Bystander Activation and Anti-Tumor Effects of CD8+ T Cells Following Interleukin-2 Based Immunotherapy Is Independent of CD4+ T Cell Help
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{"title"=>"Bystander activation and anti-tumor effects of CD8+ T cells following interleukin-2 based immunotherapy is independent of CD4+ T cell help", "type"=>"journal", "authors"=>[{"first_name"=>"Arta M.", "last_name"=>"Monjazeb", "scopus_author_id"=>"6506334494"}, {"first_name"=>"Julia K.", "last_name"=>"Tietze", "scopus_author_id"=>"15822836800"}, {"first_name"=>"Steven K.", "last_name"=>"Grossenbacher", "scopus_author_id"=>"55095592500"}, {"first_name"=>"Hui Hua", "last_name"=>"Hsiao", "scopus_author_id"=>"57154883700"}, {"first_name"=>"Anthony E.", "last_name"=>"Zamora", "scopus_author_id"=>"55910640300"}, {"first_name"=>"Annie", "last_name"=>"Mirsoian", "scopus_author_id"=>"55270314500"}, {"first_name"=>"Brent", "last_name"=>"Koehn", "scopus_author_id"=>"12754089700"}, {"first_name"=>"Bruce R.", "last_name"=>"Blazar", "scopus_author_id"=>"35465989800"}, {"first_name"=>"Jonathan M.", "last_name"=>"Weiss", "scopus_author_id"=>"13611857300"}, {"first_name"=>"Robert H.", "last_name"=>"Wiltrout", "scopus_author_id"=>"7006408170"}, {"first_name"=>"Gail D.", "last_name"=>"Sckisel", "scopus_author_id"=>"24538160100"}, {"first_name"=>"William J.", "last_name"=>"Murphy", "scopus_author_id"=>"55757782229"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1098-5514 (Electronic)\\r0022-538X (Linking)", "pmid"=>"25119341", "doi"=>"10.1371/journal.pone.0102709", "pui"=>"373752559", "issn"=>"19326203", "sgr"=>"84905919686", "scopus"=>"2-s2.0-84905919686"}, "id"=>"44dd739b-ae8c-3fc0-bb3c-66b7187a76c8", "abstract"=>"We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent \"bystander-activated\" (CD8(+)CD44high) T cells displaying a CD25(-)NKG2D(+) phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4(+) T cell help for antigen-specific CD8(+) T cell expansion, little is known regarding the role of CD4(+) T cells in antigen-nonspecific bystander-memory CD8(+) T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8(+) T cells upregulated PD-1 in the absence of CD4(+) T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8(+) T cells. Interestingly, compared to CD8(+) T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8(+) response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8(+) T cell expansion, CD4(+) T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8(+) T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.", "link"=>"http://www.mendeley.com/research/bystander-activation-antitumor-effects-cd8-t-cells-following-interleukin2-based-immunotherapy-indepe", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>6, "Professor"=>2, "Student > Postgraduate"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>6, "Professor"=>2, "Student > Postgraduate"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>7, "Chemistry"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1634438"], "description"=>"<p>Three C57BL/6 mice per group were treated with IT or PBS/rIgG (control) and effects on CD8+ T cell expansion were quantified by flow cytometric analysis 11 days after the initiation of therapy. For <i>in vivo</i> tumor studies one million 3LL cells were administered by s.c. injection into the flank of C57BL/6 mice seven days prior to initiation of therapy. Six to eight 3LL bearing mice were treated with IT and/or CD8+ T cell depletion to examine CD8+ dependence of anti-tumor effects. (<b>a</b>) Gating strategy for bystander memory CD8+ CD44<sup>high</sup> NKG2D+ CD25− cells. (<b>b–e</b>) Expansion of bystander memory CD8+ T cells in the spleen and lymph nodes of IT or vehicle treated mice expressed as total numbers (<b>b,c</b>) or as a percentage of total CD8+ T cells (<b>d,e</b>). Effects of IT and/or CD8 depletion on tumor growth (<b>f</b>) and survival (<b>g</b>).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138061, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g001", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD40_IL_2_Immunotherapy_induces_massive_expansion_of_bystander_memory_CD8_cells_and_anti_tumor_effects_are_CD8_dependent_/1138061", "title"=>"CD40/IL-2 Immunotherapy induces massive expansion of bystander memory CD8+ cells and anti-tumor effects are CD8 dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634441"], "description"=>"<p>Control or CD4 deficient (depleted or knockout) C57BL/6 mice were treated with IT or PBS/rIgG (control) and effects on CD8+ T cell expansion were quantified by flow cytometric analysis 11 days after the initiation of IT. CD8+ (<b>a,b</b>) and memory CD8+ (<b>c,d</b>) T cell numbers in the LNs (<b>a,c</b>) and spleens (<b>b,d</b>) of control or CD4+ T cell depleted mice treated with vehicle or IT. (<b>e</b>) BrdU incorporation in CD8+ T cells from spleens of control or CD4+ T cell depleted mice treated with vehicle or IT. CD8+ (<b>f,g</b>) and memory CD8+ (<b>h,i</b>) T cell numbers in the LNs (<b>f,h</b>) and spleens (<b>g,i</b>) of wild-type or CD4 knockout mice treated with vehicle or IT. Results are representative of two (CD4 knockout) or three (CD4 depletion) independent experiments with a minimum of three mice per group. (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138064, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IT_induced_expansion_of_memory_CD8_T_cells_in_CD4_T_cell_deficient_models_/1138064", "title"=>"IT induced expansion of memory CD8+ T cells in CD4+ T cell deficient models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634454"], "description"=>"<p>Control or long term CD4+ depleted C57BL/6 mice were treated with IT or PBS/rIgG (control) and harvested at Day 15 after the initiation of therapy. Bystander memory CD8+ T cells, PD-1 expression, interferon gamma production, and granzyme B production were quantified by flow cytometric analysis. Cytotoxic effector function was assayed by a redirected lysis assay. The percentage of CD8+ T cells with the CD44<sup>high</sup> NKG2D+ CD25− bystander memory phenotype in the spleen (<b>a</b>) and LNs (<b>b</b>). PD-1 expression on the memory CD8+ T cells in the spleen (<b>c</b>) and LNs (<b>d</b>). Interferon gamma production (<b>e</b>) and granzyme B expression (<b>f</b>) in splenic memory CD8+ T cells. (<b>g</b>) Killing function of splenocytes from long term CD4 depleted mice expressed as percentage of maximal lysis. N = 3 mice per group (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138077, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g006", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD4_independence_of_IT_induced_bystander_activated_memory_CD8_T_cells_persists_at_longer_time_points_/1138077", "title"=>"CD4 independence of IT induced bystander activated memory CD8+ T cells persists at longer time points.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634472", "https://ndownloader.figshare.com/files/1634473", "https://ndownloader.figshare.com/files/1634474"], "description"=>"<div><p>We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent “bystander-activated” (CD8<sup>+</sup>CD44<sup>high</sup>) T cells displaying a CD25<sup>−</sup>NKG2D<sup>+</sup> phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.</p></div>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138094, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0102709.s001", "https://dx.doi.org/10.1371/journal.pone.0102709.s002", "https://dx.doi.org/10.1371/journal.pone.0102709.s003"], "stats"=>{"downloads"=>6, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bystander_Activation_and_Anti_Tumor_Effects_of_CD8_T_Cells_Following_Interleukin_2_Based_Immunotherapy_Is_Independent_of_CD4_T_Cell_Help_/1138094", "title"=>"Bystander Activation and Anti-Tumor Effects of CD8+ T Cells Following Interleukin-2 Based Immunotherapy Is Independent of CD4+ T Cell Help", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634450"], "description"=>"<p>3LL tumor bearing WT or CD4 knockout (B6.129S2-CD4<sup>tm1Mak</sup>/J) mice were treated with IT or PBS/rIgG (control) and survival and tumor growth were measured. For <i>in vivo</i> tumor studies one million 3LL cells were administered by s.c. injection into the flank of C57BL/6 mice seven days prior to initiation of therapy. (<b>a</b>) Survival. (<b>b</b>) Mean tumor volume with SEM. (<b>c–f</b>) Growth plots of individual tumors in each group. N = 12 mice per group. (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138072, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_tumor_effects_of_IT_in_CD4_knockout_mice_/1138072", "title"=>"Anti-tumor effects of IT in CD4 knockout mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634447"], "description"=>"<p>Control or CD4 deficient (depleted or knockout) C57BL/6 mice were treated with IT or PBS/rIgG (control) and assessed for function of memory CD8+ T cells 11 days after the initiation of IT. NKG2D and granzyme B expression were quantified by flow cytometric analysis. Interferon gamma production was quantified by flow cytometric analysis after <i>in vitro</i> restimulation of splenocytes with PMA/Ionomycin (0.16/1.6 ug/ml) for one hour followed by incubation with golgi stop (0.7 ug/ml) for three hours. CD8+ T cell killing function was assayed by scintillation counting using an <i>in vitro</i> redirected lysis assay with <sup>51</sup>Cr labeled P815 target cells incubated for 30 minutes with 10 ug/mL anti-CD3e. (<b>a,f</b>) NKG2D expression on memory CD8+ T cells in CD4 depletion (<b>a</b>) and knockout (<b>f</b>) models. Representative dot plots for NKG2D+ CD25− gating are presented in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102709#pone-0102709-g001\" target=\"_blank\">Figure 1</a>. (<b>b</b>) Representative dot plots for IFNγ+ gating on CD8+ CD44<sup>high</sup> cells in the spleens of CD4+ depletion model mice. (<b>c,g</b>) Interferon gamma production by memory CD8+ T cells in CD4 depletion (<b>c</b>) and knockout (<b>g</b>) models. (<b>d</b>) Representative dot plots for Granzyme B+ gating on CD8+ CD44<sup>high</sup> cells in the spleens of CD4+ depletion model mice. (<b>e,h</b>) Granzyme B expression by memory CD8+ T cells in CD4 depletion (<b>e</b>) and knockout (<b>h</b>) models. Killing function of splenocytes from CD4 depleted (<b>i</b>) or CD knockout (<b>j</b>) mice expressed as percentage of maximal lysis. Results are representative of two (CD4 knockout) or three (CD4 depletion) independent experiments with a minimum of three mice per group. (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138070, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Memory_CD8_T_cell_function_after_IT_in_CD4_T_cell_deficient_models_/1138070", "title"=>"Memory CD8+ T cell function after IT in CD4+ T cell deficient models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634444"], "description"=>"<p>Control or CD4 deficient (depleted or knockout) C57BL/6 mice were treated with IT or PBS/rIgG (control) and PD-1 expression on memory T-cells was quantified by flow cytometric analysis 11 days after the initiation of IT. (<b>a</b>) Representative dot plots for PD-1+ gating on CD8+ CD44<sup>high</sup> cells in the spleens of CD4+ depletion model mice. Number of PD-1+ memory (CD44<sup>high</sup>) CD8+ T cells in spleens (<b>b,d</b>) and LNs+ (<b>c,e</b>) of IT or vehicle treated mice in CD4+ depletion (<b>b,c</b>) or CD4 knockout (<b>d,e</b>) models. Results are representative of two (CD4 knockout) or three (CD4 depletion) independent experiments with a minimum of three mice per group. (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138067, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g003", "stats"=>{"downloads"=>3, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_number_of_PD_1_memory_CD8_T_cells_after_IT_in_CD4_T_cell_deficient_mice_/1138067", "title"=>"Increased number of PD-1+ memory CD8+ T cells after IT in CD4+ T cell deficient mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1634461"], "description"=>"<p>Control or CD4+ depleted C57BL/6 mice were treated with IT or PBS/rIgG (control). CD62L and PD-1 expression on memory T-cells was quantified by flow cytometric analysis 11 days after the initiation of IT. (<b>a,b</b>) Examples of the gating strategy for PD-1 expression on the CM and EM components of the memory CD8+ T cell compartment. The majority of cells in the memory compartment are CM in untreated mice (<b>a</b>) and EM in IT treated mice (<b>b</b>). (<b>c</b>) PD-1 expression on CM and EM cells. (<b>d</b>) The composition of the memory CD8+ T cell compartment in control or CD4 depleted mice treated with IT or PBS/rIgG. PD-1+ CM cells (<b>e</b>) and PD-1+ EM cells (<b>f</b>) as a percentage of the total memory CD8+ T cell compartment. Results are representative of two to three independent experiments with 3 mice per group (*<i>P</i><.05, **<i>P</i><.01, ***<i>P</i><.001, ****<i>P</i><.0001).</p>", "links"=>[], "tags"=>["effector phenotype", "pd", "Utilizing CD 4", "il"], "article_id"=>1138084, "categories"=>["Biological Sciences"], "users"=>["Arta M. Monjazeb", "Julia K. Tietze", "Steven K. Grossenbacher", "Hui-Hua Hsiao", "Anthony E. Zamora", "Annie Mirsoian", "Brent Koehn", "Bruce R. Blazar", "Jonathan M. Weiss", "Robert H. Wiltrout", "Gail D. Sckisel", "William J. Murphy"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102709.g007", "stats"=>{"downloads"=>2, "page_views"=>139, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PD_1_expression_on_central_and_effector_memory_CD8_T_cells_after_IT_in_CD4_T_cell_depleted_mice_/1138084", "title"=>"PD-1 expression on central and effector memory CD8+ T cells after IT in CD4+ T cell depleted mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-13 04:46:41"}

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Neuroscience", "average_usage"=>[289]}, {"subject_area"=>"/Medicine and health sciences/Physiology", "average_usage"=>[278]}]}
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