Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy
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{"title"=>"Non-toxic metabolic management of metastatic cancer in VM mice: Novel combination of ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy", "type"=>"journal", "authors"=>[{"first_name"=>"A. M.", "last_name"=>"Poff", "scopus_author_id"=>"56003060900"}, {"first_name"=>"N.", "last_name"=>"Ward", "scopus_author_id"=>"56719184400"}, {"first_name"=>"T. N.", "last_name"=>"Seyfried", "scopus_author_id"=>"7005071365"}, {"first_name"=>"P.", "last_name"=>"Arnold", "scopus_author_id"=>"55756745000"}, {"first_name"=>"D. P.", "last_name"=>"D'Agostino", "scopus_author_id"=>"18436502000"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "doi"=>"10.1371/journal.pone.0127407", "sgr"=>"84936976775", "scopus"=>"2-s2.0-84936976775", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"26061868", "pui"=>"605098377"}, "id"=>"164209df-39af-3a3b-ae01-dc3e3740d04c", "abstract"=>"The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies - the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation - could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.", "link"=>"http://www.mendeley.com/research/nontoxic-metabolic-management-metastatic-cancer-vm-mice-novel-combination-ketogenic-diet-ketone-supp", "reader_count"=>77, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>11, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>3, "Other"=>8, "Student > Master"=>20, "Student > Bachelor"=>12, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>11, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>3, "Other"=>8, "Student > Master"=>20, "Student > Bachelor"=>12, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Unspecified"=>2, "Nursing and Health Professions"=>10, "Biochemistry, Genetics and Molecular Biology"=>15, "Medicine and Dentistry"=>28, "Agricultural and Biological Sciences"=>15, "Business, Management and Accounting"=>1, "Sports and Recreations"=>2, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>28}, "Sports and Recreations"=>{"Sports and Recreations"=>2}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>10}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>15}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>2}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2105186", "https://ndownloader.figshare.com/files/2105187", "https://ndownloader.figshare.com/files/2105188"], "description"=>"<div><p>The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.</p></div>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444812, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0127407.s001", "https://dx.doi.org/10.1371/journal.pone.0127407.s002", "https://dx.doi.org/10.1371/journal.pone.0127407.s003"], "stats"=>{"downloads"=>23, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Non_Toxic_Metabolic_Management_of_Metastatic_Cancer_in_VM_Mice_Novel_Combination_of_Ketogenic_Diet_Ketone_Supplementation_and_Hyperbaric_Oxygen_Therapy_/1444812", "title"=>"Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105182"], "description"=>"<p>Macronutrient information of diets and ketone ester.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444809, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.t001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Macronutrient_information_of_diets_and_ketone_ester_/1444809", "title"=>"Macronutrient information of diets and ketone ester.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105181"], "description"=>"<p><b>(A-B)</b> VM-M3 cells were treated for 24 hours with individual or combination metabolic therapies: LG, βHB, HBOT, or LG+βHB+HBOT. Superoxide production was measured with DHE fluorescence microscopy and was significantly increased with HBOT alone or in combination with LG+βHB. Results were considered significant when p<0.05. Error bars represent <b>±</b>SEM.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444808, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g008", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Metabolic_therapy_increases_ROS_production_in_VM_M3_cells_/1444808", "title"=>"Metabolic therapy increases ROS production in VM-M3 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105158"], "description"=>"<p><b>(A)</b><i>In vivo</i> bioluminescence imaging of representative animals from each treatment group 3 weeks post tumor cell inoculation. Treated mice exhibited reduced tumor burden and metastatic spread. <b>(B)</b> Whole animal bioluminescence (photons/sec) was tracked over time as a measure of tumor growth rate. In order to avoid misleading representation of tumor burden, data for treatment groups where ≥50% of animals had succumbed to disease progression are no longer shown. Tumor bioluminescence was highly variable, but treated animals demonstrated a notable trend of slower tumor growth compared to controls throughout the study. KD treated mice had less bioluminescence than controls at week 2, while KD+KE+HBOT mice had less bioluminescence than control animals at weeks 1, 2, and 3. KD+KE+HBOT mice also had less bioluminescence than KD+KE mice at weeks 1, 2, 3, and 5, and had less tumor bioluminescence than KD mice at weeks 3 and 5. Error bars represent <b>±</b>SEM. Results were considered significant when p<0.05.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444785, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_slows_tumor_growth_/1444785", "title"=>"Combination metabolic therapy slows tumor growth.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105175"], "description"=>"<p>VM-M3 cells were treated with high (control; 25mM) or low (LG; 3mM) glucose for 24 hours, with or without 5mM βHB or one session of HBOT. Viability was measured with calcein AM and Ethd-1 fluorescence microscopy. <b>(A-B)</b> βHB, LG, and LG+βHB+HBOT treatment decreased viability compared to control and HBOT treated cells. LG+βHB+HBOT cell viability was significantly decreased compared to βHB but not LG treated cells. Results were considered significant when p<0.05. Error bars represent <b>±</b>SEM.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444802, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g007", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_decreases_VM_M3_cell_viability_in_vitro_/1444802", "title"=>"Combination metabolic therapy decreases VM-M3 cell viability <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105170"], "description"=>"<p><b>(A-C)</b> KD+KE treated mice had significantly decreased blood glucose and body weight and increased blood βHB compared to control mice by day 7. Blood glucose was significantly reduced only in KD+KE treated mice by day 7. Both KD+KE and KD+KE+HBOT treated mice exhibited increased blood βHB compared to control and KD treated mice by day 7. Only KD+KE mice had a significant reduction in body weight by day 7. <b>(D)</b> Only KD+KE mice demonstrated a significant and consistent decrease in body weight over the course of the study. Results were considered significant when p<0.05. Error bars represent <b>±</b>SEM.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444797, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g005", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Blood_glucose_946_HB_and_body_weight_of_VM_M3_survival_study_mice_prior_to_significant_disease_onset_day_7_/1444797", "title"=>"Blood glucose, βHB, and body weight of VM-M3 survival study mice prior to significant disease onset (day 7).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105169"], "description"=>"<p>Morphology and vascularization of KD+KE+HBOT-treated mouse liver tumors were analyzed by H&E staining and CD31 immunohistochemistry. Tumors from KD+KE+HBOT-treated mice were smaller with more well-defined borders (A, C) and exhibited a significant reduction in vascularization (B, D, E) from controls (*p<0.05; unpaired t-test). Error bars represent ±SEM.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444796, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_decreases_metastatic_liver_tumor_size_and_vascularization_/1444796", "title"=>"Combination metabolic therapy decreases metastatic liver tumor size and vascularization.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105165"], "description"=>"<p><b>(A)</b> Kaplan-Meier survival curve of study groups. KD, KD+KE, and KD+KE+HBOT treated mice demonstrated prolonged survival compared to controls (p = 0.03, p = 0.009, and p<0.0001, respectively; log-rank Mantel-Cox test for survival distribution). There was a strong trend of more prolonged survival in the combination treatment mice compared to KD or KD+KE, but these curves were not significantly different from each other (KD vs. KD+KE+HBOT p = 0.0622; KD+KE vs. KD+KE+HBOT p = 0.1924; log-rank Mantel-Cox test). <b>(B)</b> Cohort size (N), mean survival (days), and percent increase in mean survival time from control. KD, KD+KE, and KD+KE+HBOT treated mice exhibited a 44.6%, 65.4%, and 103.2% increase in mean survival time compared to controls, respectively (*p<0.05, **p<0.01, ***p<0.001; One-Way ANOVA). Similar to the survival curve analysis, there was a trend of increased mean survival time in combination treated mice compared to KD and KD+KE, but these differences were not significant (KD vs. KD+KE+HBOT p = 0.1062; KD+KE vs. KD+KE+HBOT p = 0.2763). Results were considered significant when p<0.05.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444792, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g003", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_extends_survival_time_in_mice_with_metastatic_cancer_/1444792", "title"=>"Combination metabolic therapy extends survival time in mice with metastatic cancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105163"], "description"=>"<p><b>(A)</b><i>In vivo</i> bioluminescence of key metastatic regions 21 days after tumor cell inoculation demonstrated a marked reduction in metastatic tumor burden and spread for treated animals. KD+KE+HBOT mice had significantly less metastatic spread to the brain, lung, and liver compared to controls at 3 weeks. There were no significant differences in metastatic spread between the three treatment groups. <b>(B-C)</b> To provide a more sensitive measure of metastatic spread in our multi-combination therapy, a separate group of control and KD+KE+HBOT treated animals were treated for 21 days following tumor cell inoculation and euthanized. <i>Ex vivo</i> bioluminescent imaging of harvested organs confirmed a significant decrease in metastatic tumor burden and spread in combination treated animals compared to controls. All organs tested—brain, kidneys, spleen, lungs, adipose, and liver—exhibited significantly reduced bioluminescent signal compared to controls. Error bars represent <b>±</b>SEM. Results were considered significant when p<0.05.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444790, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g002", "stats"=>{"downloads"=>4, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_slows_tumor_growth_and_inhibits_metastatic_spread_/1444790", "title"=>"Combination metabolic therapy slows tumor growth and inhibits metastatic spread.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/2105172"], "description"=>"<p>VM-M3 cells were grown in conditions mimicking metabolic therapy, including combinations of varied glucose concentration (25mM, 15mM, or 3mM) media, ketone supplementation (5mM βHB), and daily HBOT sessions (100% O<sub>2</sub>, 2.5 ATA, 90 min). Cell density was measured with trypan blue hemocytometry to produce a growth curve over 96 hours. <b>(A)</b> Proliferation of VM-M3 cells was inhibited with decreasing glucose concentration and the addition of HBOT. At 24 hours, cell density of 3mM glu and 3mM glu + HBOT cells was significantly less than control (25mM) glucose treated cells. At 48, 72, and 96 hours, the cell density of all treatment groups was significantly reduced compared to control (*p<0.05; Two-way ANOVA). <b>(B)</b> Combining low glucose, ketone supplementation, and HBOT resulted in a marked decrease in cell proliferation which was significant from control at all time points tested. (p<0.05; one-way ANOVA). Cells receiving combination therapy had a significant decrease in proliferation compared to cells treated with LG only at 24, 48, and 72 hours, and compared to βHB only at 48, 72, and 96 hours, and exhibited a non-significant trend of decreased proliferation compared to LG + HBOT treated cells for the duration of the growth curve. Results were considered significant when p<0.05. Error bars represent <b>±</b>SEM.</p>", "links"=>[], "tags"=>["hbot", "combination therapy", "hb", "ros", "metastatic", "hyperbaric oxygen therapy", "glucose", "tumor growth rate", "kd", "lg", "vm"], "article_id"=>1444799, "categories"=>["Biological Sciences"], "users"=>["A. M. Poff", "N. Ward", "T. N. Seyfried", "P. Arnold", "D. P. D’Agostino"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127407.g006", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_metabolic_therapy_decreases_VM_M3_cell_proliferation_in_vitro_/1444799", "title"=>"Combination metabolic therapy decreases VM-M3 cell proliferation <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-10 03:10:53"}

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  • {"unique-ip"=>"77", "full-text"=>"90", "pdf"=>"21", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"68", "full-text"=>"90", "pdf"=>"13", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"86", "full-text"=>"115", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"62", "full-text"=>"72", "pdf"=>"17", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"62", "full-text"=>"88", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"50", "full-text"=>"71", "pdf"=>"13", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"52", "full-text"=>"72", "pdf"=>"10", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"62", "full-text"=>"78", "pdf"=>"14", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"5", "cited-by"=>"1", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"85", "full-text"=>"119", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}
  • {"unique-ip"=>"45", "full-text"=>"82", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2020", "month"=>"11"}
  • {"unique-ip"=>"48", "full-text"=>"60", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"12"}
  • {"unique-ip"=>"43", "full-text"=>"73", "pdf"=>"12", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2021", "month"=>"1"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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