Endothelial Membrane Remodeling Is Obligate for Anti-Angiogenic Radiosensitization during Tumor Radiosurgery
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{"title"=>"Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery", "type"=>"journal", "authors"=>[{"first_name"=>"Jean Philip", "last_name"=>"Truman", "scopus_author_id"=>"7004926464"}, {"first_name"=>"Mónica", "last_name"=>"García-Barros", "scopus_author_id"=>"6506729489"}, {"first_name"=>"Matthew", "last_name"=>"Kaag", "scopus_author_id"=>"22953821400"}, {"first_name"=>"Dolores", "last_name"=>"Hambardzumyan", "scopus_author_id"=>"15122025700"}, {"first_name"=>"Branka", "last_name"=>"Stancevic", "scopus_author_id"=>"25925363600"}, {"first_name"=>"Michael", "last_name"=>"Chan", "scopus_author_id"=>"36342232200"}, {"first_name"=>"Zvi", "last_name"=>"Fuks", "scopus_author_id"=>"35420034600"}, {"first_name"=>"Richard", "last_name"=>"Kolesnick", "scopus_author_id"=>"7006248068"}, {"first_name"=>"Adriana", "last_name"=>"Haimovitz-Friedman", "scopus_author_id"=>"6701792689"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"20808818", "doi"=>"10.1371/journal.pone.0012310", "sgr"=>"77957890055", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "scopus"=>"2-s2.0-77957890055", "issn"=>"19326203", "pui"=>"359761486"}, "id"=>"fd93d98a-bacc-34cd-9400-522b15e9e41b", "abstract"=>"BACKGROUND: While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either \"normalize\" dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C(16)-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase(+/+) mice or asmase(-/-) littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase(-/-) mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect.\\n\\nCONCLUSIONS/SIGNIFICANCE: These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.", "link"=>"http://www.mendeley.com/research/endothelial-membrane-remodeling-obligate-antiangiogenic-radiosensitization-during-tumor-radiosurgery", "reader_count"=>47, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>6, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>2, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>6, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>2, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>17, "Physics and Astronomy"=>8, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>17}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Canada"=>2, "United States"=>2, "Norway"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/834625"], "description"=>"<p>(<b>A</b>) Impact of a 1 h pre-treatment with DC101 (1600 µg/animal) on the tumor response to 13.5 Gy using MCA/129 fibrosarcomas grown in <i>asmase<sup>+/+</sup></i> or (<b>B</b>) in <i>asmase<sup>−/−</sup></i> littermates. Data (mean±s.e.m.) are collated from <i>asmase<sup>+/+</sup></i> control mice (n = 7), DC101-treated <i>asmase<sup>+/+</sup></i> mice (n = 9), and <i>asmase<sup>−/−</sup></i> mice (n = 10 each). (<b>C</b>) Quantification of the G6–31 effect on radiation-induced endothelial cell apoptosis. Endothelial cells (mean±s.e.m.) from cross sections of 14.5 Gy-irradiated MCA/129 fibrosarcomas were stained with both an endothelial cell specific Ab (MECA-32) and TUNEL. Data was collated from 20 fields from 1 of 2 similar experiments employing 2 animals per group at the times shown. (<b>D</b>) Quantification of the effect of DC101 on 13.5 Gy radiation-induced endothelial cell apoptosis. Data (mean±s.e.m.) represent TUNEL-positive endothelial cells collated from 20 fields from 1 of 2 similar experiments employing 2 animals per group.</p>", "links"=>[], "tags"=>["asmase", "anti-angiogenic"], "article_id"=>504992, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Role_of_ASMase_in_anti_angiogenic_therapy_/504992", "title"=>"Role of ASMase in anti-angiogenic therapy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:23:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/415804", "https://ndownloader.figshare.com/files/415850", "https://ndownloader.figshare.com/files/415870", "https://ndownloader.figshare.com/files/415890", "https://ndownloader.figshare.com/files/415904", "https://ndownloader.figshare.com/files/415921", "https://ndownloader.figshare.com/files/415943", "https://ndownloader.figshare.com/files/415965", "https://ndownloader.figshare.com/files/415985", "https://ndownloader.figshare.com/files/416017", "https://ndownloader.figshare.com/files/416030", "https://ndownloader.figshare.com/files/416045", "https://ndownloader.figshare.com/files/416062", "https://ndownloader.figshare.com/files/416079"], "description"=>"<div><h3>Background</h3><p>While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either “normalize” dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study.</p><h3>Methodology/Principal Findings</h3><p>Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C<sub>16</sub>-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. <em>In vivo</em>, MCA/129 fibrosarcoma tumors were implanted in <em>asmase<sup>+/+</sup></em> mice or <em>asmase<sup>−/−</sup></em> littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in <em>asmase<sup>−/−</sup></em> mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect.</p><h3>Conclusions/Significance</h3><p>These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.</p></div>", "links"=>[], "tags"=>["endothelial", "membrane", "remodeling", "obligate", "anti-angiogenic", "radiosensitization", "radiosurgery"], "article_id"=>142098, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0012310.s001", "https://dx.doi.org/10.1371/journal.pone.0012310.s002", "https://dx.doi.org/10.1371/journal.pone.0012310.s003", "https://dx.doi.org/10.1371/journal.pone.0012310.s004", "https://dx.doi.org/10.1371/journal.pone.0012310.s005", "https://dx.doi.org/10.1371/journal.pone.0012310.s006", "https://dx.doi.org/10.1371/journal.pone.0012310.s007", "https://dx.doi.org/10.1371/journal.pone.0012310.s008", "https://dx.doi.org/10.1371/journal.pone.0012310.s009", "https://dx.doi.org/10.1371/journal.pone.0012310.s010", "https://dx.doi.org/10.1371/journal.pone.0012310.s011", "https://dx.doi.org/10.1371/journal.pone.0012310.s012", "https://dx.doi.org/10.1371/journal.pone.0012310.s013", "https://dx.doi.org/10.1371/journal.pone.0012310.s014"], "stats"=>{"downloads"=>4, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Endothelial_Membrane_Remodeling_Is_Obligate_for_Anti_Angiogenic_Radiosensitization_during_Tumor_Radiosurgery/142098", "title"=>"Endothelial Membrane Remodeling Is Obligate for Anti-Angiogenic Radiosensitization during Tumor Radiosurgery", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-08-19 00:34:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/834715"], "description"=>"<p>DC101 (1600 µg/kg) was injected i.v. at the indicated times before (<b>A</b>) and after (<b>B</b>) irradiation. Data (means ±s.e.m.) were collated from 5 mice per group. Arrows indicate time of irradiation.</p>", "links"=>[], "tags"=>["dc101"], "article_id"=>505083, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impact_of_timing_of_DC101_addition_on_the_radiation_response_of_MCA_129_fibrosarcomas_/505083", "title"=>"Impact of timing of DC101 addition on the radiation response of MCA/129-fibrosarcomas.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:24:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/834467"], "description"=>"<p>(<b>A</b>) DC101-pre-treatment increases radiation-induced ceramide elevation. Cells were pre-treated for 16 h with 0.2 µg/ml DC101, irradiated at 8 Gy, and ceramide was measured by diacylglycerol kinase assay as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1B</b></a>. Data (mean±s.d.) represent triplicate determinations from 2 experiments. (<b>B</b>) DC101 increases radiation-induced apoptosis. Cells were pre-incubated for 16 h with 0.2 µg/ml DC101. At 8 h post-irradiation, apoptosis was quantified using <i>bis</i>-benzimide staining. (<b>C</b>) Anti-ceramide antibody inhibits DC101-enhanced radiation-induced apoptosis. BAEC were treated with 350 ng/ml MAS0020 15 min prior to 0.2 µg/ml DC101, and after 16 h irradiated at 5 Gy. Apoptosis was quantified 8 h post-irradiation by <i>bis</i>-benzimide staining. Data in (<b>2C–F, 3A, and 3C</b>) represent means±s.d. of duplicate determinations from at least 400 scored nuclei from 2 separate experiments.</p>", "links"=>[], "tags"=>["radiosensitizes", "asmase"], "article_id"=>504838, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_angiogenic_treatment_DC101_radiosensitizes_via_ASMase_activation_/504838", "title"=>"Anti-angiogenic treatment (DC101) radiosensitizes via ASMase activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:20:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/834275"], "description"=>"<p>(<b>A</b>) ASMase activity following 10 Gy is inhibited by VEGF pre-treatment. Irradiated BAEC samples were collected at the indicated times and ASMase activity measured by quantifying conversion of [<sup>14</sup>C]sphingomyelin to the product [<sup>14</sup>C]phosphocholine. Data (mean±s.d.) represent duplicate determinations from 2 experiments. (<b>B</b>) Radiation-induced ceramide generation is inhibited by VEGF pre-incubation. VEGF (1 ng/ml) was added 15 min before irradiation. Ceramide was quantified at the indicated times by the diacylglycerol kinase assay. Data (mean±s.d.) represent triplicate determinations from 2 experiments. (<b>C</b>, <b>D</b>) VEGF pre-treatment inhibits radiation-induced apoptosis. C<sub>16</sub>-ceramide (C<sub>16</sub>, 1 µM) was added 30 min prior to irradiation. Samples were fixed in 10% paraformaldehyde prior to <i>bis</i>-benzimide staining. For apoptosis quantification, data (mean±s.d) represent duplicate determinations of at least 400 <i>bis</i>-benzimide stained nuclei counted from 2 experiments. Caspase 3 activity was measured by quantitation of the luminescence of cleaved DEVD-AMC substrate. Data (mean±s.d.) represent duplicate points from 3 experiments.</p>", "links"=>[], "tags"=>["inhibits", "radiation-induced", "apoptosis", "repression", "asmase"], "article_id"=>504630, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGF_inhibits_radiation_induced_apoptosis_via_repression_of_ASMase_activation_/504630", "title"=>"VEGF inhibits radiation-induced apoptosis via repression of ASMase activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:17:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/834365"], "description"=>"<p>(<b>A</b>) ASMase activation in response to DC101. A19 BAEC were incubated with 5 µg/ml DC101 and ASMase activity was measured every 2 h for 24 h by quantifying conversion of [<sup>14</sup>C]sphingomyelin to the product [<sup>14</sup>C]phosphocholine as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1A</b></a>. Data (mean±s.d.) represent triplicate determinations from 2 experiments. (<b>B</b>) DC101 (5 µg/ml) induces ceramide elevation. Ceramide was quantified by the diacylglycerol kinase assay as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1B</b></a> at the times indicated. Data (mean±s.d.) represent triplicate determinations from 2 experiments. (<b>C</b>) DC101 induces apoptosis. DC101(5 µg/ml) was added and cells collected every 2 h, fixed and apoptosis quantified using <i>bis</i>-benzimide method as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1C</b></a>. (<b>D</b>) Disruption of GEMs inhibits DC101-induced apoptosis. Nystatin (30 µg/ml) was added 30 min prior to the addition of escalating doses of DC101 and apoptosis quantified after 24 h as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1C</b></a>. (<b>E</b>) Anti-ceramide antibody MAS0020 inhibits apoptosis induction by DC101. MAS0020 was added at 250 ng/ml 30 min prior to the addition of increasing concentrations of DC101. After 24 h, apoptosis was quantified as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1C</b></a>. (<b>F</b>) bFGF inhibits DC101-induced apoptosis by inhibition of ceramide generation. bFGF (1 ng/ml) and C<sub>16</sub>-ceramide (1 µM) were added as detailed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012310#pone-0012310-g001\" target=\"_blank\"><b>Fig. 1C</b></a>, and apoptosis was quantified after 24 h.</p>", "links"=>[], "tags"=>["regulates", "pro-apoptotic", "ceramide", "rheostat", "asmase"], "article_id"=>504726, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g002", "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGF_regulates_a_pro_apoptotic_ceramide_rheostat_via_ASMase_repression_/504726", "title"=>"VEGF regulates a pro-apoptotic ceramide rheostat <i>via</i> ASMase repression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:18:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/834551"], "description"=>"<p>(<b>A</b> and <b>B</b>) Impact of 1 h pre-treatment with G6–31 (5 mg/kg) on tumor response to 14.5 Gy. N equals number of animals per group. (<b>C</b> and <b>D</b>) Impact of a 1 h pre-treatment with G6–31 (5 mg/kg) on tumor response to 13.5 Gy using tumor xenografts grown in <i>asmase<sup>+/+</sup></i> (left panel) or <i>asmase<sup>−/−</sup></i> littermates (right panel). No tumor growth delay was observed in tumors growing in ASMase deficient mice after 13.5 Gy pre-treated with G6–31 as compared to tumors growing in the <i>asmase<sup>+/+</sup></i> littermates. Data (mean±s.e.m.) are collated from 5 animals per group. Arrows indicate the day of treatment. (<b>E</b>) Impact of anti-ceramide treatment on G6–31-enhanced radiation-response. G6–31 (5 mg/kg) was injected i.v. 1 h before 14.5 Gy irradiation. Anti-ceramide Ab MAS0020 (25 µg) was injected i.v. immediately before irradiation. Anti-ceramide treated mice displayed a significantly reduced tumor growth delay. Data (means ± s.e.m.) were collated from 4 mice per group.</p>", "links"=>[], "tags"=>["anti-vegf", "mab", "radiosensitization"], "article_id"=>504909, "categories"=>["Cell Biology"], "users"=>["Jean-Philip Truman", "Mónica García-Barros", "Matthew Kaag", "Dolores Hambardzumyan", "Branka Stancevic", "Michael Chan", "Zvi Fuks", "Richard Kolesnick", "Adriana Haimovitz-Friedman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012310.g004", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ASMase_is_required_for_anti_VEGF_G6_31_mAb_radiosensitization_in_vivo_/504909", "title"=>"ASMase is required for anti-VEGF (G6–31) mAb radiosensitization <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-08-19 01:21:49"}

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  • {"unique-ip"=>"22", "full-text"=>"11", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"6", "cited-by"=>"1", "year"=>"2014", "month"=>"10"}
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  • {"unique-ip"=>"8", "full-text"=>"11", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
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  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
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  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"11", "full-text"=>"18", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"6", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
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  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"11", "full-text"=>"10", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
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  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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Relative Metric

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