Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing
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{"title"=>"Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing", "type"=>"journal", "authors"=>[{"first_name"=>"Dan", "last_name"=>"Xu", "scopus_author_id"=>"25229234200"}, {"first_name"=>"Toshi", "last_name"=>"Nishimura", "scopus_author_id"=>"56157450600"}, {"first_name"=>"Sachiko", "last_name"=>"Nishimura", "scopus_author_id"=>"56157953500"}, {"first_name"=>"Haili", "last_name"=>"Zhang", "scopus_author_id"=>"56158223600"}, {"first_name"=>"Ming", "last_name"=>"Zheng", "scopus_author_id"=>"19236458100"}, {"first_name"=>"Ying Ying", "last_name"=>"Guo", "scopus_author_id"=>"9737868700"}, {"first_name"=>"Marylin", "last_name"=>"Masek", "scopus_author_id"=>"57200908949"}, {"first_name"=>"Sara A.", "last_name"=>"Michie", "scopus_author_id"=>"7004779977"}, {"first_name"=>"Jeffrey", "last_name"=>"Glenn", "scopus_author_id"=>"7202479598"}, {"first_name"=>"Gary", "last_name"=>"Peltz", "scopus_author_id"=>"7005048967"}], "year"=>2014, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491676", "sgr"=>"84900460907", "doi"=>"10.1371/journal.pmed.1001628", "scopus"=>"2-s2.0-84900460907", "isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "pmid"=>"24736310", "pui"=>"373076982"}, "id"=>"f4b43c75-56d3-377a-9b80-85729fa1abf8", "abstract"=>"BACKGROUND Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. METHODS AND FINDINGS Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. CONCLUSIONS FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.", "link"=>"http://www.mendeley.com/research/fialuridine-induces-acute-liver-failure-chimeric-tknog-mice-model-detecting-hepatic-drug-toxicity-pr", "reader_count"=>48, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>6}, "reader_count_by_subject_area"=>{"Engineering"=>4, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>8, "Materials Science"=>3, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>7, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>3, "Psychology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>4}, "Materials Science"=>{"Materials Science"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"United States"=>1, "United Kingdom"=>1}, "group_count"=>7}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1465355"], "description"=>"<p>Control (non-humanized) (Cont, <i>n</i> = 5 per group) or chimeric TK-NOG mice (Hu, <i>n</i> = 6 per group) were treated with sofosbuvir (440 or 44 mg/kg/d po) or vehicle (Veh) for 14 d, and their body weights (A) and plasma ALT (B) and lactate (C) levels were measured on the indicated days. (A) There was no difference in the weights of vehicle- or sofosbuvir-treated control TK-NOG mice or TK-NOG mice with humanized livers. In (B and C), each symbol represents the value measured in a control TK-NOG mouse or a TK-NOG mouse with a humanized liver, the dotted line across the graph indicates the upper limit of normal, and the short dashed lines show the average for each group.</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "toxicity", "tk-nog", "mice", "humanized"], "article_id"=>1000045, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g006", "stats"=>{"downloads"=>6, "page_views"=>40, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sofosbuvir_does_not_cause_liver_toxicity_in_TK_NOG_mice_with_humanized_livers_/1000045", "title"=>"Sofosbuvir does not cause liver toxicity in TK-NOG mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465340"], "description"=>"<p>Control (non-humanized) (TK or Cont, <i>n</i> = 6 per group) or chimeric (Hu, <i>n</i> = 6 per group) TK-NOG mice were treated with 25 mg/kg/d FIAU or vehicle (Veh) for 14 d, and their body weights (A) and plasma ALT (B) and lactate (C) levels were measured on the indicated days. (A) There was no difference in the weights of vehicle- or FIAU-treated control TK-NOG mice or TK-NOG mice with humanized livers. In (B and C), each symbol represents the value measured in a control TK-NOG mouse or a TK-NOG mouse with a humanized liver, the dotted line across the graph indicates the upper limit of normal, and the short dashed lines show the average for each group.</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "toxicity", "develops", "tk-nog", "mice", "humanized", "livers", "treated", "25"], "article_id"=>1000030, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g002", "stats"=>{"downloads"=>3, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_toxicity_develops_in_TK_NOG_mice_with_humanized_livers_treated_with_25_mg_kg_d_FIAU_/1000030", "title"=>"Liver toxicity develops in TK-NOG mice with humanized livers treated with 25 mg/kg/d FIAU.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465337"], "description"=>"<p>Control (non-humanized) (Cont, <i>n</i> = 12 per group) or chimeric (Hu, <i>n</i> = 15 per group) TK-NOG mice were treated with 400 mg/kg/d FIAU or vehicle (Veh) for 0, 4, or 14 d, and the plasma ALT (A) and lactate (B) levels were measured on the indicated days. The lactate and ALT levels were elevated in FIAU-treated chimeric mice, while control mice had normal ALT and lactate levels after 14 d of FIAU dosing. Each symbol represents the value measured in a control TK-NOG mouse or a TK-NOG mouse with a humanized liver; the dotted line across the graph indicates the upper limit of normal, and the short dashed lines show the average for each group. (C) The correlation between the human albumin and plasma lactate levels measured in 15 chimeric TK-NOG mice after 4 d of treatment with 400 mg/kg/d FIAU. The human serum albumin is a measure of the extent of liver humanization in chimeric TK-NOG mice. Each dot represents the values measured in one chimeric TK-NOG mouse.</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "toxicity", "develops", "tk-nog", "mice", "humanized"], "article_id"=>1000027, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g001", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FIAU_induced_liver_toxicity_develops_in_TK_NOG_mice_with_humanized_livers_/1000027", "title"=>"FIAU-induced liver toxicity develops in TK-NOG mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465351"], "description"=>"<p>TEMs (original magnification 2,500×) of liver sections with human cells in liver tissue obtained from untreated (#202) (A) or FIAU-treated (#183) (B) chimeric mice are shown. (C) and (D) are enlarged views (30,000×) of the boxed regions in (A) and (B), respectively. The human hepatocytes within the liver tissue obtained from the FIAU-treated chimeric mouse (B) have many large lipid droplets, which are not found in the human hepatocytes in the untreated chimeric mouse (A). There are abundant mitochondria in the human hepatocytes in the untreated chimeric mouse, and cristae are readily apparent (C). In contrast, human hepatocytes in FIAU-treated chimeric mice have altered mitochondria with variable sizes and a reduced number of cristae (D).</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "induced", "fiau", "tk-nog", "mice", "humanized"], "article_id"=>1000041, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g005", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ultra_structural_changes_induced_by_FIAU_in_TK_NOG_mice_with_humanized_livers_/1000041", "title"=>"Ultra-structural changes induced by FIAU in TK-NOG mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465371", "https://ndownloader.figshare.com/files/1465372", "https://ndownloader.figshare.com/files/1465373", "https://ndownloader.figshare.com/files/1465374", "https://ndownloader.figshare.com/files/1465375", "https://ndownloader.figshare.com/files/1465376"], "description"=>"<div><p>Background</p><p>Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.</p><p>Methods and Findings</p><p>Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.</p><p>Conclusions</p><p>FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "acute", "chimeric", "tk-nog", "detecting", "hepatic", "toxicity"], "article_id"=>1000058, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001628.s001", "https://dx.doi.org/10.1371/journal.pmed.1001628.s002", "https://dx.doi.org/10.1371/journal.pmed.1001628.s003", "https://dx.doi.org/10.1371/journal.pmed.1001628.s004", "https://dx.doi.org/10.1371/journal.pmed.1001628.s005", "https://dx.doi.org/10.1371/journal.pmed.1001628.s006"], "stats"=>{"downloads"=>23, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fialuridine_Induces_Acute_Liver_Failure_in_Chimeric_TK_NOG_Mice_A_Model_for_Detecting_Hepatic_Drug_Toxicity_Prior_to_Human_Testing_/1000058", "title"=>"Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465350"], "description"=>"<p>Liver tissues were obtained from mice with humanized livers treated with FIAU 400/kg/d (#192) (A) or FIAU 0 mg/kg/d (#202) (B) for 4 d, or from a control TK-NOG mouse treated with FIAU 400 mg/kg/d for 4 d (C). The images (at 100× magnification) shown in the left column are of formalin-fixed paraffin-embedded tissues stained with a monoclonal anti–human cytokeratin 8 antibody and counterstained with hematoxylin. The antibody-stained dark brown regions have human hepatocytes, while the mouse hepatocytes appear in the light tan regions. The middle and right columns are higher magnification views (600×) of the boxed regions of the images shown on the left; the upper and lower images in (A) and (B) are from the boxed regions containing human and mouse hepatocytes, respectively. The middle column shows formalin-fixed paraffin-embedded tissues stained with H/E, and the images in the right column were stained with oil red O and counterstained with hematoxylin. The hepatocytes in livers obtained from the FIAU-treated control or from untreated mice with humanized livers do not contain the markedly increased number of vacuoles that are present in the H/E-strained sections of the FIAU-treated humanized mouse liver. Many of these vacuoles are stained with oil red O (arrows), which indicates that they contain fat. However, not all of the vacuoles are stained by oil red O (arrowheads).</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "fiau-induced", "toxicity", "tk-nog", "mice", "humanized"], "article_id"=>1000040, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g004", "stats"=>{"downloads"=>4, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histopathology_of_FIAU_induced_liver_toxicity_in_TK_NOG_mice_with_humanized_livers_/1000040", "title"=>"Histopathology of FIAU-induced liver toxicity in TK-NOG mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1465345"], "description"=>"<p>Control (non-humanized) (TK or Cont, <i>n</i> = 6 per group) or chimeric (Hu, <i>n</i> = 6 per group) TK-NOG mice were treated with 2.5 mg/kg/d FIAU or vehicle (Veh) for 14 d, and their body weights (A) and plasma ALT (B) and lactate (C) levels were measured on the indicated days. (A) There was no difference in the weights of vehicle- or FIAU-treated control TK-NOG mice or TK-NOG mice with humanized livers. In (B and C), each symbol represents the value measured in a control TK-NOG mouse or a TK-NOG mouse with a humanized liver, the dotted line across the graph indicates the upper limit of normal, and the short dashed lines show the average for each group.</p>", "links"=>[], "tags"=>["Clinical medicine", "pharmacology", "Adverse reactions", "Pharmacodynamics", "toxicity", "dose-dependent", "tk-nog", "mice", "humanized"], "article_id"=>1000035, "categories"=>["Biological Sciences"], "users"=>["Dan Xu", "Toshi Nishimura", "Sachiko Nishimura", "Haili Zhang", "Ming Zheng", "Ying-Ying Guo", "Marylin Masek", "Sara A. Michie", "Jeffrey Glenn", "Gary Peltz"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001628.g003", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FIAU_induced_liver_toxicity_is_dose_dependent_in_TK_NOG_mice_with_humanized_livers_/1000035", "title"=>"FIAU-induced liver toxicity is dose-dependent in TK-NOG mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-15 03:41:57"}

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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/Anatomy", "average_usage"=>[267]}, {"subject_area"=>"/Biology and life sciences/Toxicology", "average_usage"=>[266, 408]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[285]}, {"subject_area"=>"/Medicine and health sciences/Surgical and invasive medical procedures", "average_usage"=>[248, 388]}]}
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