{"id":"67e44fe7-2840-5378-b61c-e2176be2e6e8","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-histidine-mtx-xenograft","predicate":"enhances_tested","statement":"Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"0c62b729-67fa-5fdf-ae13-4c45b2edc0c7","mechanism_event_label":"Changing substrate supply strengthened a drug effect in this animal model.","subject":{"id":"44374451-3436-5136-a8ae-5dcc6d8c353b","slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"},"object":{"id":"9f8b1e6a-25aa-5d36-9bb1-efdd8f9c2e1d","slug":"mouse-human-leukemia-xenograft-mtx-response","display_name":"Methotrexate response of human leukemia xenografts in mice","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"0c62b729-67fa-5fdf-ae13-4c45b2edc0c7","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-histidine-mtx-xenograft-event","event_type":"observed_relationship","label":"Changing substrate supply strengthened a drug effect in this animal model.","description":"Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"44374451-3436-5136-a8ae-5dcc6d8c353b","slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9f8b1e6a-25aa-5d36-9bb1-efdd8f9c2e1d","slug":"mouse-human-leukemia-xenograft-mtx-response","display_name":"Methotrexate response of human leukemia xenografts in mice","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"1f13ebf9-42c9-516e-b462-0e1b3952c2a2","slug":"methotrexate","display_name":"Methotrexate","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"d2b23343-c688-5fc3-9f42-bfac0050552b","slug":"tetrahydrofolate","display_name":"Tetrahydrofolate","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"Changing substrate supply strengthened a drug effect in this animal model.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"236a2153-24a5-554c-af51-4ac9cafb0611","evidence_kind":"source_excerpt","locator":"Lines 178-184","start_line":178,"end_line":184,"excerpt":"## histidine-histidine-mtx-xenograft\nChanging substrate supply strengthened a drug effect in this animal model.\nCombined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment.\nModel: NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.\nLimitations: Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2\nEvidence access: Primary full text\nHistidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7","model_system":"NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Original curation paraphrase; evidence access and experimental limitations specified.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"ce59e6c9-1213-523b-9d0b-400b7a81cd1c","stable_key":"import-911fb3c7-8cc3-5667-b677-5682fab67648","title":"L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text.","file_path":"","sha256":"cb672530ec8b4a4542d0f3957e80ca76bb0449e9f988845b0f7681f623c4ec9b","revision_id":"19a7f26c-d9a1-5411-a81d-025f3d98a452","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}