239900", "issn"=>"1553734X", "pui"=>"370341755"}, "id"=>"2af654bc-f75d-343a-95c5-af368f4a1409", "abstract"=>"Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.", "link"=>"http://www.mendeley.com/research/silico-analysis-cell-cycle-synchronisation-effects-radiotherapy-tumour-spheroids", "reader_count"=>46, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>10, "Student > Ph. D. Student"=>17, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>10, "Student > Ph. D. Student"=>17, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>6}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Mathematics"=>6, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>10, "Physics and Astronomy"=>12}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Physics and Astronomy"=>{"Physics and Astronomy"=>12}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Mathematics"=>{"Mathematics"=>6}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "United Kingdom"=>1, "Germany"=>3}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1281021"], "description"=>"<p>Black circles mark cell cycle checkpoints. Cells can enter and leave quiescence in response to the local pressure at the G1/S checkpoint. If the critical conditions improve, cells re-enter the active cell cycle by passing the restriction point. Growing cells double their volume during G1 and G2 phase, so that the cell volume is conserved in mitosis. At the G2/M checkpoint cells will be halted if their DNA is damaged. This arrest is subject to a chance of failure, so that, with a defined probability, cells can pass into mitosis even though their DNA is damaged. Cell death in response to critical nutrient deprivation is possible at any time via necrosis. In response to irradiation, individual cells will commit to cell death if a random value exceeds their cell-cycle specific survival chance from the linear-quadratic model in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295.e020\" target=\"_blank\">equation 1</a>. Cell death in response to radiation is realised either via a fast, acute commitment to cell death or by prolonged fixation at the G2/M checkpoint which will lead to cell death via apoptosis as a result of mitotic catastrophe or other fatal errors.</p>", "links"=>[], "tags"=>["implemented"], "article_id"=>850858, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_cycle_response_to_environmental_factors_and_radiation_as_implemented_in_the_model_/850858", "title"=>"Cell cycle, response to environmental factors and radiation as implemented in the model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281022"], "description"=>"<p>Panel <b>A</b> shows the cell phase distribution during growth of a tumour spheroid and in response to irradiation with 4 Gy. <b>B</b> Redistribution in response to 4 Gy and subsequent dynamics in the fraction of viable cells. <b>C</b> Lateral cut through a tumour spheroid during different phases of growth and irradiation. An initial small number of seeder cells will form a solid tumour spheroid, where cells in high-density regions go into quiescence. Nutrient deprivation and subsequent dissolution of necrotic cells lead to the formation of a hollow core. After irradiation with 4 Gy a majority of cells will be apoptotic, which leads to a reactivation of quiescent cells. Consequently a fast regrowth and the re-establishment of the necrotic core are observed. Cells are visualised as spheres but are handled as polyhedra while in contact within the 3D Delaunay triangulation used in the model <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Kempf1\" target=\"_blank\">[25]</a>. Cells in G1, S or G2-phase in cyan, mitotic cells in red, quiescent cells in grey, necrotic cells in brown and apoptotic cells in green.</p>", "links"=>[], "tags"=>["tumour", "spheroid"], "article_id"=>850859, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g002", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reaction_of_a_tumour_spheroid_to_irradiation_/850859", "title"=>"Reaction of a tumour spheroid to irradiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281024"], "description"=>"<p>A Comparison of the cell cycle redistribution <i>in silico</i> after irradiation with 2 Gy and <i>in vitro</i> for LN229 cells from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Bohl1\" target=\"_blank\">[57]</a>. <b>B</b> Effect of a single radiation dose on post-irradiation sensitivity of the tumour. Depending on the applied dose the effects of a growing quiescent, radioresistant sub-population are increasing, as can be seen in the development of the enhancement during the tumour growth up to the irradiation at time zero. After irradiation an initial period of increased radioresistance is followed by transient maxima in radiosensitivity which are suitable for targeting by subsequent fractions. Oscillations of enhancement are dampened by the entry of cells into quiescence after regrowth and by the normal distribution of cell cycle phaselengths.</p>", "links"=>[], "tags"=>["redistribution", "radiosensitivity"], "article_id"=>850861, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g003", "stats"=>{"downloads"=>4, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_phase_redistribution_and_according_change_in_overall_radiosensitivity_in_response_to_irradiation_/850861", "title"=>"Cell phase redistribution and according change in overall radiosensitivity in response to irradiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281025"], "description"=>"<p><b>A</b> Visualisation of the radiation timing in selected fractionation schedules is provided in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi-1003295-t002\" target=\"_blank\">table 2</a>. Marker size is indicative of fraction dose. At time zero the tumour is seeded with a small number of cells. Treatment schedules were started at day 14 of tumour growth, when a fully structured tumour spheroid had developed. <b>B–C</b> Comparison of total tumour size during high dose-per-time and low dose-per-time scheduling (left >2 Gy/24 h, right ≤2 Gy/24 h ). <b>D–E</b> Development of enhancement during selected schedules can explain the different performance of the schedules (radiation times marked with circles).</p>", "links"=>[], "tags"=>["schedules", "tumour"], "article_id"=>850862, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_different_treatment_schedules_on_the_tumour_spheroid_/850862", "title"=>"Effect of different treatment schedules on the tumour spheroid.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281026"], "description"=>"<p><b>A</b> Comparison of total tumour size in response to altered scheduling of the standard dose of 2 Gy/24 h. While high-dose fractions have an advantage because of the quadratic term in the LQ radiation response, they are outperformed by some lower-dose schemes due to a better timing of the treatment to the tumour radiosensitivity development (compare e.g. 2 Gy/24 h and 2.5 Gy/30 h). <b>B</b> Overall performance of varied dose distribution measured as tumour burden for the time period from treatment begin at day 14 to day 44. <b>C–D</b> Timing of fractions in relation to the enhancement development for selected runs can explain the different schedule performance. <b>E–F</b> Repeated delivery of doses of 3 Gy with different delivery intervals until full sterilisation is achieved. The number of fractions required for sterilisation depends non-linearly on the inter-fraction time. This complex dependency is a result of the enhancement development within the tumour as discussed in the text and further illustrated in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295.s006\" target=\"_blank\">figure S6</a>.</p>", "links"=>[], "tags"=>["scheduling"], "article_id"=>850863, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g005", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Systematic_investigation_of_the_performance_of_different_scheduling_schemes_/850863", "title"=>"Systematic investigation of the performance of different scheduling schemes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281027"], "description"=>"<p>Protocols were designed to induce a cell cycle response in the tumour which can be exploited in follow-up irradiations. <b>A</b> The overall reduction in tumour size achieved by different conventional and triggered schedules, which consist of trigger- and effector-dose followed by a pause to achieve a constant dose per time interval of 2 Gy/24 h. The performance of other triggered schedules can be found in the supplementary material <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295.s005\" target=\"_blank\">figure S5</a>. <b>B</b> Automatic triggering with a minimal inter-fraction time of and a minimal dose of compared to full manual optimal triggering. <b>C</b> Example of a stable and unstable repeated sensitivity development in A. <b>D</b> Enhancement during automatic and full manual triggering in B (radiation timing marks omitted for visibility).</p>", "links"=>[], "tags"=>["triggered", "irradiation"], "article_id"=>850864, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.g006", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Performance_of_specific_triggered_irradiation_schedules_/850864", "title"=>"Performance of specific triggered irradiation schedules.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281028"], "description"=>"<p>Further parameters and sources for the handling of cell interaction, nutrient diffusion and consumption can be found in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Kempf1\" target=\"_blank\">[25]</a> and <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Schaller1\" target=\"_blank\">[28]</a>. The model aims to describe a generic tumour so the analysis does not rely on data for one specific tumour cell line only but on parameters which are within the established physiological range. Parameters for glucose and oxygen diffusion from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Stein1\" target=\"_blank\">[89]</a><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Casciari1\" target=\"_blank\">[90]</a><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Grote1\" target=\"_blank\">[91]</a> and according cell uptake rates from <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Wehrle1\" target=\"_blank\">[44]</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi.1003295-Freyer2\" target=\"_blank\">[86]</a>.</p>", "links"=>[], "tags"=>["irradiation"], "article_id"=>850865, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.t001", "stats"=>{"downloads"=>8, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Selection_of_parameters_for_growth_and_irradiation_used_within_the_simulation_/850865", "title"=>"Selection of parameters for growth and irradiation used within the simulation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281029"], "description"=>"<p>For better comparison of effects the integral dose for all runs has been chosen to be 60 Gy (except for CHART treatment with 54 Gy). In order to test the results of hypo- and hyperfractionation, extreme cases with doubled or halved doses per fraction where chosen. A visualisation of the according fractionation timings is presented in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003295#pcbi-1003295-g004\" target=\"_blank\">figure 4</a>.</p>", "links"=>[], "tags"=>["fractionation", "schemes", "been", "tested"], "article_id"=>850866, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003295.t002", "stats"=>{"downloads"=>9, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_selected_clinical_fractionation_schemes_that_have_been_tested_in_the_simulation_/850866", "title"=>"Overview of selected clinical fractionation schemes that have been tested in the simulation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-11-14 03:36:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/1281031", "https://ndownloader.figshare.com/files/1281032", "https://ndownloader.figshare.com/files/1281033", "https://ndownloader.figshare.com/files/1281034", "https://ndownloader.figshare.com/files/1281035", "https://ndownloader.figshare.com/files/1281036"], "description"=>"<div><p>Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.</p></div>", "links"=>[], "tags"=>["synchronisation", "radiotherapy", "tumour", "spheroids"], "article_id"=>850868, "categories"=>["Biological Sciences"], "users"=>["Harald Kempf", "Haralampos Hatzikirou", "Marcus Bleicher", "Michael Meyer-Hermann"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1003295.s001", "https://dx.doi.org/10.1371/journal.pcbi.1003295.s002", "https://dx.doi.org/10.1371/journal.pcbi.1003295.s003", "https://dx.doi.org/10.1371/journal.pcbi.1003295.s004", "https://dx.doi.org/10.1371/journal.pcbi.1003295.s005", "https://dx.doi.org/10.1371/journal.pcbi.1003295.s006"], "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_Silico_Analysis_of_Cell_Cycle_Synchronisation_Effects_in_Radiotherapy_of_Tumour_Spheroids/850868", "title"=>"<i>In Silico</i> Analysis of Cell Cycle Synchronisation Effects in Radiotherapy of Tumour Spheroids", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-11-14 03:36:11"}

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  • {"unique-ip"=>"17", "full-text"=>"16", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"7", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"3", "full-text"=>"5", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"10", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"14", "full-text"=>"8", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"16", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"5", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"9", "full-text"=>"5", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"7", "full-text"=>"4", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}

Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[269, 466, 588, 697, 800, 896, 988, 1076, 1165, 1254, 1340, 1417]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[284, 491, 620, 738, 843, 945, 1043, 1137, 1225, 1315, 1400, 1479, 1555]}, {"subject_area"=>"/Engineering and technology/Industrial engineering", "average_usage"=>[244, 415, 530, 647, 750, 829, 915, 999, 1097, 1201, 1293, 1361, 1439]}]}
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