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bionlp_st_2013_cg

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[ { "id": "PMID-15193260__text", "type": "abstract", "text": [ "Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes. \nWe identified dynein light chain 1 (DLC1) as a physiologic substrate of p21-activated kinase 1 (Pak1). Pak1-DLC1 interaction plays an essential role in cell survival, which depends on Pak1's phosphorylation of DLC1 on Ser88. Pak1 associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein, and phosphorylates both proteins. Phosphorylation of BimL by Pak1 prevents it from interacting with and inactivation of Bcl-2, an antiapoptotic protein. Overexpression of DLC1 but not DLC1-Ser88Ala mutant promotes cancerous properties of breast cancer cells. DLC1 protein level is elevated in more than 90% of human breast tumors. The regulation of cell survival functions by Pak1-DLC1 interaction represents a novel mechanism by which a signaling kinase might regulate the cancerous phenotypes.\n" ], "offsets": [ [ 0, 907 ] ] } ]

[ { "id": "PMID-15193260_T1", "type": "Gene_or_gene_product", "text": [ "Dynein light chain 1" ], "offsets": [ [ 0, 20 ] ], "normalized": [] }, { "id": "PMID-15193260_T2", "type": "Gene_or_gene_product", "text": [ "p21-activated kinase 1" ], "offsets": [ [ 24, 46 ] ], "normalized": [] }, { "id": "PMID-15193260_T3", "type": "Cancer", "text": [ "cancerous" ], "offsets": [ [ 79, 88 ] ], "normalized": [] }, { "id": "PMID-15193260_T4", "type": "Gene_or_gene_product", "text": [ "dynein light chain 1" ], "offsets": [ [ 116, 136 ] ], "normalized": [] }, { "id": "PMID-15193260_T5", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 138, 142 ] ], "normalized": [] }, { "id": "PMID-15193260_T6", "type": "Gene_or_gene_product", "text": [ "p21-activated kinase 1" ], "offsets": [ [ 174, 196 ] ], "normalized": [] }, { "id": "PMID-15193260_T7", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 198, 202 ] ], "normalized": [] }, { "id": "PMID-15193260_T8", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 205, 209 ] ], "normalized": [] }, { "id": "PMID-15193260_T9", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 210, 214 ] ], "normalized": [] }, { "id": "PMID-15193260_T10", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 254, 258 ] ], "normalized": [] }, { "id": "PMID-15193260_T11", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 286, 290 ] ], "normalized": [] }, { "id": "PMID-15193260_T12", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 312, 316 ] ], "normalized": [] }, { "id": "PMID-15193260_T13", "type": "Amino_acid", "text": [ "Ser88" ], "offsets": [ [ 320, 325 ] ], "normalized": [] }, { "id": "PMID-15193260_T14", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 327, 331 ] ], "normalized": [] }, { "id": "PMID-15193260_T15", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 363, 367 ] ], "normalized": [] }, { "id": "PMID-15193260_T16", "type": "Gene_or_gene_product", "text": [ "BimL" ], "offsets": [ [ 372, 376 ] ], "normalized": [] }, { "id": "PMID-15193260_T17", "type": "Gene_or_gene_product", "text": [ "BimL" ], "offsets": [ [ 464, 468 ] ], "normalized": [] }, { "id": "PMID-15193260_T18", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 472, 476 ] ], "normalized": [] }, { "id": "PMID-15193260_T19", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 531, 536 ] ], "normalized": [] }, { "id": "PMID-15193260_T20", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 582, 586 ] ], "normalized": [] }, { "id": "PMID-15193260_T21", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 595, 599 ] ], "normalized": [] }, { "id": "PMID-15193260_T22", "type": "Amino_acid", "text": [ "Ser88" ], "offsets": [ [ 600, 605 ] ], "normalized": [] }, { "id": "PMID-15193260_T23", "type": "Cancer", "text": [ "cancerous" ], "offsets": [ [ 625, 634 ] ], "normalized": [] }, { "id": "PMID-15193260_T24", "type": "Cell", "text": [ "breast cancer cells" ], "offsets": [ [ 649, 668 ] ], "normalized": [] }, { "id": "PMID-15193260_T25", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-15193260_T26", "type": "Organism", "text": [ "human" ], "offsets": [ [ 721, 726 ] ], "normalized": [] }, { "id": "PMID-15193260_T27", "type": "Cancer", "text": [ "breast tumors" ], "offsets": [ [ 727, 740 ] ], "normalized": [] }, { "id": "PMID-15193260_T28", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 760, 764 ] ], "normalized": [] }, { "id": "PMID-15193260_T29", "type": "Gene_or_gene_product", "text": [ "Pak1" ], "offsets": [ [ 787, 791 ] ], "normalized": [] }, { "id": "PMID-15193260_T30", "type": "Gene_or_gene_product", "text": [ "DLC1" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "PMID-15193260_T31", "type": "Cancer", "text": [ "cancerous" ], "offsets": [ [ 885, 894 ] ], "normalized": [] } ]

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"role": "Cause", "ref_id": "PMID-15193260_E14" } ] }, { "id": "PMID-15193260_E18", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 477, 485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_E21" }, { "role": "Cause", "ref_id": "PMID-15193260_E15" } ] }, { "id": "PMID-15193260_E19", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 477, 485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_E20" }, { "role": "Cause", "ref_id": "PMID-15193260_E15" } ] }, { "id": "PMID-15193260_E20", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 494, 505 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_T19" }, { "role": "Theme", "ref_id": "PMID-15193260_T18" }, { "role": "Theme", "ref_id": "PMID-15193260_T17" } ] }, { "id": "PMID-15193260_E21", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 515, 527 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_T19" } ] }, { "id": "PMID-15193260_E22", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 564, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_T20" } ] }, { "id": "PMID-15193260_E23", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 564, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_T21" } ] }, { "id": "PMID-15193260_E24", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 564, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_E23" } ] }, { "id": "PMID-15193260_E25", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 564, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15193260_E22" } ] }, { "id": "PMID-15193260_E26", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 616, 624 ] ] }, 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[]

[ { "id": "PMID-10913166__text", "type": "abstract", "text": [ "TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1. \nTEL is a member of the ETS family of transcription factors that interacts with the mSin3 and SMRT corepressors to regulate transcription. TEL is biallelically disrupted in acute leukemia, and loss of heterozygosity at the TEL locus has been observed in various cancers. Here we show that expression of TEL in Ras-transformed NIH 3T3 cells inhibits cell growth in soft agar and in normal cultures. Unexpectedly, cells expressing both Ras and TEL grew as aggregates. To begin to explain the morphology of Ras-plus TEL-expressing cells, we demonstrated that the endogenous matrix metalloproteinase stromelysin-1 was repressed by TEL. TEL bound sequences in the stromelysin-1 promoter and repressed the promoter in transient-expression assays, suggesting that it is a direct target for TEL-mediated regulation. Mutants of TEL that removed a binding site for the mSin3A corepressor but retained the ETS domain failed to repress stromelysin-1. When BB-94, a matrix metalloproteinase inhibitor, was added to the culture medium of Ras-expressing cells, it caused a cell aggregation phenotype similar to that caused by TEL expression. In addition, TEL inhibited the invasiveness of Ras-transformed cells in vitro and in vivo. Our results suggest that TEL acts as a tumor suppressor, in part, by transcriptional repression of stromelysin-1.\n" ], "offsets": [ [ 0, 1486 ] ] } ]

[ { "id": "PMID-10913166_T1", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-10913166_T2", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 16, 21 ] ], "normalized": [] }, { "id": "PMID-10913166_T3", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 44, 48 ] ], "normalized": [] }, { "id": "PMID-10913166_T4", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "PMID-10913166_T5", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 79, 82 ] ], "normalized": [] }, { "id": "PMID-10913166_T6", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 95, 100 ] ], "normalized": [] }, { "id": "PMID-10913166_T7", "type": "Gene_or_gene_product", "text": [ "stromelysin-1" ], "offsets": [ [ 139, 152 ] ], "normalized": [] }, { "id": "PMID-10913166_T8", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 155, 158 ] ], "normalized": [] }, { "id": "PMID-10913166_T9", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 178, 181 ] ], "normalized": [] }, { "id": "PMID-10913166_T10", "type": "Gene_or_gene_product", "text": [ "mSin3" ], "offsets": [ [ 238, 243 ] ], "normalized": [] }, { "id": "PMID-10913166_T11", "type": "Gene_or_gene_product", "text": [ "SMRT" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "PMID-10913166_T12", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 293, 296 ] ], "normalized": [] }, { "id": "PMID-10913166_T13", "type": "Cancer", "text": [ "acute leukemia" ], "offsets": [ [ 327, 341 ] ], "normalized": [] }, { "id": "PMID-10913166_T14", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 377, 380 ] ], "normalized": [] }, { "id": "PMID-10913166_T15", "type": "Cancer", "text": [ "cancers" ], "offsets": [ [ 416, 423 ] ], "normalized": [] }, { "id": "PMID-10913166_T16", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 457, 460 ] ], "normalized": [] }, { "id": "PMID-10913166_T17", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 464, 467 ] ], "normalized": [] }, { "id": "PMID-10913166_T18", "type": "Cell", "text": [ "NIH 3T3 cells" ], "offsets": [ [ 480, 493 ] ], "normalized": [] }, { "id": "PMID-10913166_T19", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 503, 507 ] ], "normalized": [] }, { "id": "PMID-10913166_T20", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 566, 571 ] ], "normalized": [] }, { "id": "PMID-10913166_T21", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 588, 591 ] ], "normalized": [] }, { "id": "PMID-10913166_T22", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 596, 599 ] ], "normalized": [] }, { "id": "PMID-10913166_T23", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 658, 661 ] ], "normalized": [] }, { "id": "PMID-10913166_T24", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 667, 670 ] ], "normalized": [] }, { "id": "PMID-10913166_T25", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 682, 687 ] ], "normalized": [] }, { "id": "PMID-10913166_T26", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase stromelysin-1" ], "offsets": [ [ 725, 763 ] ], "normalized": [] }, { "id": "PMID-10913166_T27", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 781, 784 ] ], "normalized": [] }, { "id": "PMID-10913166_T28", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 786, 789 ] ], "normalized": [] }, { "id": "PMID-10913166_T29", "type": "Gene_or_gene_product", "text": [ "stromelysin-1" ], "offsets": [ [ 813, 826 ] ], "normalized": [] }, { "id": "PMID-10913166_T30", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 937, 940 ] ], "normalized": [] }, { "id": "PMID-10913166_T31", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 973, 976 ] ], "normalized": [] }, { "id": "PMID-10913166_T32", "type": "Gene_or_gene_product", "text": [ "mSin3A" ], "offsets": [ [ 1013, 1019 ] ], "normalized": [] }, { "id": "PMID-10913166_T33", "type": "Gene_or_gene_product", "text": [ "stromelysin-1" ], "offsets": [ [ 1078, 1091 ] ], "normalized": [] }, { "id": "PMID-10913166_T34", "type": "Simple_chemical", "text": [ "BB-94" ], "offsets": [ [ 1098, 1103 ] ], "normalized": [] }, { "id": "PMID-10913166_T35", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase" ], "offsets": [ [ 1107, 1131 ] ], "normalized": [] }, { "id": "PMID-10913166_T36", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 1178, 1181 ] ], "normalized": [] }, { "id": "PMID-10913166_T37", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1193, 1198 ] ], "normalized": [] }, { "id": "PMID-10913166_T38", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "PMID-10913166_T39", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 1265, 1268 ] ], "normalized": [] }, { "id": "PMID-10913166_T40", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 1294, 1297 ] ], "normalized": [] }, { "id": "PMID-10913166_T41", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 1328, 1331 ] ], "normalized": [] }, { "id": "PMID-10913166_T42", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1344, 1349 ] ], "normalized": [] }, { "id": "PMID-10913166_T43", "type": "Gene_or_gene_product", "text": [ "TEL" ], "offsets": [ [ 1397, 1400 ] ], "normalized": [] }, { "id": "PMID-10913166_T44", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1411, 1416 ] ], "normalized": [] }, { "id": "PMID-10913166_T45", "type": "Gene_or_gene_product", "text": [ "stromelysin-1" ], "offsets": [ [ 1471, 1484 ] ], "normalized": [] }, { "id": "PMID-10913166_T63", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 827, 835 ] ], "normalized": [] } ]

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"text": [ "transcription" ], "offsets": [ [ 122, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T7" } ] }, { "id": "PMID-10913166_E6", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 219, 228 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T10" }, { "role": "Theme", "ref_id": "PMID-10913166_T11" }, { "role": "Theme", "ref_id": "PMID-10913166_T8" } ] }, { "id": "PMID-10913166_E7", "type": "Mutation", "trigger": { "text": [ "disrupted" ], "offsets": [ [ 314, 323 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T12" }, { "role": "AtLoc", "ref_id": "PMID-10913166_T13" } ] }, { "id": "PMID-10913166_E8", "type": "Mutation", "trigger": { "text": [ "loss of heterozygosity" ], "offsets": [ [ 347, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T14" }, { "role": "AtLoc", "ref_id": "PMID-10913166_T15" } ] }, { "id": "PMID-10913166_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 443, 453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T16" } ] }, { "id": "PMID-10913166_E10", "type": "Planned_process", "trigger": { "text": [ "transformed" ], "offsets": [ [ 468, 479 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10913166_T17" }, { "role": "Theme", "ref_id": "PMID-10913166_T18" } ] }, { "id": "PMID-10913166_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 494, 502 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10913166_E9" }, { "role": "Theme", "ref_id": "PMID-10913166_E12" } ] }, { "id": "PMID-10913166_E12", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 508, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T19" } ] }, { "id": "PMID-10913166_E13", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 572, 582 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T21" }, { "role": "Theme", "ref_id": "PMID-10913166_T22" } ] }, { "id": "PMID-10913166_E14", "type": "Growth", "trigger": { "text": [ "grew" ], "offsets": [ [ 600, 604 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T20" } ] }, { "id": "PMID-10913166_E15", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 671, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T24" }, { "role": "Theme", "ref_id": "PMID-10913166_T23" } ] }, { "id": "PMID-10913166_E16", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 768, 777 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T26" }, { "role": "Cause", "ref_id": "PMID-10913166_T27" } ] }, { "id": "PMID-10913166_E17", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 790, 795 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T29" }, { "role": "Theme", "ref_id": "PMID-10913166_T28" }, { "role": "Site", "ref_id": "PMID-10913166_T63" } ] }, { "id": "PMID-10913166_E18", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 840, 849 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_E19" }, { "role": "Cause", "ref_id": "PMID-10913166_T28" } ] }, { "id": "PMID-10913166_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 876, 886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T29" } ] }, { "id": "PMID-10913166_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 992, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T31" } ] }, { "id": "PMID-10913166_E21", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 1070, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T33" } ] }, { "id": "PMID-10913166_E22", "type": "Planned_process", "trigger": { "text": [ "added" ], "offsets": [ [ 1147, 1152 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10913166_T34" }, { "role": "Theme", "ref_id": "PMID-10913166_T37" } ] }, { "id": "PMID-10913166_E23", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1182, 1192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T36" } ] }, { "id": "PMID-10913166_E24", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1203, 1209 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10913166_T34" }, { "role": "Theme", "ref_id": "PMID-10913166_E25" } ] }, { "id": "PMID-10913166_E25", "type": "Binding", "trigger": { "text": [ "aggregation" ], "offsets": [ [ 1217, 1228 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T38" } ] }, { "id": "PMID-10913166_E26", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1255, 1261 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10913166_E27" }, { "role": "Theme", "ref_id": "PMID-10913166_E25" } ] }, { "id": "PMID-10913166_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1269, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T39" } ] }, { "id": "PMID-10913166_E28", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1298, 1307 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10913166_T40" }, { "role": "Theme", "ref_id": "PMID-10913166_T42" } ] }, { "id": "PMID-10913166_E29", "type": "Planned_process", "trigger": { "text": [ "transformed" ], "offsets": [ [ 1332, 1343 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10913166_T41" }, { "role": "Theme", "ref_id": "PMID-10913166_T42" } ] }, { "id": "PMID-10913166_E30", "type": "Negative_regulation", "trigger": { "text": [ "suppressor" ], "offsets": [ [ 1417, 1427 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T44" }, { "role": "Cause", "ref_id": "PMID-10913166_E32" } ] }, { "id": "PMID-10913166_E31", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 1441, 1456 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_T45" } ] }, { "id": "PMID-10913166_E32", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1457, 1467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10913166_E31" }, { "role": "Cause", "ref_id": "PMID-10913166_T43" } ] } ]

[]

[]

[ { "id": "PMID-12484699__text", "type": "abstract", "text": [ "Regulation of transforming growth factor-beta signaling and vascular diseases.\nPURPOSE: Members of the transforming growth factor (TGF)-beta superfamily play critical roles in regulation of various cellular functions. Dysregulation of the signaling mechanisms of the TGF-beta superfamily proteins is associated with clinical diseases such as cancer, fibrotic diseases, and vascular disorders. Therefore, understanding these signaling mechanisms may provide us with novel ways to develop strategies for treating clinical diseases induced by these cytokines. METHODS: This review discusses our current understanding of the mechanisms of TGF-beta signaling, focusing on the roles of TGF-beta in regulation of vascular wall cells and on the regulation of TGF-beta superfamily signals by inhibitory Smads.\n" ], "offsets": [ [ 0, 801 ] ] } ]

[ { "id": "PMID-12484699_T1", "type": "Gene_or_gene_product", "text": [ "transforming growth factor-beta" ], "offsets": [ [ 14, 45 ] ], "normalized": [] }, { "id": "PMID-12484699_T2", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 60, 68 ] ], "normalized": [] }, { "id": "PMID-12484699_T3", "type": "Gene_or_gene_product", "text": [ "transforming growth factor (TGF)-beta" ], "offsets": [ [ 103, 140 ] ], "normalized": [] }, { "id": "PMID-12484699_T4", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 198, 206 ] ], "normalized": [] }, { "id": "PMID-12484699_T5", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 267, 275 ] ], "normalized": [] }, { "id": "PMID-12484699_T6", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 342, 348 ] ], "normalized": [] }, { "id": "PMID-12484699_T7", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 373, 381 ] ], "normalized": [] }, { "id": "PMID-12484699_T8", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 635, 643 ] ], "normalized": [] }, { "id": "PMID-12484699_T9", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 680, 688 ] ], "normalized": [] }, { "id": "PMID-12484699_T10", "type": "Cell", "text": [ "vascular wall cells" ], "offsets": [ [ 706, 725 ] ], "normalized": [] }, { "id": "PMID-12484699_T11", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 751, 759 ] ], "normalized": [] }, { "id": "PMID-12484699_T12", "type": "Gene_or_gene_product", "text": [ "Smads" ], "offsets": [ [ 794, 799 ] ], "normalized": [] } ]

[ { "id": "PMID-12484699_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_E2" } ] }, { "id": "PMID-12484699_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 46, 55 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12484699_T1" } ] }, { "id": "PMID-12484699_E3", "type": "Regulation", "trigger": { "text": [ "Dysregulation" ], "offsets": [ [ 218, 231 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T5" } ] }, { "id": "PMID-12484699_E4", "type": "Pathway", "trigger": { "text": [ "signaling mechanisms" ], "offsets": [ [ 239, 259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T5" } ] }, { "id": "PMID-12484699_E5", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 300, 310 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T6" }, { "role": "Cause", "ref_id": "PMID-12484699_E3" } ] }, { "id": "PMID-12484699_E6", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 644, 653 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12484699_T8" } ] }, { "id": "PMID-12484699_E7", "type": "Regulation", "trigger": { "text": [ "roles" ], "offsets": [ [ 671, 676 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12484699_T9" }, { "role": "Theme", "ref_id": "PMID-12484699_E8" } ] }, { "id": "PMID-12484699_E8", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T10" } ] }, { "id": "PMID-12484699_E9", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 737, 747 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T11" }, { "role": "Cause", "ref_id": "PMID-12484699_E10" } ] }, { "id": "PMID-12484699_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 783, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T12" } ] } ]

[]

[]

[ { "id": "PMID-16268479__text", "type": "abstract", "text": [ "Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt.\nDomain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the P13-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response toVEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3alpha HKa and D5 inhibit phosphorylation of Akt and GSK-3alpha after stimulation withVEGF and S1P. Inhibitors of Akt and P13-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P. Therefore we suggest that HKa through its D5 domain alters P13-kinase-Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions.\n" ], "offsets": [ [ 0, 1758 ] ] } ]

[ { "id": "PMID-16268479_T1", "type": "Gene_or_gene_product", "text": [ "high molecular weight kininogen" ], "offsets": [ [ 20, 51 ] ], "normalized": [] }, { "id": "PMID-16268479_T2", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 61, 77 ] ], "normalized": [] }, { "id": "PMID-16268479_T3", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 96, 99 ] ], "normalized": [] }, { "id": "PMID-16268479_T4", "type": "Gene_or_gene_product", "text": [ "high molecular weight kininogen" ], "offsets": [ [ 126, 157 ] ], "normalized": [] }, { "id": "PMID-16268479_T5", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 159, 162 ] ], "normalized": [] }, { "id": "PMID-16268479_T6", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 198, 214 ] ], "normalized": [] }, { "id": "PMID-16268479_T7", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 243, 247 ] ], "normalized": [] }, { "id": "PMID-16268479_T8", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 279, 282 ] ], "normalized": [] }, { "id": "PMID-16268479_T9", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 304, 320 ] ], "normalized": [] }, { "id": "PMID-16268479_T10", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 397, 400 ] ], "normalized": [] }, { "id": "PMID-16268479_T11", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 448, 464 ] ], "normalized": [] }, { "id": "PMID-16268479_T12", "type": "Gene_or_gene_product", "text": [ "sphingosine 1-phosphate" ], "offsets": [ [ 476, 499 ] ], "normalized": [] }, { "id": "PMID-16268479_T13", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 501, 504 ] ], "normalized": [] }, { "id": "PMID-16268479_T14", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 510, 544 ] ], "normalized": [] }, { "id": "PMID-16268479_T15", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 546, 550 ] ], "normalized": [] }, { "id": "PMID-16268479_T16", "type": "Gene_or_gene_product", "text": [ "P13-kinase" ], "offsets": [ [ 574, 584 ] ], "normalized": [] }, { "id": "PMID-16268479_T17", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 585, 588 ] ], "normalized": [] }, { "id": "PMID-16268479_T18", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 608, 611 ] ], "normalized": [] }, { "id": "PMID-16268479_T19", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 627, 633 ] ], "normalized": [] }, { "id": "PMID-16268479_T20", "type": "Cell", "text": [ "pulmonary artery endothelial cell" ], "offsets": [ [ 634, 667 ] ], "normalized": [] }, { "id": "PMID-16268479_T21", "type": "Cell", "text": [ "BPAE" ], "offsets": [ [ 669, 673 ] ], "normalized": [] }, { "id": "PMID-16268479_T22", "type": "Cell", "text": [ "human umbilical vein endothelial cell" ], "offsets": [ [ 678, 715 ] ], "normalized": [] }, { "id": "PMID-16268479_T23", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 772, 776 ] ], "normalized": [] }, { "id": "PMID-16268479_T24", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 780, 783 ] ], "normalized": [] }, { "id": "PMID-16268479_T25", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 816, 819 ] ], "normalized": [] }, { "id": "PMID-16268479_T26", "type": "Gene_or_gene_product", "text": [ "urokinase-type plasminogen activator receptor" ], "offsets": [ [ 849, 894 ] ], "normalized": [] }, { "id": "PMID-16268479_T27", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 901, 904 ] ], "normalized": [] }, { "id": "PMID-16268479_T28", "type": "Cell", "text": [ "BPAE cell" ], "offsets": [ [ 934, 943 ] ], "normalized": [] }, { "id": "PMID-16268479_T29", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1033, 1036 ] ], "normalized": [] }, { "id": "PMID-16268479_T30", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1040, 1044 ] ], "normalized": [] }, { "id": "PMID-16268479_T31", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1046, 1049 ] ], "normalized": [] }, { "id": "PMID-16268479_T32", "type": "Gene_or_gene_product", "text": [ "paxillin" ], "offsets": [ [ 1084, 1092 ] ], "normalized": [] }, { "id": "PMID-16268479_T33", "type": "Cellular_component", "text": [ "focal adhesions" ], "offsets": [ [ 1100, 1115 ] ], "normalized": [] }, { "id": "PMID-16268479_T34", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1122, 1125 ] ], "normalized": [] }, { "id": "PMID-16268479_T35", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1130, 1134 ] ], "normalized": [] }, { "id": "PMID-16268479_T36", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1173, 1186 ] ], "normalized": [] }, { "id": "PMID-16268479_T37", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1233, 1236 ] ], "normalized": [] }, { "id": "PMID-16268479_T38", "type": 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"role": "Cause", "ref_id": "PMID-16268479_E57" } ] }, { "id": "PMID-16268479_E60", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1704, 1713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T56" } ] }, { "id": "PMID-16268479_E61", "type": "Regulation", "trigger": { "text": [ "alterations" ], "offsets": [ [ 1722, 1733 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T57" } ] } ]

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[]

[ { "id": "PMID-11121230__text", "type": "abstract", "text": [ "RNA damage and inhibition of neoplastic endothelial cell growth: effects of human and amphibian ribonucleases.\nAngiogenesis defines the many steps involved in the growth and migration of endothelial cell-derived blood vessels. This process is necessary for the growth and metastasis of tumors, and considerable effort is being expended to find inhibitors of tumor angiogenesis. This usually involves screening of potential anti-angiogenic compounds on endothelial cells. To this end, two candidate anti-angiogenic RNA-damaging agents, onconase and (-4)rhEDN, were screened for their effects on endothelial cell proliferation using three distinct types of endothelial cells in culture: HPV-16 E6/E7-immortalized human umbilical vein endothelial cells (HUVECs), a Kras-transformed HPV-16 E6/E7 HUVEC (Rhim et al., Carcinogenesis 4, 673-681, 1998), and primary HUVECs. Onconase similarly inhibited proliferation in all three cell lines (IC(50) = 0.3-1.0 microM) while (-4)rhEDN was more effective on immortalized HUVEC cell lines (IC(50) = 0.02-0.06 microM) than on primary HUVECs (IC(50) > 0.1 microM). Differential sensitivity to these agents implies that more than one endothelial cell type must be used in proliferation assays to screen for novel anti-angiogenic compounds.\n" ], "offsets": [ [ 0, 1275 ] ] } ]

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"derived" ], "offsets": [ [ 204, 211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T5" } ] }, { "id": "PMID-11121230_E7", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 243, 252 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_E3" }, { "role": "Theme", "ref_id": "PMID-11121230_E9" } ] }, { "id": "PMID-11121230_E8", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 243, 252 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_E3" }, { "role": "Theme", "ref_id": "PMID-11121230_E10" } ] }, { "id": "PMID-11121230_E9", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 261, 267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T6" } ] }, { "id": "PMID-11121230_E10", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 272, 282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T6" } ] }, { "id": "PMID-11121230_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 364, 376 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-11121230_T7" } ] }, { "id": "PMID-11121230_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 428, 438 ] ] }, "arguments": [] }, { "id": "PMID-11121230_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 503, 513 ] ] }, "arguments": [] }, { "id": "PMID-11121230_E14", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 583, 590 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_E16" }, { "role": "Cause", "ref_id": "PMID-11121230_T10" } ] }, { "id": "PMID-11121230_E15", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 583, 590 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_E16" }, { "role": "Cause", "ref_id": "PMID-11121230_T9" } ] }, { "id": "PMID-11121230_E16", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 611, 624 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T11" } ] }, { "id": "PMID-11121230_E17", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 698, 710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T15" }, { "role": "Instrument", "ref_id": "PMID-11121230_T14" } ] }, { "id": "PMID-11121230_E18", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 698, 710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T15" }, { "role": "Instrument", "ref_id": "PMID-11121230_T13" } ] }, { "id": "PMID-11121230_E19", "type": "Planned_process", "trigger": { "text": [ "transformed" ], "offsets": [ [ 767, 778 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11121230_T17" }, { "role": "Theme", "ref_id": "PMID-11121230_T20" } ] }, { "id": "PMID-11121230_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 885, 894 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T22" }, { "role": "Theme", "ref_id": "PMID-11121230_E21" } ] }, { "id": "PMID-11121230_E21", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 895, 908 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T23" } ] }, { "id": "PMID-11121230_E22", "type": "Positive_regulation", "trigger": { "text": [ "effective" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T24" }, { "role": "Theme", "ref_id": "PMID-11121230_T25" } ] }, { "id": "PMID-11121230_E23", "type": "Positive_regulation", "trigger": { "text": [ "effective" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T24" }, { "role": "Theme", "ref_id": "PMID-11121230_T26" } ] }, { "id": "PMID-11121230_E24", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 997, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T25" } ] }, { "id": "PMID-11121230_E25", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1207, 1220 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T27" } ] }, { "id": "PMID-11121230_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1253, 1263 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-12610665__text", "type": "abstract", "text": [ "Arteriogenesis: the development and growth of collateral arteries.\nIn patients with atherosclerotic vascular diseases, collateral vessels bypassing major arterial obstructions have frequently been observed. This may explain why some patients remain without symptoms or signs of ischemia. The term \"arteriogenesis\" was introduced to differentiate the formation of collateral arteries from angiogenesis, which mainly occurs in the ischemic, collateral flow-dependent tissue. Many observations in various animal models and humans support that the remodeling of preexisting collateral vessels is the mechanism of collateral artery formation. This remodeling process seems to be mainly flow-mediated. It involves endothelial cell activation, basal membrane degradation, leukocyte invasion, proliferation of vascular cells, neointima formation (in most species studied), and changes of the extracellular matrix. The contribution of ischemia to arteriogenesis is still unclear, but arteriogenesis clearly can occur in the absence of any significant ischemia. It is questionable, whether collateral arteries also form de novo in ischemic vascular diseases. A better understanding of the mechanisms of arteriogenesis will be important for the design of more effective strategies for the treatment of patients with ischemic vascular diseases.\n" ], "offsets": [ [ 0, 1333 ] ] } ]

[ { "id": "PMID-12610665_T1", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 46, 65 ] ], "normalized": [] }, { "id": "PMID-12610665_T2", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 70, 78 ] ], "normalized": [] }, { "id": "PMID-12610665_T3", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 100, 108 ] ], "normalized": [] }, { "id": "PMID-12610665_T4", "type": "Multi-tissue_structure", "text": [ "collateral vessels" ], "offsets": [ [ 119, 137 ] ], "normalized": [] }, { "id": "PMID-12610665_T5", "type": "Pathological_formation", "text": [ "arterial obstructions" ], "offsets": [ [ 154, 175 ] ], "normalized": [] }, { "id": "PMID-12610665_T6", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 233, 241 ] ], "normalized": [] }, { "id": "PMID-12610665_T7", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 363, 382 ] ], "normalized": [] }, { "id": "PMID-12610665_T8", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 465, 471 ] ], "normalized": [] }, { "id": "PMID-12610665_T9", "type": "Organism", "text": [ "humans" ], "offsets": [ [ 520, 526 ] ], "normalized": [] }, { "id": "PMID-12610665_T10", "type": "Multi-tissue_structure", "text": [ "collateral vessels" ], "offsets": [ [ 570, 588 ] ], "normalized": [] }, { "id": "PMID-12610665_T11", "type": "Multi-tissue_structure", "text": [ "collateral artery" ], "offsets": [ [ 609, 626 ] ], "normalized": [] }, { "id": "PMID-12610665_T12", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 708, 724 ] ], "normalized": [] }, { "id": "PMID-12610665_T13", "type": "Cellular_component", "text": [ "basal membrane" ], "offsets": [ [ 737, 751 ] ], "normalized": [] }, { "id": "PMID-12610665_T14", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 765, 774 ] ], "normalized": [] }, { "id": "PMID-12610665_T15", "type": "Cell", "text": [ "vascular cells" ], "offsets": [ [ 802, 816 ] ], "normalized": [] }, { "id": "PMID-12610665_T16", "type": "Tissue", "text": [ "neointima" ], "offsets": [ [ 818, 827 ] ], "normalized": [] }, { "id": "PMID-12610665_T17", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 884, 904 ] ], "normalized": [] }, { "id": "PMID-12610665_T18", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 1080, 1099 ] ], "normalized": [] }, { "id": "PMID-12610665_T19", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1130, 1138 ] ], "normalized": [] }, { "id": "PMID-12610665_T20", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1291, 1299 ] ], "normalized": [] }, { "id": "PMID-12610665_T21", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1314, 1322 ] ], "normalized": [] } ]

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"PMID-12610665_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 388, 400 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E7", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 455, 464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T8" } ] }, { "id": "PMID-12610665_E8", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 544, 554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T10" } ] }, { "id": "PMID-12610665_E9", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 627, 636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T11" } ] }, { "id": "PMID-12610665_E10", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 643, 653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T10" } ] }, { "id": "PMID-12610665_E11", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E17" } ] }, { "id": "PMID-12610665_E12", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E18" } ] }, { "id": "PMID-12610665_E13", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E19" } ] }, { "id": "PMID-12610665_E14", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E20" } ] }, { "id": "PMID-12610665_E15", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E21" } ] }, { "id": "PMID-12610665_E16", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 699, 707 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E10" }, { "role": "Theme", "ref_id": "PMID-12610665_E22" } ] }, { "id": "PMID-12610665_E17", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 725, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T12" } ] }, { "id": "PMID-12610665_E18", "type": "Breakdown", "trigger": { "text": [ "degradation" ], "offsets": [ [ 752, 763 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T13" } ] }, { "id": "PMID-12610665_E19", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 775, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T14" } ] }, { "id": "PMID-12610665_E20", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 785, 798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T15" } ] }, { "id": "PMID-12610665_E21", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 828, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T16" } ] }, { "id": "PMID-12610665_E22", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 869, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T17" } ] }, { "id": "PMID-12610665_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 938, 952 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 975, 989 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E25", "type": "Development", "trigger": { "text": [ "form" ], "offsets": [ [ 1105, 1109 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T18" } ] }, { "id": "PMID-12610665_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 1193, 1207 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-20978953__text", "type": "abstract", "text": [ "Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. \nBACKGROUND: Recently, the desmoplastic reaction has been implicated as having an important function in epithelial solid tumor biology. There have been no reports showing the relativity of invasive breast cancer and the desmoplastic reaction by a quantitative analysis of the myofibroblasts that were an important player in the desmoplastic reaction. The purpose of this study was to immunohistochemically investigate the correlation between the desmoplastic reaction and the clinicopathology of invasive breast cancer. METHODS: The study included 60 patients with a known prognosis of invasive breast cancer. We quantified the expression of alpha-SMA as a marker of myofibroblasts in the invasive breast cancer. After staining samples for alpha-SMA, their expression was extracted and quantified as a relative percentage by computer-assisted image analysis. RESULTS: There was relatively wide variation in the expression of alpha-SMA with the percentage of the area from 0.68 to 28.15% (mean 8.48 +/- 5.40%). The metastasis group showed significantly higher alpha-SMA expression compared with the no metastasis group (p < 0.001). When the patients were divided into two groups according to their alpha-SMA expression using a cutoff point at the mean value of 8.48%, the high alpha-SMA group had a significantly poorer overall survival rate (p < 0.001). Multivariate analysis demonstrated that alpha-SMA and lymph node metastasis were identified as independent predictive factors of metastasis. CONCLUSION: Myofibroblasts represent an important prognostic factor for invasive growth that is translated into a poor clinical prognosis for patients with invasive breast cancer.\n" ], "offsets": [ [ 0, 1821 ] ] } ]

[ { "id": "PMID-20978953_T1", "type": "Cell", "text": [ "stromal myofibroblasts" ], "offsets": [ [ 8, 30 ] ], "normalized": [] }, { "id": "PMID-20978953_T2", "type": "Cancer", "text": [ "breast cancer" ], "offsets": [ [ 43, 56 ] ], "normalized": [] }, { "id": "PMID-20978953_T3", "type": "Cell", "text": [ "stromal" ], "offsets": [ [ 58, 65 ] ], "normalized": [] }, { "id": "PMID-20978953_T4", "type": "Gene_or_gene_product", "text": [ "alpha-smooth muscle actin" ], "offsets": [ [ 80, 105 ] ], "normalized": [] }, { "id": "PMID-20978953_T5", "type": "Cancer", "text": [ "epithelial solid tumor" ], "offsets": [ [ 250, 272 ] ], "normalized": [] }, { "id": "PMID-20978953_T6", "type": "Cancer", "text": [ "breast cancer" ], "offsets": [ [ 344, 357 ] ], "normalized": [] }, { "id": "PMID-20978953_T7", "type": "Cell", "text": [ "myofibroblasts" ], "offsets": [ [ 422, 436 ] ], "normalized": [] }, { "id": "PMID-20978953_T8", "type": "Cancer", "text": [ "breast cancer" ], "offsets": [ [ 651, 664 ] ], "normalized": [] }, { "id": "PMID-20978953_T9", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 697, 705 ] ], "normalized": [] }, { "id": "PMID-20978953_T10", "type": "Cancer", "text": [ "invasive breast cancer" ], "offsets": [ [ 732, 754 ] ], "normalized": [] }, { "id": "PMID-20978953_T11", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 788, 797 ] ], "normalized": [] }, { "id": "PMID-20978953_T12", "type": "Cell", "text": [ "myofibroblasts" ], "offsets": [ [ 813, 827 ] ], "normalized": [] }, { "id": "PMID-20978953_T13", "type": "Cancer", "text": [ "breast cancer" ], "offsets": [ [ 844, 857 ] ], "normalized": [] }, { "id": "PMID-20978953_T14", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 886, 895 ] ], "normalized": [] }, { "id": "PMID-20978953_T15", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 1071, 1080 ] ], "normalized": [] }, { "id": "PMID-20978953_T16", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 1205, 1214 ] ], "normalized": [] }, { "id": "PMID-20978953_T17", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1286, 1294 ] ], "normalized": [] }, { "id": "PMID-20978953_T18", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 1343, 1352 ] ], "normalized": [] }, { "id": "PMID-20978953_T19", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 1422, 1431 ] ], "normalized": [] }, { "id": "PMID-20978953_T20", "type": "Gene_or_gene_product", "text": [ "alpha-SMA" ], "offsets": [ [ 1540, 1549 ] ], "normalized": [] }, { "id": "PMID-20978953_T21", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 1554, 1564 ] ], "normalized": [] }, { "id": "PMID-20978953_T22", "type": "Cell", "text": [ "Myofibroblasts" ], "offsets": [ [ 1653, 1667 ] ], "normalized": [] }, { "id": "PMID-20978953_T23", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1783, 1791 ] ], "normalized": [] }, { "id": "PMID-20978953_T24", "type": "Cancer", "text": [ "invasive breast cancer" ], "offsets": [ [ 1797, 1819 ] ], "normalized": [] } ]

[ { "id": "PMID-20978953_E1", "type": "Regulation", "trigger": { "text": [ "Role" ], "offsets": [ [ 0, 4 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20978953_T1" }, { "role": "Theme", "ref_id": "PMID-20978953_E2" } ] }, { "id": "PMID-20978953_E2", "type": "Localization", "trigger": { "text": [ "invasive" ], "offsets": [ [ 34, 42 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T2" } ] }, { "id": "PMID-20978953_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 66, 76 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T4" } ] }, { "id": "PMID-20978953_E4", "type": "Regulation", "trigger": { "text": [ "having an important function" ], "offsets": [ [ 218, 246 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T5" } ] }, { "id": "PMID-20978953_E5", "type": "Localization", "trigger": { "text": [ "invasive" ], "offsets": [ [ 335, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T6" } ] }, { "id": "PMID-20978953_E6", "type": "Localization", "trigger": { "text": [ "invasive" ], "offsets": [ [ 642, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T8" } ] }, { "id": "PMID-20978953_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 774, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T11" } ] }, { "id": "PMID-20978953_E8", "type": "Localization", "trigger": { "text": [ "invasive" ], "offsets": [ [ 835, 843 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T13" } ] }, { "id": "PMID-20978953_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 903, 913 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T14" } ] }, { "id": "PMID-20978953_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1057, 1067 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T15" } ] }, { "id": "PMID-20978953_E11", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1160, 1170 ] ] }, "arguments": [] }, { "id": "PMID-20978953_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1215, 1225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T16" } ] }, { "id": "PMID-20978953_E13", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1247, 1257 ] ] }, "arguments": [] }, { "id": "PMID-20978953_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1353, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T18" } ] }, { "id": "PMID-20978953_E15", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1473, 1481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T17" } ] }, { "id": "PMID-20978953_E16", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1565, 1575 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-20978953_T21" } ] }, { "id": "PMID-20978953_E17", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1629, 1639 ] ] }, "arguments": [] }, { "id": "PMID-20978953_E18", "type": "Localization", "trigger": { "text": [ "invasive" ], "offsets": [ [ 1713, 1721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T22" } ] }, { "id": "PMID-20978953_E19", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 1722, 1728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20978953_T22" } ] } ]

[]

[]

[ { "id": "PMID-7474113__text", "type": "abstract", "text": [ "The inhibition of cultured myoblast differentiation by the simian virus 40 large T antigen occurs after myogenin expression and Rb up-regulation and is not exerted by transformation-competent cytoplasmic mutants. \nWe have investigated the mechanism by which the simian virus 40 large T antigen (SVLT) interferes with the differentiation of C2 myoblasts. SVLT mutants, defective either in the Rb binding site, near the N-terminal end, in a region that affects binding to p53, or in the nuclear transport signal, were also employed to determine whether the interference was especially dependent on these functional domains. It was found that wild-type (wt) SVLT strongly inhibited the terminal differentiation of mouse C2 myoblasts, but this arrest occurred only after the synthesis of myogenin, an initial step in biochemical differentiation. Neither the synthesis nor some basic activities of MyoD appeared to be affected by wt SVLT. In these transformants, mitogen depletion elicited an increase in the Rb level comparable to that in normal C2 cells; wt SVLT, however, promoted the phosphorylation of a large part of the induced Rb. Mutations affecting nuclear transport were far more critical for the ability to interfere with myogenic differentiation than were those affecting the transforming potential; cytoplasmic SVLT expression was fully compatible with the terminal differentiation of C2 cells, despite enabling them to grow in semisolid medium, thus showing that the myogenesis-inhibiting property can be dissociated from transforming competence. The remaining SVLT mutants presented different degrees of ability to inhibit differentiation (as shown by the expression of tissue-specific markers in transformants). The inhibiting mutants, including the Rb binding site mutant, were able to promote a higher state of Rb phosphorylation than that observed in either normal cells or cytoplasmic-SVLT transformants.\n" ], "offsets": [ [ 0, 1921 ] ] } ]

[ { "id": "PMID-7474113_T1", "type": "Cell", "text": [ "myoblast" ], "offsets": [ [ 27, 35 ] ], "normalized": [] }, { "id": "PMID-7474113_T2", "type": "Organism", "text": [ "simian virus 40" ], "offsets": [ [ 59, 74 ] ], "normalized": [] }, { "id": "PMID-7474113_T3", "type": "Gene_or_gene_product", "text": [ "large T antigen" ], "offsets": [ [ 75, 90 ] ], "normalized": [] }, { "id": "PMID-7474113_T4", "type": "Gene_or_gene_product", "text": [ "myogenin" ], "offsets": [ [ 104, 112 ] ], "normalized": [] }, { "id": "PMID-7474113_T5", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 128, 130 ] ], "normalized": [] }, { "id": "PMID-7474113_T6", "type": "Organism_substance", "text": [ "cytoplasmic" ], "offsets": [ [ 192, 203 ] ], "normalized": [] }, { "id": "PMID-7474113_T7", "type": "Organism", "text": [ "simian virus 40" ], "offsets": [ [ 262, 277 ] ], "normalized": [] }, { "id": "PMID-7474113_T8", "type": "Gene_or_gene_product", "text": [ "large T antigen" ], "offsets": [ [ 278, 293 ] ], "normalized": [] }, { "id": "PMID-7474113_T9", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 295, 299 ] ], "normalized": [] }, { "id": "PMID-7474113_T10", "type": "Cell", "text": [ "C2 myoblasts" ], "offsets": [ [ 340, 352 ] ], "normalized": [] }, { "id": "PMID-7474113_T11", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 354, 358 ] ], "normalized": [] }, { "id": "PMID-7474113_T12", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 392, 394 ] ], "normalized": [] }, { "id": "PMID-7474113_T13", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 470, 473 ] ], "normalized": [] }, { "id": "PMID-7474113_T14", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "PMID-7474113_T15", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "PMID-7474113_T16", "type": "Cell", "text": [ "C2 myoblasts" ], "offsets": [ [ 717, 729 ] ], "normalized": [] }, { "id": "PMID-7474113_T17", "type": "Gene_or_gene_product", "text": [ "myogenin" ], "offsets": [ [ 784, 792 ] ], "normalized": [] }, { "id": "PMID-7474113_T18", "type": "Gene_or_gene_product", "text": [ "MyoD" ], "offsets": [ [ 893, 897 ] ], "normalized": [] }, { "id": "PMID-7474113_T19", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "PMID-7474113_T20", "type": "Cell", "text": [ "transformants" ], "offsets": [ [ 943, 956 ] ], "normalized": [] }, { "id": "PMID-7474113_T21", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1004, 1006 ] ], "normalized": [] }, { "id": "PMID-7474113_T22", "type": "Cell", "text": [ "C2 cells" ], "offsets": [ [ 1042, 1050 ] ], "normalized": [] }, { "id": "PMID-7474113_T23", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 1055, 1059 ] ], "normalized": [] }, { "id": "PMID-7474113_T24", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1130, 1132 ] ], "normalized": [] }, { "id": "PMID-7474113_T25", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1154, 1161 ] ], "normalized": [] }, { "id": "PMID-7474113_T26", "type": "Organism_substance", "text": [ "cytoplasmic" ], "offsets": [ [ 1308, 1319 ] ], "normalized": [] }, { "id": "PMID-7474113_T27", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 1320, 1324 ] ], "normalized": [] }, { "id": "PMID-7474113_T28", "type": "Cell", "text": [ "C2 cells" ], "offsets": [ [ 1394, 1402 ] ], "normalized": [] }, { "id": "PMID-7474113_T29", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 1571, 1575 ] ], "normalized": [] }, { "id": "PMID-7474113_T30", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 1681, 1687 ] ], "normalized": [] }, { "id": "PMID-7474113_T31", "type": "Cell", "text": [ "transformants" ], "offsets": [ [ 1708, 1721 ] ], "normalized": [] }, { "id": "PMID-7474113_T32", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1762, 1764 ] ], "normalized": [] }, { "id": "PMID-7474113_T33", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1825, 1827 ] ], "normalized": [] }, { "id": "PMID-7474113_T34", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1880, 1885 ] ], "normalized": [] }, { "id": "PMID-7474113_T35", "type": "Organism_substance", "text": [ "cytoplasmic" ], "offsets": [ [ 1889, 1900 ] ], "normalized": [] }, { "id": "PMID-7474113_T36", "type": "Gene_or_gene_product", "text": [ "SVLT" ], "offsets": [ [ 1901, 1905 ] ], "normalized": [] }, { "id": "PMID-7474113_T37", "type": "Cell", "text": [ "transformants" ], "offsets": [ [ 1906, 1919 ] ], "normalized": [] } ]

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[ { "id": "PMID-7474113_1", "entity_ids": [ "PMID-7474113_T8", "PMID-7474113_T9" ] } ]

[]

[ { "id": "PMID-17462601__text", "type": "abstract", "text": [ "An antibody directed against PDGF receptor beta enhances the antitumor and the anti-angiogenic activities of an anti-VEGF receptor 2 antibody.\nPlatelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment and vessel maturation. Here we produced a neutralizing antibody, 1B3, directed against mouse PDGFRbeta. 1B3 binds to PDGFRbeta with high affinity (9x10(-11)M) and blocks PDGF-BB from binding to the receptor with an IC(50) of approximately 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of 1B3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFRbeta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.\n" ], "offsets": [ [ 0, 1380 ] ] } ]

[ { "id": "PMID-17462601_T1", "type": "Gene_or_gene_product", "text": [ "antibody directed against PDGF receptor beta" ], "offsets": [ [ 3, 47 ] ], "normalized": [] }, { "id": "PMID-17462601_T2", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 65, 70 ] ], "normalized": [] }, { "id": "PMID-17462601_T3", "type": "Gene_or_gene_product", "text": [ "anti-VEGF receptor 2 antibody" ], "offsets": [ [ 112, 141 ] ], "normalized": [] }, { "id": "PMID-17462601_T4", "type": "Gene_or_gene_product", "text": [ "Platelet-derived growth factor" ], "offsets": [ [ 143, 173 ] ], "normalized": [] }, { "id": "PMID-17462601_T5", "type": "Gene_or_gene_product", "text": [ "PDGF" ], "offsets": [ [ 175, 179 ] ], "normalized": [] }, { "id": "PMID-17462601_T6", "type": "Gene_or_gene_product", "text": [ "PDGFR" ], "offsets": [ [ 200, 205 ] ], "normalized": [] }, { "id": "PMID-17462601_T7", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 265, 270 ] ], "normalized": [] }, { "id": "PMID-17462601_T8", "type": "Cell", "text": [ "pericyte" ], "offsets": [ [ 319, 327 ] ], "normalized": [] }, { "id": "PMID-17462601_T9", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 344, 350 ] ], "normalized": [] }, { "id": "PMID-17462601_T10", "type": "Simple_chemical", "text": [ "1B3" ], "offsets": [ [ 405, 408 ] ], "normalized": [] }, { "id": "PMID-17462601_T11", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 427, 432 ] ], "normalized": [] }, { "id": "PMID-17462601_T12", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 433, 442 ] ], "normalized": [] }, { "id": "PMID-17462601_T13", "type": "Simple_chemical", "text": [ "1B3" ], "offsets": [ [ 444, 447 ] ], "normalized": [] }, { "id": "PMID-17462601_T14", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 457, 466 ] ], "normalized": [] }, { "id": "PMID-17462601_T15", "type": "Gene_or_gene_product", "text": [ "PDGF-BB" ], "offsets": [ [ 510, 517 ] ], "normalized": [] }, { "id": "PMID-17462601_T16", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 644, 653 ] ], "normalized": [] }, { "id": "PMID-17462601_T17", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 700, 703 ] ], "normalized": [] }, { "id": "PMID-17462601_T18", "type": "Gene_or_gene_product", "text": [ "MAPK p42/44" ], "offsets": [ [ 708, 719 ] ], "normalized": [] }, { "id": "PMID-17462601_T19", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 724, 735 ] ], "normalized": [] }, { "id": "PMID-17462601_T20", "type": "Simple_chemical", "text": [ "1B3" ], "offsets": [ [ 756, 759 ] ], "normalized": [] }, { "id": "PMID-17462601_T21", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 791, 796 ] ], "normalized": [] }, { "id": "PMID-17462601_T22", "type": "Simple_chemical", "text": [ "DC101" ], "offsets": [ [ 835, 840 ] ], "normalized": [] }, { "id": "PMID-17462601_T23", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 871, 876 ] ], "normalized": [] }, { "id": "PMID-17462601_T24", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptor 2" ], "offsets": [ [ 877, 922 ] ], "normalized": [] }, { "id": "PMID-17462601_T25", "type": "Cancer", "text": [ "pancreatic" ], "offsets": [ [ 929, 939 ] ], "normalized": [] }, { "id": "PMID-17462601_T26", "type": "Cancer", "text": [ "BxPC-3" ], "offsets": [ [ 941, 947 ] ], "normalized": [] }, { "id": "PMID-17462601_T27", "type": "Cancer", "text": [ "non-small cell lung (NCI-H460) tumor xenograft" ], "offsets": [ [ 955, 1001 ] ], "normalized": [] }, { "id": "PMID-17462601_T28", "type": "Simple_chemical", "text": [ "1B3" ], "offsets": [ [ 1044, 1047 ] ], "normalized": [] }, { "id": "PMID-17462601_T29", "type": "Simple_chemical", "text": [ "DC101" ], "offsets": [ [ 1052, 1057 ] ], "normalized": [] }, { "id": "PMID-17462601_T30", "type": "Cancer", "text": [ "BxPC-3 xenograft" ], "offsets": [ [ 1061, 1077 ] ], "normalized": [] }, { "id": "PMID-17462601_T31", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1086, 1090 ] ], "normalized": [] }, { "id": "PMID-17462601_T32", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1103, 1108 ] ], "normalized": [] }, { "id": "PMID-17462601_T33", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1130, 1134 ] ], "normalized": [] }, { "id": "PMID-17462601_T34", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1162, 1166 ] ], "normalized": [] }, { "id": "PMID-17462601_T35", "type": "Simple_chemical", "text": [ "DC101" ], "offsets": [ [ 1180, 1185 ] ], "normalized": [] }, { "id": "PMID-17462601_T36", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta antagonists" ], "offsets": [ [ 1249, 1270 ] ], "normalized": [] }, { "id": "PMID-17462601_T37", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1302, 1307 ] ], "normalized": [] }, { "id": "PMID-17462601_T38", "type": "Cancer", "text": [ "cancers" ], "offsets": [ [ 1371, 1378 ] ], "normalized": [] } ]

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[ [ 95, 105 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T3" }, { "role": "Theme", "ref_id": "PMID-17462601_E4" } ] }, { "id": "PMID-17462601_E6", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 95, 105 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T3" }, { "role": "Theme", "ref_id": "PMID-17462601_T2" } ] }, { "id": "PMID-17462601_E7", "type": "Regulation", "trigger": { "text": [ "roles" ], "offsets": [ [ 222, 227 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E9" }, { "role": "Cause", "ref_id": "PMID-17462601_T4" } ] }, { "id": "PMID-17462601_E8", "type": "Regulation", "trigger": { "text": [ "roles" ], "offsets": [ [ 222, 227 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E9" }, { "role": "Cause", "ref_id": "PMID-17462601_T6" } ] }, { "id": "PMID-17462601_E9", "type": "Carcinogenesis", "trigger": { "text": [ "tumorigenesis" ], "offsets": [ [ 231, 244 ] ] }, "arguments": [] }, { "id": "PMID-17462601_E10", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 253, 264 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T6" }, { "role": "Theme", "ref_id": "PMID-17462601_E12" } ] }, { "id": "PMID-17462601_E11", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 253, 264 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T4" }, { "role": "Theme", "ref_id": "PMID-17462601_E12" } ] }, { "id": "PMID-17462601_E12", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 271, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T7" } ] }, { "id": "PMID-17462601_E13", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 282, 291 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T6" }, { "role": "Theme", "ref_id": "PMID-17462601_E15" } ] }, { "id": "PMID-17462601_E14", "type": 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[ { "id": "PMID-19369582__text", "type": "abstract", "text": [ "Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets.\nAngiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-(13)C(2)]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-(13)C(2)]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.\n" ], "offsets": [ [ 0, 1782 ] ] } ]

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[]

[ { "id": "PMID-10589785__text", "type": "abstract", "text": [ "The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice.\nThe aim of this study was to ascertain the potential usefulness of the antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for \"prevention\" experiments; and (b) 2-3-mm fragments allowed to grow to 1 cm for \"intervention\" studies. Both groups received either 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention and intervention experiments, a significant diminution of tumor size and weight was observed in the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor blood flow in linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of tumors from linomide-treated animals revealed marked avascularity. Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels. Taken together, our data indicate that in VHL disease, therapy directed at inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.\n" ], "offsets": [ [ 0, 1522 ] ] } ]

[ { "id": "PMID-10589785_T1", "type": "Simple_chemical", "text": [ "linomide" ], "offsets": [ [ 25, 33 ] ], "normalized": [] }, { "id": "PMID-10589785_T2", "type": "Cancer", "text": [ "von Hippel-Lindau paraganglioma xenografts" ], "offsets": [ [ 62, 104 ] ], "normalized": [] }, { "id": "PMID-10589785_T3", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 108, 112 ] ], "normalized": [] }, { "id": "PMID-10589785_T4", "type": "Simple_chemical", "text": [ "linomide" ], "offsets": [ [ 209, 217 ] ], "normalized": [] }, { "id": "PMID-10589785_T5", "type": "Cancer", "text": [ "von Hippel-Lindau (VHL)-related tumors" ], "offsets": [ [ 235, 273 ] ], "normalized": [] }, { "id": "PMID-10589785_T6", "type": "Tissue", "text": [ "Paraganglioma tissue fragments" ], "offsets": [ [ 275, 305 ] ], "normalized": [] }, { "id": "PMID-10589785_T7", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 345, 352 ] ], "normalized": [] }, { "id": "PMID-10589785_T8", "type": "Organism", "text": [ "BALB/c nu/nu (nude) mice" ], "offsets": [ [ 384, 408 ] ], "normalized": [] }, { "id": "PMID-10589785_T9", "type": "Simple_chemical", "text": [ "linomide" ], "offsets": [ [ 576, 584 ] ], "normalized": [] }, { "id": "PMID-10589785_T10", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 646, 651 ] ], "normalized": [] }, { "id": "PMID-10589785_T11", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 771, 776 ] ], "normalized": [] }, { "id": "PMID-10589785_T12", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 882, 887 ] ], "normalized": [] }, { "id": "PMID-10589785_T13", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 888, 893 ] ], "normalized": [] }, { "id": "PMID-10589785_T14", "type": "Simple_chemical", "text": [ "linomide" ], "offsets": [ [ 902, 910 ] ], "normalized": [] }, { "id": "PMID-10589785_T15", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 950, 963 ] ], "normalized": [] }, { "id": "PMID-10589785_T16", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 1027, 1033 ] ], "normalized": [] }, { "id": "PMID-10589785_T17", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1071, 1079 ] ], "normalized": [] }, { "id": "PMID-10589785_T18", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 1140, 1146 ] ], "normalized": [] }, { "id": "PMID-10589785_T19", "type": "Simple_chemical", "text": [ "linomide" ], "offsets": [ [ 1152, 1160 ] ], "normalized": [] }, { "id": "PMID-10589785_T20", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1262, 1267 ] ], "normalized": [] }, { "id": "PMID-10589785_T21", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1268, 1302 ] ], "normalized": [] }, { "id": "PMID-10589785_T22", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1430, 1434 ] ], "normalized": [] }, { "id": "PMID-10589785_T23", "type": "Cancer", "text": [ "VHL tumors" ], "offsets": [ [ 1464, 1474 ] ], "normalized": [] } ]

[ { "id": "PMID-10589785_E1", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 8, 18 ] ] }, "arguments": [] }, { "id": "PMID-10589785_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 34, 42 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_E3" }, { "role": "Cause", "ref_id": "PMID-10589785_T1" } ] }, { "id": "PMID-10589785_E3", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 47, 53 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T2" } ] }, { "id": "PMID-10589785_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 189, 199 ] ] }, "arguments": [] }, { "id": "PMID-10589785_E5", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 222, 231 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10589785_T4" }, { "role": "Theme", "ref_id": "PMID-10589785_T5" } ] }, { "id": "PMID-10589785_E6", "type": "Planned_process", "trigger": { "text": [ "obtained" ], "offsets": [ [ 306, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T6" } ] }, { "id": "PMID-10589785_E7", "type": "Planned_process", "trigger": { "text": [ "transplanted" ], "offsets": [ [ 358, 370 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10589785_T6" }, { "role": "Theme", "ref_id": "PMID-10589785_T8" } ] }, { "id": "PMID-10589785_E8", "type": "Planned_process", "trigger": { "text": [ "received" ], "offsets": [ [ 550, 558 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10589785_T9" } ] }, { "id": "PMID-10589785_E9", "type": "Negative_regulation", "trigger": { "text": [ "diminution" ], "offsets": [ [ 757, 767 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T11" } ] }, { "id": "PMID-10589785_E10", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 911, 918 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10589785_T14" } ] }, { "id": "PMID-10589785_E11", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 934, 946 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T15" } ] }, { "id": "PMID-10589785_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "vascularized" ], "offsets": [ [ 1014, 1026 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10589785_T16" } ] }, { "id": "PMID-10589785_E13", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1161, 1168 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10589785_T19" } ] }, { "id": "PMID-10589785_E14", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1249, 1258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T21" } ] }, { "id": "PMID-10589785_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1391, 1401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_E17" }, { "role": "Cause", "ref_id": "PMID-10589785_T23" } ] }, { "id": "PMID-10589785_E16", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1420, 1429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_T22" } ] }, { "id": "PMID-10589785_E17", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1435, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10589785_E18" }, { "role": "Cause", "ref_id": "PMID-10589785_T22" } ] }, { "id": "PMID-10589785_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1448, 1460 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-12140030__text", "type": "abstract", "text": [ "Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration.\nPURPOSE: To optimize the method of treating choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). DESIGN: Experimental study and interventional case series. METHODS: The parameters associated with locating and then photocoagulating CNV feeder vessels were identified and optimized using published data and data derived from modeling the choroidal vasculature. Based on these optimized parameters, a prototype diagnostic/treatment system was designed that captures high-speed indocyanine green (ICG) angiogram images and facilitates analysis of the images by enhancing visualization of dye movement through CNV feeder vessels (FVs). The system also permits precise aiming and delivery of 810- nm wavelength photocoagulation laser energy to target FVs on a real-time ICG angiogram image of the choroidal vasculature. Target FVs are tracked by a joy-stick controlled laser aiming beam until an intravenously-injected high-concentration ICG dye bolus is observed to enter the target vessel, at which time the laser is fired. Proof of principle of the combined diagnosis/treatment system design for performing dye-enhanced photocoagulation (DEP) in the clinical setting and determination of the minimum DEP laser energy needed to close CNV FVs was made in 11 AMD patients requiring treatment of CNV, but for whom other treatment was not appropriate. RESULTS: Using ICG-DEP, CNV feeder vessels were closed with single pulse laser energy, delivering as little as 0.6 to 1.8 J of energy to the fundus, producing no visible change in the fundus. Successful FV closure was usually indicated immediately by presence of incarcerated ICG dye in the vessel adjacent to the burn site. The prototype system proved relatively easy to operate. After acquiring and interpreting diagnostic angiograms and repositioning a patient in front of the device, feeder vessel DEP and treatment evaluation required 15 to 20 minutes. CONCLUSIONS: Indocyanine green dye-enhanced photocoagulation of CNV feeder vessels, facilitated by use of a device that permits real-time visualization of the choroidal circulation while aiming the treatment laser beam, appears to minimize the amount of energy applied to the fundus and the volume of fundus tissue affected by treatment, compared with other treatment modalities. The combination diagnosis/treatment device should be useful in optimizing FV treatment and in refining and evaluating the efficacy of DEP in future clinical trials.\n" ], "offsets": [ [ 0, 2603 ] ] } ]

[ { "id": "PMID-12140030_T1", "type": "Multi-tissue_structure", "text": [ "choroidal" ], "offsets": [ [ 24, 33 ] ], "normalized": [] }, { "id": "PMID-12140030_T2", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 53, 67 ] ], "normalized": [] }, { "id": "PMID-12140030_T3", "type": "Tissue", "text": [ "macular" ], "offsets": [ [ 96, 103 ] ], "normalized": [] }, { "id": "PMID-12140030_T4", "type": "Multi-tissue_structure", "text": [ "choroidal" ], "offsets": [ [ 162, 171 ] ], "normalized": [] }, { "id": "PMID-12140030_T5", "type": "Tissue", "text": [ "macular" ], "offsets": [ [ 225, 232 ] ], "normalized": [] }, { "id": "PMID-12140030_T6", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 391, 405 ] ], "normalized": [] }, { "id": "PMID-12140030_T7", "type": "Multi-tissue_structure", "text": [ "choroidal vasculature" ], "offsets": [ [ 492, 513 ] ], "normalized": [] }, { "id": "PMID-12140030_T8", "type": "Simple_chemical", "text": [ "indocyanine green" ], "offsets": [ [ 630, 647 ] ], "normalized": [] }, { "id": "PMID-12140030_T9", "type": "Simple_chemical", "text": [ "ICG" ], "offsets": [ [ 649, 652 ] ], "normalized": [] }, { "id": "PMID-12140030_T10", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 765, 779 ] ], "normalized": [] }, { "id": "PMID-12140030_T11", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 781, 784 ] ], "normalized": [] }, { "id": "PMID-12140030_T12", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 901, 904 ] ], "normalized": [] }, { "id": "PMID-12140030_T13", "type": "Simple_chemical", "text": [ "ICG" ], "offsets": [ [ 920, 923 ] ], "normalized": [] }, { "id": "PMID-12140030_T14", "type": "Multi-tissue_structure", "text": [ "choroidal vasculature" ], "offsets": [ [ 947, 968 ] ], "normalized": [] }, { "id": "PMID-12140030_T15", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 977, 980 ] ], "normalized": [] }, { "id": "PMID-12140030_T16", "type": "Immaterial_anatomical_entity", "text": [ "intravenously" ], "offsets": [ [ 1046, 1059 ] ], "normalized": [] }, { "id": "PMID-12140030_T17", "type": "Simple_chemical", "text": [ "ICG dye" ], "offsets": [ [ 1088, 1095 ] ], "normalized": [] }, { "id": "PMID-12140030_T18", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1134, 1140 ] ], "normalized": [] }, { "id": "PMID-12140030_T19", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 1390, 1393 ] ], "normalized": [] }, { "id": "PMID-12140030_T20", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1413, 1421 ] ], "normalized": [] }, { "id": "PMID-12140030_T21", "type": "Simple_chemical", "text": [ "ICG" ], "offsets": [ [ 1515, 1518 ] ], "normalized": [] }, { "id": "PMID-12140030_T22", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 1528, 1542 ] ], "normalized": [] }, { "id": "PMID-12140030_T23", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 1641, 1647 ] ], "normalized": [] }, { "id": "PMID-12140030_T24", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 1684, 1690 ] ], "normalized": [] }, { "id": "PMID-12140030_T25", "type": "Multi-tissue_structure", "text": [ "FV" ], "offsets": [ [ 1703, 1705 ] ], "normalized": [] }, { "id": "PMID-12140030_T26", "type": "Simple_chemical", "text": [ "ICG dye" ], "offsets": [ [ 1776, 1783 ] ], "normalized": [] }, { "id": "PMID-12140030_T27", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1791, 1797 ] ], "normalized": [] }, { "id": "PMID-12140030_T28", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1956, 1963 ] ], "normalized": [] }, { "id": "PMID-12140030_T29", "type": "Multi-tissue_structure", "text": [ "feeder vessel" ], "offsets": [ [ 1988, 2001 ] ], "normalized": [] }, { "id": "PMID-12140030_T30", "type": "Simple_chemical", "text": [ "Indocyanine green dye" ], "offsets": [ [ 2071, 2092 ] ], "normalized": [] }, { "id": "PMID-12140030_T31", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 2126, 2140 ] ], "normalized": [] }, { "id": "PMID-12140030_T32", "type": "Multi-tissue_structure", "text": [ "choroidal" ], "offsets": [ [ 2217, 2226 ] ], "normalized": [] }, { "id": "PMID-12140030_T33", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 2334, 2340 ] ], "normalized": [] }, { "id": "PMID-12140030_T34", "type": "Tissue", "text": [ "fundus tissue" ], "offsets": [ [ 2359, 2372 ] ], "normalized": [] }, { "id": "PMID-12140030_T35", "type": "Multi-tissue_structure", "text": [ "FV" ], "offsets": [ [ 2512, 2514 ] ], "normalized": [] } ]

[ { "id": "PMID-12140030_E1", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 11, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_E2" } ] }, { "id": "PMID-12140030_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 34, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T2" }, { "role": "AtLoc", "ref_id": "PMID-12140030_T1" } ] }, { "id": "PMID-12140030_E3", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 68, 78 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_E4" }, { "role": "Cause", "ref_id": "PMID-12140030_E2" } ] }, { "id": "PMID-12140030_E4", "type": "Breakdown", "trigger": { "text": [ "degeneration" ], "offsets": [ [ 104, 116 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T3" } ] }, { "id": "PMID-12140030_E5", "type": "Planned_process", "trigger": { "text": [ "treating" ], "offsets": [ [ 153, 161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_E6" } ] }, { "id": "PMID-12140030_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 172, 190 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12140030_T4" } ] }, { "id": "PMID-12140030_E7", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 192, 195 ] ] }, "arguments": [] }, { "id": "PMID-12140030_E8", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 197, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_E9" }, { "role": "Cause", "ref_id": "PMID-12140030_E6" } ] }, { "id": "PMID-12140030_E9", "type": "Breakdown", "trigger": { "text": [ "degeneration" ], "offsets": [ [ 233, 245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T5" } ] }, { "id": "PMID-12140030_E10", "type": "Planned_process", "trigger": { "text": [ "photocoagulating" ], "offsets": [ [ 370, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T6" } ] }, { "id": "PMID-12140030_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 387, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T6" } ] }, { "id": "PMID-12140030_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 761, 764 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T10" } ] }, { "id": "PMID-12140030_E13", "type": "Planned_process", "trigger": { "text": [ "injected" ], "offsets": [ [ 1060, 1068 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12140030_T17" } ] }, { "id": "PMID-12140030_E14", "type": "Localization", "trigger": { "text": [ "observed" ], "offsets": [ [ 1105, 1113 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T17" }, { "role": "ToLoc", "ref_id": "PMID-12140030_T18" } ] }, { "id": "PMID-12140030_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1386, 1389 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T19" } ] }, { "id": "PMID-12140030_E16", "type": "Positive_regulation", "trigger": { "text": [ "requiring" ], "offsets": [ [ 1422, 1431 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12140030_E17" }, { "role": "Theme", "ref_id": "PMID-12140030_T20" } ] }, { "id": "PMID-12140030_E17", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1432, 1441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_E18" } ] }, { "id": "PMID-12140030_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1445, 1448 ] ] }, "arguments": [] }, { "id": "PMID-12140030_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1524, 1527 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T22" } ] }, { "id": "PMID-12140030_E20", "type": "Planned_process", "trigger": { "text": [ "closed" ], "offsets": [ [ 1548, 1554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T22" }, { "role": "Instrument", "ref_id": "PMID-12140030_T21" } ] }, { "id": "PMID-12140030_E21", "type": "Planned_process", "trigger": { "text": [ "closure" ], "offsets": [ [ 1706, 1713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T25" } ] }, { "id": "PMID-12140030_E22", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 2093, 2101 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12140030_T30" }, { "role": "Theme", "ref_id": "PMID-12140030_E23" } ] }, { "id": "PMID-12140030_E23", "type": "Planned_process", "trigger": { "text": [ "photocoagulation" ], "offsets": [ [ 2102, 2118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T31" } ] }, { "id": "PMID-12140030_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 2122, 2125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T31" } ] }, { "id": "PMID-12140030_E25", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 2515, 2524 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T35" } ] } ]

[ { "id": "PMID-12140030_1", "entity_ids": [ "PMID-12140030_T8", "PMID-12140030_T9" ] }, { "id": "PMID-12140030_2", "entity_ids": [ "PMID-12140030_T10", "PMID-12140030_T11" ] } ]

[]

[ { "id": "PMID-11238633__text", "type": "abstract", "text": [ "IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk.\nIn vivo IL-12-dependent tumor inhibition rests on the ability of IL-12 to activate a CD8-mediated cytotoxicity, inhibit angiogenesis, and cause vascular injury. Although in vivo studies have shown that such inhibition stems from complex interactions of immune cells and the production of IFN-gamma and other downstream angiostatic chemokines, the mechanisms involved are still poorly defined. Here we show that IL-12 activates an anti-angiogenic program in Con A-activated mouse spleen cells (activated spc) or human PBMC (activated PBMC). The soluble factors they release in its presence arrest the cycle of endothelial cells (EC), inhibit in vitro angiogenesis, negatively modulate the production of matrix metalloproteinase-9, and the ability of EC to adhere to vitronectin and up-regulate ICAM-1 and VCAM-1 expression. These effects do not require direct cell-cell contact, yet result from continuous interaction between activated lymphoid cells and EC. We used neutralizing Abs to show that the IFN-inducible protein-10 and monokine-induced by IFN-gamma chemokines are pivotal in inducing these effects. Experiments with nu/nu mice, nonobese diabetic-SCID mice, or activated spc enriched in specific cell subpopulations demonstrated that CD4(+), CD8(+), and NK cells are all needed to mediate the full anti-angiogenetic effect of IL-12.\n" ], "offsets": [ [ 0, 1457 ] ] } ]

[ { "id": "PMID-11238633_T1", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-11238633_T2", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 20, 36 ] ], "normalized": [] }, { "id": "PMID-11238633_T3", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 75, 85 ] ], "normalized": [] }, { "id": "PMID-11238633_T4", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 86, 102 ] ], "normalized": [] }, { "id": "PMID-11238633_T5", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 123, 128 ] ], "normalized": [] }, { "id": "PMID-11238633_T6", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 139, 144 ] ], "normalized": [] }, { "id": "PMID-11238633_T7", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 180, 185 ] ], "normalized": [] }, { "id": "PMID-11238633_T8", "type": "Gene_or_gene_product", "text": [ "CD8" ], "offsets": [ [ 200, 203 ] ], "normalized": [] }, { "id": "PMID-11238633_T9", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 259, 267 ] ], "normalized": [] }, { "id": "PMID-11238633_T10", "type": "Cell", "text": [ "immune cells" ], "offsets": [ [ 368, 380 ] ], "normalized": [] }, { "id": "PMID-11238633_T11", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 403, 412 ] ], "normalized": [] }, { "id": "PMID-11238633_T12", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 526, 531 ] ], "normalized": [] }, { "id": "PMID-11238633_T13", "type": "Simple_chemical", "text": [ "Con A" ], "offsets": [ [ 572, 577 ] ], "normalized": [] }, { "id": "PMID-11238633_T14", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 588, 593 ] ], "normalized": [] }, { "id": "PMID-11238633_T15", "type": "Cell", "text": [ "spleen cells" ], "offsets": [ [ 594, 606 ] ], "normalized": [] }, { "id": "PMID-11238633_T16", "type": "Cell", "text": [ "spc" ], "offsets": [ [ 618, 621 ] ], "normalized": [] }, { "id": "PMID-11238633_T17", "type": "Organism", "text": [ "human" ], "offsets": [ [ 626, 631 ] ], "normalized": [] }, { "id": "PMID-11238633_T18", "type": "Cell", "text": [ "PBMC" ], "offsets": [ [ 632, 636 ] ], "normalized": [] }, { "id": "PMID-11238633_T19", "type": "Cell", "text": [ "PBMC" ], "offsets": [ [ 648, 652 ] ], "normalized": [] }, { "id": "PMID-11238633_T20", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 724, 741 ] ], "normalized": [] }, { "id": "PMID-11238633_T21", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 743, 745 ] ], "normalized": [] }, { "id": "PMID-11238633_T22", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 817, 843 ] ], "normalized": [] }, { "id": "PMID-11238633_T23", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 864, 866 ] ], "normalized": [] }, { "id": "PMID-11238633_T24", "type": "Gene_or_gene_product", "text": [ "vitronectin" ], "offsets": [ [ 880, 891 ] ], "normalized": [] }, { "id": "PMID-11238633_T25", "type": "Gene_or_gene_product", "text": [ "ICAM-1" ], "offsets": [ [ 908, 914 ] ], "normalized": [] }, { "id": "PMID-11238633_T26", "type": "Gene_or_gene_product", "text": [ "VCAM-1" ], "offsets": [ [ 919, 925 ] ], "normalized": [] }, { "id": "PMID-11238633_T27", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 974, 978 ] ], "normalized": [] }, { "id": "PMID-11238633_T28", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 979, 983 ] ], "normalized": [] }, { "id": "PMID-11238633_T29", "type": "Cell", "text": [ "lymphoid cells" ], "offsets": [ [ 1050, 1064 ] ], "normalized": [] }, { "id": "PMID-11238633_T30", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1069, 1071 ] ], "normalized": [] }, { "id": "PMID-11238633_T31", "type": "Gene_or_gene_product", "text": [ "IFN-inducible protein-10" ], "offsets": [ [ 1115, 1139 ] ], "normalized": [] }, { "id": "PMID-11238633_T32", "type": "Organism", "text": [ "nu/nu mice" ], "offsets": [ [ 1241, 1251 ] ], "normalized": [] }, { "id": "PMID-11238633_T33", "type": "Organism", "text": [ "nonobese diabetic-SCID mice" ], "offsets": [ [ 1253, 1280 ] ], "normalized": [] }, { "id": "PMID-11238633_T34", "type": "Cell", "text": [ "spc" ], "offsets": [ [ 1295, 1298 ] ], "normalized": [] }, { "id": "PMID-11238633_T35", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1320, 1324 ] ], "normalized": [] }, { "id": "PMID-11238633_T36", "type": "Gene_or_gene_product", "text": [ "CD4" ], "offsets": [ [ 1358, 1361 ] ], "normalized": [] }, { "id": "PMID-11238633_T37", "type": "Cell", "text": [ "CD4(+)" ], "offsets": [ [ 1358, 1364 ] ], "normalized": [] }, { "id": "PMID-11238633_T38", "type": "Gene_or_gene_product", "text": [ "CD8" ], "offsets": [ [ 1366, 1369 ] ], "normalized": [] }, { "id": "PMID-11238633_T39", "type": "Cell", "text": [ "CD8(+)" ], "offsets": [ [ 1366, 1372 ] ], "normalized": [] }, { "id": "PMID-11238633_T40", "type": "Cell", "text": [ "NK cells" ], "offsets": [ [ 1378, 1386 ] ], "normalized": [] }, { "id": "PMID-11238633_T41", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 1450, 1455 ] ], "normalized": [] } ]

[ { "id": "PMID-11238633_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 6, 16 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T1" }, { "role": "Theme", "ref_id": "PMID-11238633_T2" } ] }, { "id": "PMID-11238633_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 6, 16 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T1" }, { "role": "Theme", "ref_id": "PMID-11238633_E3" } ] }, { "id": "PMID-11238633_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 51, 63 ] ] }, "arguments": [] }, { "id": "PMID-11238633_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 129, 138 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T5" }, { "role": "Theme", "ref_id": "PMID-11238633_E5" } ] }, { "id": "PMID-11238633_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 145, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T6" } ] }, { "id": "PMID-11238633_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 227, 234 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T7" }, { "role": "Theme", "ref_id": "PMID-11238633_E7" } ] }, { "id": "PMID-11238633_E7", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 235, 247 ] ] }, "arguments": [] }, { "id": "PMID-11238633_E8", "type": "Positive_regulation", "trigger": { "text": [ "cause" ], "offsets": [ [ 253, 258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E9" }, { "role": "Cause", "ref_id": "PMID-11238633_T7" } ] }, { "id": "PMID-11238633_E9", "type": "Breakdown", "trigger": { "text": [ "injury" ], "offsets": [ [ 268, 274 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T9" } ] }, { "id": "PMID-11238633_E10", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 389, 399 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T11" } ] }, { "id": "PMID-11238633_E11", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T12" }, { "role": "Theme", "ref_id": "PMID-11238633_E13" } ] }, { "id": "PMID-11238633_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 550, 560 ] ] }, "arguments": [] }, { "id": "PMID-11238633_E13", "type": "Negative_regulation", "trigger": { "text": [ "program" ], "offsets": [ [ 561, 568 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E12" } ] }, { "id": "PMID-11238633_E14", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 578, 587 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T13" }, { "role": "Theme", "ref_id": "PMID-11238633_T15" } ] }, { "id": "PMID-11238633_E15", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 578, 587 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T13" }, { "role": "Theme", "ref_id": "PMID-11238633_T18" } ] }, { "id": "PMID-11238633_E16", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 608, 617 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T16" } ] }, { "id": "PMID-11238633_E17", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 638, 647 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T19" } ] }, { "id": "PMID-11238633_E18", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 704, 710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T20" } ] }, { "id": "PMID-11238633_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 748, 755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E20" } ] }, { "id": "PMID-11238633_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 765, 777 ] ] }, "arguments": [] }, { "id": "PMID-11238633_E21", "type": "Negative_regulation", "trigger": { "text": [ "negatively modulate" ], "offsets": [ [ 779, 798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E23" } ] }, { "id": "PMID-11238633_E22", "type": "Negative_regulation", "trigger": { "text": [ "negatively modulate" ], "offsets": [ [ 779, 798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E24" } ] }, { "id": "PMID-11238633_E23", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 803, 813 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T22" } ] }, { "id": "PMID-11238633_E24", "type": "Binding", "trigger": { "text": [ "adhere" ], "offsets": [ [ 870, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T23" }, { "role": "Theme", "ref_id": "PMID-11238633_T24" } ] }, { "id": "PMID-11238633_E25", "type": "Positive_regulation", "trigger": { "text": [ "up-regulate" ], "offsets": [ [ 896, 907 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E27" } ] }, { "id": "PMID-11238633_E26", "type": "Positive_regulation", "trigger": { "text": [ "up-regulate" ], "offsets": [ [ 896, 907 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E28" } ] }, { "id": "PMID-11238633_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 926, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T26" } ] }, { "id": "PMID-11238633_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 926, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T25" } ] }, { "id": "PMID-11238633_E29", "type": "Regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 959, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E30" } ] }, { "id": "PMID-11238633_E30", "type": "Binding", "trigger": { "text": [ "contact" ], "offsets": [ [ 984, 991 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T28" }, { "role": "Theme", "ref_id": "PMID-11238633_T27" } ] }, { "id": "PMID-11238633_E31", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1020, 1031 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T29" }, { "role": "Theme", "ref_id": "PMID-11238633_T30" } ] }, { "id": "PMID-11238633_E32", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1040, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T29" } ] }, { "id": "PMID-11238633_E33", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1040, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T30" } ] }, { "id": "PMID-11238633_E34", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1285, 1294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_T34" } ] }, { "id": "PMID-11238633_E35", "type": "Regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 1405, 1412 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11238633_E37" } ] }, { "id": "PMID-11238633_E36", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenetic" ], "offsets": [ [ 1427, 1439 ] ] }, "arguments": [] }, { "id": "PMID-11238633_E37", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1440, 1446 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11238633_T41" }, { "role": "Theme", "ref_id": "PMID-11238633_E36" } ] } ]

[ { "id": "PMID-11238633_1", "entity_ids": [ "PMID-11238633_T16", "PMID-11238633_T15" ] }, { "id": "PMID-11238633_2", "entity_ids": [ "PMID-11238633_T19", "PMID-11238633_T18" ] }, { "id": "PMID-11238633_3", "entity_ids": [ "PMID-11238633_T20", "PMID-11238633_T21" ] } ]

[]

[ { "id": "PMID-16310808__text", "type": "abstract", "text": [ "Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells.\nAngiogenesis, new blood vessel formation, is a multistep process, precisely regulated by pro-angiogenic cytokines, which stimulate endothelial cells to migrate, proliferate and differentiate to form new capillary microvessels. Excessive vascular development and blood vessel remodeling appears in psoriasis, rheumatoid arthritis, diabetic retinopathy and solid tumors formation. Thalidomide [alpha-(N-phthalimido)-glutarimide] is known to be a potent inhibitor of angiogenesis, but the mechanism of its inhibitory action remains unclear. The aim of the study was to investigate the potential influence of thalidomide on the several steps of angiogenesis, using in vitro models. We have evaluated the effect of thalidomide on VEGF secretion, cell migration, adhesion as well as in capillary formation of human endothelial cell line EA.hy 926. Thalidomide at the concentrations of 0.01 microM and 10 microM inhibited VEGF secretion into supernatants, decreased the number of formed capillary tubes and increased cell adhesion to collagen. Administration of thalidomide at the concentration of 0.01 microM increased cell migration, while at 10 microM, it decreased cell migration. Thalidomide in concentrations from 0.1 microM to 10 microM did not change cell proliferation of 72-h cell cultures. We conclude that anti-angiogenic action of thalidomide is due to direct inhibitory action on VEGF secretion and capillary microvessel formation as well as immunomodulatory influence on EA.hy 926 cells migration and adhesion.\n" ], "offsets": [ [ 0, 1659 ] ] } ]

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[ { "id": "PMID-16855378__text", "type": "abstract", "text": [ "Differential mechanisms of radiosensitization by 2-deoxy-D-glucose in the monolayers and multicellular spheroids of a human glioma cell line.\nIn vitro studies using monolayer cultures of human tumor cell lines have shown that 2-DG selectively inhibits energy-dependent DNA repair and cellular recovery processes in cancer cells. However, monolayer cultures differ greatly from the complex environmental conditions generated in solid tumors that develop inhomogeneous hypoxic and necrotic regions. In contrast, multicellular spheroids mimic heterogeneous cellular behavior and the consequent functional characteristics of in vivo solid tumors, and serve as important in vitro model to investigate tumor biology and responses to potential therapeutic agents. The present study compares the radiomodification by 2-DG in monolayer cultures and spheroids of a human glioma cell line (BMG-1) to gain insight into the effects in solid tumors. In spheroids, the glucose consumption (2.1 p mole/cell/h) and lactate production (3.67 p mole/cell/h) was nearly 2-3 fold higher than in monolayer cells (0.83 and 1.43 p mole/cell/h respectively). Presence of 2-DG (5 mM) for 2-4 h inhibited the glucose usage and lactate production by 70% in spheroids, while a 35% reduction was observed in monolayer cells. Under these conditions, 2-DG drastically enhanced the radiation-induced cell death of spheroids (by 2-3 folds); while a 40% increase was observed in monolayer cells. Radiosensitization by 2-DG in monolayer cells was primarily due to an increase in mitotic death (23%) linked to cytogenetic damage (micronuclei), whereas a profound induction of apoptosis (40%) accounted for the sensitization in spheroids. Although the Bcl-2 and Bax levels were significantly higher in spheroids, Bcl-2/Bax ratio was similar in monolayers and spheroids. Comet assay revealed a late onset of DNA breaks in the presence of 2- DG following irradiation only in spheroids, which corroborated well with the late onset of oxidative stress. 2-DG did not induce a significant cell cycle delay in monolayers, while a transient G(2) delay was apparent in spheroids.\n" ], "offsets": [ [ 0, 2132 ] ] } ]

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"id": "PMID-16855378_T9", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 226, 230 ] ], "normalized": [] }, { "id": "PMID-16855378_T10", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 269, 272 ] ], "normalized": [] }, { "id": "PMID-16855378_T11", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 284, 292 ] ], "normalized": [] }, { "id": "PMID-16855378_T12", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 315, 327 ] ], "normalized": [] }, { "id": "PMID-16855378_T13", "type": "Cell", "text": [ "monolayer cultures" ], "offsets": [ [ 338, 356 ] ], "normalized": [] }, { "id": "PMID-16855378_T14", "type": "Cancer", "text": [ "solid tumors" ], "offsets": [ [ 427, 439 ] ], "normalized": [] }, { "id": "PMID-16855378_T15", "type": "Pathological_formation", "text": [ "inhomogeneous hypoxic" ], "offsets": [ [ 453, 474 ] ], "normalized": [] }, { "id": "PMID-16855378_T16", "type": "Pathological_formation", "text": [ "necrotic regions" ], "offsets": [ [ 479, 495 ] ], "normalized": [] }, { "id": "PMID-16855378_T17", "type": "Cell", "text": [ "multicellular spheroids" ], "offsets": [ [ 510, 533 ] ], "normalized": [] }, { "id": "PMID-16855378_T18", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 554, 562 ] ], "normalized": [] }, { "id": "PMID-16855378_T19", "type": "Cancer", "text": [ "solid tumors" ], "offsets": [ [ 629, 641 ] ], "normalized": [] }, { "id": "PMID-16855378_T20", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 696, 701 ] ], "normalized": [] }, { "id": "PMID-16855378_T21", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "PMID-16855378_T22", "type": "Cell", "text": [ "monolayer cultures" ], "offsets": [ [ 817, 835 ] ], "normalized": [] }, { "id": "PMID-16855378_T23", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 840, 849 ] ], "normalized": [] }, { "id": "PMID-16855378_T24", "type": "Organism", "text": [ "human" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "PMID-16855378_T25", "type": "Cell", "text": [ "glioma cell line" ], "offsets": [ [ 861, 877 ] ], "normalized": [] }, { "id": "PMID-16855378_T26", "type": "Cell", "text": [ "BMG-1" ], "offsets": [ [ 879, 884 ] ], "normalized": [] }, { "id": "PMID-16855378_T27", "type": "Cancer", "text": [ "solid tumors" ], "offsets": [ [ 922, 934 ] ], "normalized": [] }, { "id": "PMID-16855378_T28", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 939, 948 ] ], "normalized": [] }, { "id": "PMID-16855378_T29", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 954, 961 ] ], "normalized": [] }, { "id": "PMID-16855378_T30", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 998, 1005 ] ], "normalized": [] }, { "id": "PMID-16855378_T31", "type": "Cell", "text": [ "monolayer cells" ], "offsets": [ [ 1073, 1088 ] ], "normalized": [] }, { "id": "PMID-16855378_T32", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 1145, 1149 ] ], "normalized": [] }, { "id": "PMID-16855378_T33", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 1181, 1188 ] ], "normalized": [] }, { "id": "PMID-16855378_T34", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 1199, 1206 ] ], "normalized": [] }, { "id": "PMID-16855378_T35", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1228, 1237 ] ], "normalized": [] }, { "id": "PMID-16855378_T36", "type": "Cell", "text": [ "monolayer cells" ], "offsets": [ [ 1277, 1292 ] ], "normalized": [] }, { "id": "PMID-16855378_T37", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 1318, 1322 ] ], "normalized": [] }, { "id": "PMID-16855378_T38", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1366, 1370 ] ], "normalized": [] }, { "id": "PMID-16855378_T39", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1380, 1389 ] ], "normalized": [] }, { "id": "PMID-16855378_T40", "type": "Cell", "text": [ "monolayer cells" ], "offsets": [ [ 1443, 1458 ] ], "normalized": [] }, { "id": "PMID-16855378_T41", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 1482, 1486 ] ], "normalized": [] }, { "id": "PMID-16855378_T42", "type": "Cell", "text": [ "monolayer cells" ], "offsets": [ [ 1490, 1505 ] ], "normalized": [] }, { "id": "PMID-16855378_T43", "type": "Cellular_component", "text": [ "micronuclei" ], "offsets": [ [ 1592, 1603 ] ], "normalized": [] }, { "id": "PMID-16855378_T44", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1689, 1698 ] ], "normalized": [] }, { "id": "PMID-16855378_T45", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1713, 1718 ] ], "normalized": [] }, { "id": "PMID-16855378_T46", "type": "Gene_or_gene_product", "text": [ "Bax" ], "offsets": [ [ 1723, 1726 ] ], "normalized": [] }, { "id": "PMID-16855378_T47", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1763, 1772 ] ], "normalized": [] }, { "id": "PMID-16855378_T48", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1774, 1779 ] ], "normalized": [] }, { "id": "PMID-16855378_T49", "type": "Gene_or_gene_product", "text": [ "Bax" ], "offsets": [ [ 1780, 1783 ] ], "normalized": [] }, { "id": "PMID-16855378_T50", "type": "Cell", "text": [ "monolayers" ], "offsets": [ [ 1805, 1815 ] ], "normalized": [] }, { "id": "PMID-16855378_T51", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1820, 1829 ] ], "normalized": [] }, { "id": "PMID-16855378_T52", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 1868, 1871 ] ], "normalized": [] }, { "id": "PMID-16855378_T53", "type": "Simple_chemical", "text": [ "2- DG" ], "offsets": [ [ 1898, 1903 ] ], "normalized": [] }, { "id": "PMID-16855378_T54", "type": "Cell", "text": [ "spheroids" ], "offsets": [ [ 1934, 1943 ] ], "normalized": [] }, { "id": "PMID-16855378_T55", "type": "Simple_chemical", "text": [ "2-DG" ], "offsets": [ [ 2010, 2014 ] ], "normalized": [] }, { "id": "PMID-16855378_T56", "type": "Cell", "text": [ "cell" ], 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[ { "id": "PMID-15725689__text", "type": "abstract", "text": [ "Role of thrombogenic factors in the development of atherosclerosis.\nHemostatic factors play a crucial role in generating thrombotic plugs at sites of vascular damage (atherothrombosis). However, whether hemostatic factors contribute directly or indirectly to the pathogenesis of atherosclerosis remains uncertain. Autopsy studies have revealed that intimal thickening represents the first stage of atherosclerosis and that lipid-rich plaque arises from such lesions. Several factors contribute to the start of intimal thickening. Platelets release several growth factors and bioactive agents that play a central role in development of not only thrombus but also of intimal thickening. We have been investigating which coagulation factors simultaneously, or subsequently with platelet aggregation, participate in thrombus formation. Tissue factor (TF) is an essential initiator of blood coagulation that is expressed in various stages of atherosclerotic lesions in humans and other animals. Factors including thrombin and fibrin, which are downstream of the coagulation cascade activated by TF, also contribute to atherosclerosis. TF is involved in cell migration, embryogenesis and angiogenesis. Thus TF, in addition to factors downstream of the coagulation cascade and the protease-activated receptor 2 activation system, would be a multifactorial regulator of atherogenesis.\n" ], "offsets": [ [ 0, 1377 ] ] } ]

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[ { "id": "PMID-15725689_1", "entity_ids": [ "PMID-15725689_T15", "PMID-15725689_T16" ] } ]

[]

[ { "id": "PMID-9206208__text", "type": "abstract", "text": [ "[Expression of metastasis suppressor gene nm23 in human hepatocellular carcinoma]. \nFor the purpose of investigating the relationship between the metastatic potential of the tumor as well as the expression of nm23-H1 mRNA, and for determing the location of the positive sites in the cells, tumor metastasis suppressor gene nm23-H1 in human hepatocellular carcinoma (and the nonneoplastic area surrounding the tumor) was detected by in situ hybridization using digoxiginin-labeled nm23-H1 antisense complementary RNA probe. The primary results indicated (i) positive results of in situ hybridization are presence of granules or masses in the cytoplasm; (ii) the less expression of nm23-H1 mRNA, the higher metastatic rate of the human hepatocellular carcinoma (P < 0.05); (iii) expression of nm23-H1 mRNA dose not correlate with some other factors such as tumor size and the background of other liver diseases.\n" ], "offsets": [ [ 0, 910 ] ] } ]

[ { "id": "PMID-9206208_T1", "type": "Gene_or_gene_product", "text": [ "nm23" ], "offsets": [ [ 42, 46 ] ], "normalized": [] }, { "id": "PMID-9206208_T2", "type": "Organism", "text": [ "human" ], "offsets": [ [ 50, 55 ] ], "normalized": [] }, { "id": "PMID-9206208_T3", "type": "Cancer", "text": [ "hepatocellular carcinoma" ], "offsets": [ [ 56, 80 ] ], "normalized": [] }, { "id": "PMID-9206208_T4", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 174, 179 ] ], "normalized": [] }, { "id": "PMID-9206208_T5", "type": "Gene_or_gene_product", "text": [ "nm23-H1" ], "offsets": [ [ 209, 216 ] ], "normalized": [] }, { "id": "PMID-9206208_T6", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 283, 288 ] ], "normalized": [] }, { "id": "PMID-9206208_T7", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 290, 295 ] ], "normalized": [] }, { "id": "PMID-9206208_T8", "type": "Gene_or_gene_product", "text": [ "nm23-H1" ], "offsets": [ [ 323, 330 ] ], "normalized": [] }, { "id": "PMID-9206208_T9", "type": "Organism", "text": [ "human" ], "offsets": [ [ 334, 339 ] ], "normalized": [] }, { "id": "PMID-9206208_T10", "type": "Cancer", "text": [ "hepatocellular carcinoma" ], "offsets": [ [ 340, 364 ] ], "normalized": [] }, { "id": "PMID-9206208_T11", "type": "Multi-tissue_structure", "text": [ "nonneoplastic area" ], "offsets": [ [ 374, 392 ] ], "normalized": [] }, { "id": "PMID-9206208_T12", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 409, 414 ] ], "normalized": [] }, { "id": "PMID-9206208_T13", "type": "Simple_chemical", "text": [ "digoxiginin" ], "offsets": [ [ 460, 471 ] ], "normalized": [] }, { "id": "PMID-9206208_T14", "type": "Gene_or_gene_product", "text": [ "nm23-H1" ], "offsets": [ [ 480, 487 ] ], "normalized": [] }, { "id": "PMID-9206208_T15", "type": "Cellular_component", "text": [ "granules" ], "offsets": [ [ 615, 623 ] ], "normalized": [] }, { "id": "PMID-9206208_T16", "type": "Organism_substance", "text": [ "cytoplasm" ], "offsets": [ [ 641, 650 ] ], "normalized": [] }, { "id": "PMID-9206208_T17", "type": "Gene_or_gene_product", "text": [ "nm23-H1" ], "offsets": [ [ 680, 687 ] ], "normalized": [] }, { "id": "PMID-9206208_T18", "type": "Organism", "text": [ "human" ], "offsets": [ [ 728, 733 ] ], "normalized": [] }, { "id": "PMID-9206208_T19", "type": "Cancer", "text": [ "hepatocellular carcinoma" ], "offsets": [ [ 734, 758 ] ], "normalized": [] }, { "id": "PMID-9206208_T20", "type": "Gene_or_gene_product", "text": [ "nm23-H1" ], "offsets": [ [ 791, 798 ] ], "normalized": [] }, { "id": "PMID-9206208_T21", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "PMID-9206208_T22", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 894, 899 ] ], "normalized": [] } ]

[ { "id": "PMID-9206208_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 1, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T1" } ] }, { "id": "PMID-9206208_E2", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 15, 25 ] ] }, "arguments": [] }, { "id": "PMID-9206208_E3", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 146, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T4" } ] }, { "id": "PMID-9206208_E4", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 195, 205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T5" } ] }, { "id": "PMID-9206208_E5", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 296, 306 ] ] }, "arguments": [] }, { "id": "PMID-9206208_E6", "type": "Planned_process", "trigger": { "text": [ "labeled" ], "offsets": [ [ 472, 479 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-9206208_T13" } ] }, { "id": "PMID-9206208_E7", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 666, 676 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T17" } ] }, { "id": "PMID-9206208_E8", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 705, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T19" } ] }, { "id": "PMID-9206208_E9", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 777, 787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9206208_T20" } ] } ]

[]

[]

[ { "id": "PMID-18662848__text", "type": "abstract", "text": [ "Reversal of the malignant phenotype of ovarian cancer A2780 cells through transfection with wild-type PTEN gene. \nOBJECTIVE: PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor gene identified on human chromosome 10q23. Substantial studies have demonstrated that PTEN can inhibit cell proliferation, migration and invasion of many cancer cells. The purpose of this study was to determine whether upregulation of PTEN gene by transfection wild-type PTEN gene to ovarian cancer cells can inhibit growth and migration and to explore the potential for PTEN gene therapy of ovarian cancers. METHOD: Wild-type and phosphatase-inactive (C124A) PTEN plasmids were transfected into ovarian epithelial cancer A2780 cells, and their effects on cell apoptosis, cell proliferation, cell migration and cell invasion were analyzed by flow cytometry analysis, TUNEL assay, MTT assay, wound-healing assay and transwell assay. RESULTS: Both wild-type and mutant PTEN can upregulate the expression of PTEN gene dramatically; however, it is wild-type PTEN not phosphatase-inactive PTEN that can induce apoptosis and decrease cell migration, invasion and proliferation in ovarian cancer cells. CONCLUSION: These results demonstrated that PTEN had played an important role in the cell proliferation, cell migration and invasion dependent on its phosphatase activity. Enhanced expression of PTEN by gene transfer is sufficient to reverse the malignant phenotype of ovarian cancer cells and transfection of ovarian cancer cells with wild-type PTEN gene might be another novel approach for therapeutic intervention in ovarian cancer.\n" ], "offsets": [ [ 0, 1644 ] ] } ]

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[]

[ { "id": "PMID-2541348__text", "type": "abstract", "text": [ "Energy supply of the mitotic cell cycle and the Na+/H+-antiport in ascites tumors.\nThe activation of Na+ transport is due to the exchange of protons formed via glucose conversion into lactate for Na+, i.e., to the stimulation of the Na+/H+-antiport. Experimental results and theoretical calculations suggest that in glucose-containing medium the Na+ transport increases from 0.75 to 1.78 pmol/hour per cell. The permeability of plasma membranes for K+ increases 2.75 fold, while the passive flux of Na+ diminishes. The intensity of O2 adsorption by ascites tumor cells does not practically depend on the monovalent cation concentration gradient between the cells and the culture medium, whereas the rate of glycolysis decreases simultaneously with the diminution of the concentration gradient. In synchronized cultures at the beginning of the mitotic cycle, the bulk of ATP resynthesized via glycolysis is utilized for the synthesis of biopolymers, whereas that at the end of the S-phase and in the G2-phase is utilized for cation transport across plasma membranes. From 35 to 100% of the whole amount of ATP resynthesized via glycolysis is utilized for transport purposes. It is concluded that the observed increase in the Na+/K+ ratio in ascites tumor cells is connected with their enhanced ability to synthesize lactic acid. Presumably, glycolysis is one of the regulatory mechanisms of intracellular ratios of monovalent cations.\n" ], "offsets": [ [ 0, 1434 ] ] } ]

[ { "id": "PMID-2541348_T1", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 48, 51 ] ], "normalized": [] }, { "id": "PMID-2541348_T2", "type": "Simple_chemical", "text": [ "H+" ], "offsets": [ [ 52, 54 ] ], "normalized": [] }, { "id": "PMID-2541348_T3", "type": "Cancer", "text": [ "ascites tumors" ], "offsets": [ [ 67, 81 ] ], "normalized": [] }, { "id": "PMID-2541348_T4", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 101, 104 ] ], "normalized": [] }, { "id": "PMID-2541348_T5", "type": "Simple_chemical", "text": [ "protons" ], "offsets": [ [ 141, 148 ] ], "normalized": [] }, { "id": "PMID-2541348_T6", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 160, 167 ] ], "normalized": [] }, { "id": "PMID-2541348_T7", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 184, 191 ] ], "normalized": [] }, { "id": "PMID-2541348_T8", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 196, 199 ] ], "normalized": [] }, { "id": "PMID-2541348_T9", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 233, 236 ] ], "normalized": [] }, { "id": "PMID-2541348_T10", "type": "Simple_chemical", "text": [ "H+" ], "offsets": [ [ 237, 239 ] ], "normalized": [] }, { "id": "PMID-2541348_T11", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 316, 323 ] ], "normalized": [] }, { "id": "PMID-2541348_T12", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 346, 349 ] ], "normalized": [] }, { "id": "PMID-2541348_T13", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 402, 406 ] ], "normalized": [] }, { "id": "PMID-2541348_T14", "type": "Cellular_component", "text": [ "plasma membranes" ], "offsets": [ [ 428, 444 ] ], "normalized": [] }, { "id": "PMID-2541348_T15", "type": "Simple_chemical", "text": [ "K+" ], "offsets": [ [ 449, 451 ] ], "normalized": [] }, { "id": "PMID-2541348_T16", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 499, 502 ] ], "normalized": [] }, { "id": "PMID-2541348_T17", "type": "Simple_chemical", "text": [ "O2" ], "offsets": [ [ 532, 534 ] ], "normalized": [] }, { "id": "PMID-2541348_T18", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 557, 568 ] ], "normalized": [] }, { "id": "PMID-2541348_T19", "type": "Simple_chemical", "text": [ "cation" ], "offsets": [ [ 615, 621 ] ], "normalized": [] }, { "id": "PMID-2541348_T20", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 657, 662 ] ], "normalized": [] }, { "id": "PMID-2541348_T21", "type": "Cell", "text": [ "cultures" ], "offsets": [ [ 810, 818 ] ], "normalized": [] }, { "id": "PMID-2541348_T22", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 870, 873 ] ], "normalized": [] }, { "id": "PMID-2541348_T23", "type": "Simple_chemical", "text": [ "cation" ], "offsets": [ [ 1024, 1030 ] ], "normalized": [] }, { "id": "PMID-2541348_T24", "type": "Cellular_component", "text": [ "plasma membranes" ], "offsets": [ [ 1048, 1064 ] ], "normalized": [] }, { "id": "PMID-2541348_T25", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 1105, 1108 ] ], "normalized": [] }, { "id": "PMID-2541348_T26", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 1224, 1227 ] ], "normalized": [] }, { "id": "PMID-2541348_T27", "type": "Simple_chemical", "text": [ "K+" ], "offsets": [ [ 1228, 1230 ] ], "normalized": [] }, { "id": "PMID-2541348_T28", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 1248, 1259 ] ], "normalized": [] }, { "id": "PMID-2541348_T29", "type": "Simple_chemical", "text": [ "lactic acid" ], "offsets": [ [ 1315, 1326 ] ], "normalized": [] }, { "id": "PMID-2541348_T30", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1390, 1403 ] ], "normalized": [] }, { "id": "PMID-2541348_T31", "type": "Simple_chemical", "text": [ "cations" ], "offsets": [ [ 1425, 1432 ] ], "normalized": [] } ]

[ { "id": "PMID-2541348_E1", "type": "Localization", "trigger": { "text": [ "antiport" ], "offsets": [ [ 55, 63 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T1" }, { "role": "Theme", "ref_id": "PMID-2541348_T2" }, { "role": "AtLoc", "ref_id": "PMID-2541348_T3" } ] }, { "id": "PMID-2541348_E2", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 87, 97 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_E3" } ] }, { "id": "PMID-2541348_E3", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 105, 114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T4" } ] }, { "id": "PMID-2541348_E4", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 214, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_E5" } ] }, { "id": "PMID-2541348_E5", "type": "Localization", "trigger": { "text": [ "antiport" ], "offsets": [ [ 240, 248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T9" }, { "role": "Theme", "ref_id": "PMID-2541348_T10" } ] }, { "id": "PMID-2541348_E6", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 350, 359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T12" } ] }, { "id": "PMID-2541348_E7", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 360, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_E6" } ] }, { "id": "PMID-2541348_E8", "type": "Localization", "trigger": { "text": [ "flux" ], "offsets": [ [ 491, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T16" } ] }, { "id": "PMID-2541348_E9", "type": "Negative_regulation", "trigger": { "text": [ "diminishes" ], "offsets": [ [ 503, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_E8" } ] }, { "id": "PMID-2541348_E10", "type": "Glycolysis", "trigger": { "text": [ "glycolysis" ], "offsets": [ [ 707, 717 ] ] }, "arguments": [] }, { "id": "PMID-2541348_E11", "type": "Negative_regulation", "trigger": { "text": [ "decreases" ], "offsets": [ [ 718, 727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_E10" } ] }, { "id": "PMID-2541348_E12", "type": "Synthesis", "trigger": { "text": [ "resynthesized" ], "offsets": [ [ 874, 887 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T22" } ] }, { "id": "PMID-2541348_E13", "type": "Glycolysis", "trigger": { "text": [ "glycolysis" ], "offsets": [ [ 892, 902 ] ] }, "arguments": [] }, { "id": "PMID-2541348_E14", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 1031, 1040 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T23" } ] }, { "id": "PMID-2541348_E15", "type": "Synthesis", "trigger": { "text": [ "resynthesized" ], "offsets": [ [ 1109, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T25" } ] }, { "id": "PMID-2541348_E16", "type": "Glycolysis", "trigger": { "text": [ "glycolysis" ], "offsets": [ [ 1127, 1137 ] ] }, "arguments": [] }, { "id": "PMID-2541348_E17", "type": "Synthesis", "trigger": { "text": [ "synthesize" ], "offsets": [ [ 1304, 1314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2541348_T29" } ] }, { "id": "PMID-2541348_E18", "type": "Glycolysis", "trigger": { "text": [ "glycolysis" ], "offsets": [ [ 1340, 1350 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-10771470__text", "type": "abstract", "text": [ "Active hair growth (anagen) is associated with angiogenesis.\nAfter the completion of skin development, angiogenesis, i.e., the growth of new capillaries from pre-existing blood vessels, is held to occur in the skin only under pathologic conditions. It has long been noted, however, that hair follicle cycling is associated with prominent changes in skin perfusion, that the epithelial hair bulbs of anagen follicles display angiogenic properties, and that the follicular dermal papilla can produce angiogenic factors. Despite these suggestive observations, no formal proof is as yet available for the concept that angiogenesis is a physiologic event that occurs all over the mature mammalian integument whenever hair follicles switch from resting (telogen) to active growth (anagen). This study uses quantitative histomorphometry and double-immunohistologic detection techniques for the demarcation of proliferating endothelial cells, to show that synchronized hair follicle cycling in adolescent C57BL/6 mice is associated with substantial angiogenesis, and that inhibiting angiogenesis in vivo by the intraperitoneal application of a fumagillin derivative retards experimentally induced anagen development in these mice. Thus, angiogenesis is a physiologic event in normal postnatal murine skin, apparently is dictated by the hair follicle, and appears to be required for normal anagen development. Anagen-associated angiogenesis offers an attractive model for identifying the physiologic controls of cutaneous angiogenesis, and an interesting system for screening the effects of potential antiangiogenic drugs in vivo.\n" ], "offsets": [ [ 0, 1622 ] ] } ]

[ { "id": "PMID-10771470_T1", "type": "Multi-tissue_structure", "text": [ "hair" ], "offsets": [ [ 7, 11 ] ], "normalized": [] }, { "id": "PMID-10771470_T2", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 85, 89 ] ], "normalized": [] }, { "id": "PMID-10771470_T3", "type": "Tissue", "text": [ "capillaries" ], "offsets": [ [ 141, 152 ] ], "normalized": [] }, { "id": "PMID-10771470_T4", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 171, 184 ] ], "normalized": [] }, { "id": "PMID-10771470_T5", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 210, 214 ] ], "normalized": [] }, { "id": "PMID-10771470_T6", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 287, 300 ] ], "normalized": [] }, { "id": "PMID-10771470_T7", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "PMID-10771470_T8", "type": "Tissue", "text": [ "epithelial hair bulbs" ], "offsets": [ [ 374, 395 ] ], "normalized": [] }, { "id": "PMID-10771470_T9", "type": "Multi-tissue_structure", "text": [ "anagen follicles" ], "offsets": [ [ 399, 415 ] ], "normalized": [] }, { "id": "PMID-10771470_T10", "type": "Tissue", "text": [ "follicular dermal papilla" ], "offsets": [ [ 460, 485 ] ], "normalized": [] }, { "id": "PMID-10771470_T11", "type": "Multi-tissue_structure", "text": [ "hair follicles" ], "offsets": [ [ 712, 726 ] ], "normalized": [] }, { "id": "PMID-10771470_T12", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 916, 933 ] ], "normalized": [] }, { "id": "PMID-10771470_T13", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 961, 974 ] ], "normalized": [] }, { "id": "PMID-10771470_T14", "type": "Organism", "text": [ "C57BL/6 mice" ], "offsets": [ [ 997, 1009 ] ], "normalized": [] }, { "id": "PMID-10771470_T15", "type": "Immaterial_anatomical_entity", "text": [ "intraperitoneal" ], "offsets": [ [ 1103, 1118 ] ], "normalized": [] }, { "id": "PMID-10771470_T16", "type": "Simple_chemical", "text": [ "fumagillin derivative" ], "offsets": [ [ 1136, 1157 ] ], "normalized": [] }, { "id": "PMID-10771470_T17", "type": "Multi-tissue_structure", "text": [ "anagen" ], "offsets": [ [ 1189, 1195 ] ], "normalized": [] }, { "id": "PMID-10771470_T18", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1217, 1221 ] ], "normalized": [] }, { "id": "PMID-10771470_T19", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 1285, 1291 ] ], "normalized": [] }, { "id": "PMID-10771470_T20", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 1292, 1296 ] ], "normalized": [] }, { "id": "PMID-10771470_T21", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 1328, 1341 ] ], "normalized": [] }, { "id": "PMID-10771470_T22", "type": "Organism_subdivision", "text": [ "cutaneous" ], "offsets": [ [ 1503, 1512 ] ], "normalized": [] } ]

[ { "id": "PMID-10771470_E1", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 12, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T1" } ] }, { "id": "PMID-10771470_E2", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 31, 41 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10771470_E1" }, { "role": "Theme", "ref_id": "PMID-10771470_E3" } ] }, { "id": "PMID-10771470_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 47, 59 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E4", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 90, 101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T2" } ] }, { "id": "PMID-10771470_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 103, 115 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10771470_T5" } ] }, { "id": "PMID-10771470_E6", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 127, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T3" } ] }, { "id": "PMID-10771470_E7", "type": "Development", "trigger": { "text": [ "cycling" ], "offsets": [ [ 301, 308 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T6" } ] }, { "id": "PMID-10771470_E8", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 312, 322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_E7" } ] }, { "id": "PMID-10771470_E9", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 424, 434 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10771470_T8" } ] }, { "id": "PMID-10771470_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 498, 508 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 614, 626 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E12", "type": "Growth", "trigger": { "text": [ "resting" ], "offsets": [ [ 739, 746 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T11" } ] }, { "id": "PMID-10771470_E13", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 767, 773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T11" } ] }, { "id": "PMID-10771470_E14", "type": "Cell_proliferation", "trigger": { "text": [ "proliferating" ], "offsets": [ [ 902, 915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T12" } ] }, { "id": "PMID-10771470_E15", "type": "Development", "trigger": { "text": [ "cycling" ], "offsets": [ [ 975, 982 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T13" } ] }, { "id": "PMID-10771470_E16", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 1013, 1023 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10771470_E15" }, { "role": "Theme", "ref_id": "PMID-10771470_E17" } ] }, { "id": "PMID-10771470_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1041, 1053 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1064, 1074 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_E19" }, { "role": "Cause", "ref_id": "PMID-10771470_E20" } ] }, { "id": "PMID-10771470_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1075, 1087 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E20", "type": "Planned_process", "trigger": { "text": [ "application" ], "offsets": [ [ 1119, 1130 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10771470_T16" }, { "role": "Theme", "ref_id": "PMID-10771470_T15" } ] }, { "id": "PMID-10771470_E21", "type": "Negative_regulation", "trigger": { "text": [ "retards" ], "offsets": [ [ 1158, 1165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_E23" }, { "role": "Cause", "ref_id": "PMID-10771470_E18" } ] }, { "id": "PMID-10771470_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1181, 1188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_E23" } ] }, { "id": "PMID-10771470_E23", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 1196, 1207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_T17" } ] }, { "id": "PMID-10771470_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1229, 1241 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10771470_T20" } ] }, { "id": "PMID-10771470_E25", "type": "Positive_regulation", "trigger": { "text": [ "dictated" ], "offsets": [ [ 1312, 1320 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10771470_T21" }, { "role": "Theme", "ref_id": "PMID-10771470_E24" } ] }, { "id": "PMID-10771470_E26", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 1408, 1418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10771470_E27" } ] }, { "id": "PMID-10771470_E27", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1419, 1431 ] ] }, "arguments": [] }, { "id": "PMID-10771470_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1513, 1525 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10771470_T22" } ] }, { "id": "PMID-10771470_E29", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1596, 1606 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-18835936__text", "type": "abstract", "text": [ "Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity.\nOBJECTIVE: The expansion of adipose tissue is linked to the development of its vasculature. However, the regulation of adipose tissue angiogenesis in humans has not been extensively studied. Our aim was to compare the angiogenesis associated with subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from the same obese patients in an in vivo model. RESEARCH DESIGN AND METHODS: Adipose tissue samples from visceral (VAT) and subcutaneous (SAT) sites, obtained from 36 obese patients (mean BMI 46.5 kg/m(2)) during bariatric surgery, were layered on chick chorioallantoic membrane (CAM). RESULTS: Both SAT and VAT expressed angiogenic factors without significant difference for vascular endothelial growth factor (VEGF) expression. Adipose tissue layered on CAM stimulated angiogenesis. Angiogenic stimulation was macroscopically detectable, with engulfment of the samples, in 39% and was evidenced by angiography in 59% of the samples. A connection between CAM and adipose tissue vessels was evidenced by immunohistochemistry, with recruitment of both avian and human endothelial cells. The angiogenic potency of adipose tissue was not related to its localization (with an angiogenic stimulation in 60% of SAT samples and 61% of VAT samples) or to adipocyte size or inflammatory infiltrate assessed in adipose samples before the graft on CAM. Stimulation of angiogenesis by adipose tissue was nearly abolished by bevacizumab, which specifically targets human VEGF. CONCLUSIONS: We have established a model to study the regulation of angiogenesis by human adipose tissue. This model highlighted the role of VEGF in angiogenesis in both SAT and VAT.\n" ], "offsets": [ [ 0, 1759 ] ] } ]

[ { "id": "PMID-18835936_T1", "type": "Tissue", "text": [ "visceral" ], "offsets": [ [ 29, 37 ] ], "normalized": [] }, { "id": "PMID-18835936_T2", "type": "Tissue", "text": [ "subcutaneous adipose tissue" ], "offsets": [ [ 42, 69 ] ], "normalized": [] }, { "id": "PMID-18835936_T3", "type": "Organism", "text": [ "human" ], "offsets": [ [ 80, 85 ] ], "normalized": [] }, { "id": "PMID-18835936_T4", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 123, 137 ] ], "normalized": [] }, { "id": "PMID-18835936_T5", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 174, 185 ] ], "normalized": [] }, { "id": "PMID-18835936_T6", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 214, 228 ] ], "normalized": [] }, { "id": "PMID-18835936_T7", "type": "Organism", "text": [ "humans" ], "offsets": [ [ 245, 251 ] ], "normalized": [] }, { "id": "PMID-18835936_T8", "type": "Tissue", "text": [ "subcutaneous adipose tissue" ], "offsets": [ [ 342, 369 ] ], "normalized": [] }, { "id": "PMID-18835936_T9", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 371, 374 ] ], "normalized": [] }, { "id": "PMID-18835936_T10", "type": "Tissue", "text": [ "visceral adipose tissue" ], "offsets": [ [ 380, 403 ] ], "normalized": [] }, { "id": "PMID-18835936_T11", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 405, 408 ] ], "normalized": [] }, { "id": "PMID-18835936_T12", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 430, 438 ] ], "normalized": [] }, { "id": "PMID-18835936_T13", "type": "Tissue", "text": [ "Adipose tissue samples" ], "offsets": [ [ 489, 511 ] ], "normalized": [] }, { "id": "PMID-18835936_T14", "type": "Tissue", "text": [ "visceral" ], "offsets": [ [ 517, 525 ] ], "normalized": [] }, { "id": "PMID-18835936_T15", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 527, 530 ] ], "normalized": [] }, { "id": "PMID-18835936_T16", "type": "Tissue", "text": [ "subcutaneous (SAT) sites" ], "offsets": [ [ 536, 560 ] ], "normalized": [] }, { "id": "PMID-18835936_T17", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 585, 593 ] ], "normalized": [] }, { "id": "PMID-18835936_T18", "type": "Organism", "text": [ "chick" ], "offsets": [ [ 660, 665 ] ], "normalized": [] }, { "id": "PMID-18835936_T19", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membrane" ], "offsets": [ [ 666, 690 ] ], "normalized": [] }, { "id": "PMID-18835936_T20", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 692, 695 ] ], "normalized": [] }, { "id": "PMID-18835936_T21", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 712, 715 ] ], "normalized": [] }, { "id": "PMID-18835936_T22", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 720, 723 ] ], "normalized": [] }, { "id": "PMID-18835936_T23", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 788, 822 ] ], "normalized": [] }, { "id": "PMID-18835936_T24", "type": "Gene_or_gene_product", 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"type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 1224, 1238 ] ], "normalized": [] }, { "id": "PMID-18835936_T33", "type": "Tissue", "text": [ "SAT samples" ], "offsets": [ [ 1317, 1328 ] ], "normalized": [] }, { "id": "PMID-18835936_T34", "type": "Tissue", "text": [ "VAT samples" ], "offsets": [ [ 1340, 1351 ] ], "normalized": [] }, { "id": "PMID-18835936_T35", "type": "Cell", "text": [ "adipocyte" ], "offsets": [ [ 1359, 1368 ] ], "normalized": [] }, { "id": "PMID-18835936_T36", "type": "Tissue", "text": [ "adipose samples" ], "offsets": [ [ 1413, 1428 ] ], "normalized": [] }, { "id": "PMID-18835936_T37", "type": "Tissue", "text": [ "graft" ], "offsets": [ [ 1440, 1445 ] ], "normalized": [] }, { "id": "PMID-18835936_T38", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 1449, 1452 ] ], "normalized": [] }, { "id": "PMID-18835936_T39", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 1485, 1499 ] ], "normalized": [] }, { "id": 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[ { "id": "PMID-18835936_1", "entity_ids": [ "PMID-18835936_T8", "PMID-18835936_T9" ] }, { "id": "PMID-18835936_2", "entity_ids": [ "PMID-18835936_T10", "PMID-18835936_T11" ] }, { "id": "PMID-18835936_3", "entity_ids": [ "PMID-18835936_T14", "PMID-18835936_T15" ] }, { "id": "PMID-18835936_4", "entity_ids": [ "PMID-18835936_T19", "PMID-18835936_T20" ] }, { "id": "PMID-18835936_5", "entity_ids": [ "PMID-18835936_T23", "PMID-18835936_T24" ] } ]

[]

[ { "id": "PMID-20676141__text", "type": "abstract", "text": [ "Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation. \nHistone deacetylase inhibitors (HDACi) are potent anti-cancer agents for variety of cancer types. Suberoylanilide hydroxamic acid (SAHA) has been approved as a drug to treat cutaneous T cell lymphoma, and the combination of HDACi and other agents have been actively tested in many clinical trials. Adenovirus 5 early region 1A (E1A) has been shown to exhibit high tumor suppressor activity, and gene therapy using E1A has been tested in clinical trials. Here, we showed that proapoptotic activity of HDACi was robustly enhanced by E1A in multiple cancer cells, but not in normal cells. Moreover, we showed that combination of E1A gene therapy and SAHA showed high therapeutic efficacy with low toxicity in vivo ovarian and breast xenograft models. SAHA downregulated Bcl-XL and upregulated proapoptotic BH3-only protein Bim, whose expression was further enhanced by E1A in cancer cells. These alterations of Bcl-2 family proteins were critical for apoptosis induced by the combination in cancer cells. SAHA enhanced acetylation of histone H3 in Bim promoter region, while E1A upregulated Egr-1, which was directly involved in Bim transactivation. Together, our results provide not only a novel insight into the mechanisms underlying anti-tumor activity of E1A, but also a rationale for the combined HDACi and E1A gene therapy in future clinical trials.\n" ], "offsets": [ [ 0, 1470 ] ] } ]

[ { "id": "PMID-20676141_T1", "type": "Organism", "text": [ "Adenovirus 5" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "PMID-20676141_T2", "type": "Gene_or_gene_product", "text": [ "E1A" ], "offsets": [ [ 13, 16 ] ], "normalized": [] }, { "id": "PMID-20676141_T3", "type": "Gene_or_gene_product", "text": [ "histone deacetylase" ], "offsets": [ [ 26, 45 ] ], "normalized": [] }, { "id": "PMID-20676141_T4", "type": "Gene_or_gene_product", "text": [ "Egr-1" ], "offsets": [ [ 83, 88 ] ], "normalized": [] }, { "id": "PMID-20676141_T5", "type": "Gene_or_gene_product", "text": [ "Bim" ], "offsets": [ [ 98, 101 ] ], "normalized": [] }, { "id": "PMID-20676141_T6", "type": "Gene_or_gene_product", "text": [ "Histone deacetylase" ], "offsets": [ [ 117, 136 ] ], "normalized": [] }, { "id": "PMID-20676141_T7", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 172, 178 ] ], "normalized": [] }, { "id": "PMID-20676141_T8", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 201, 207 ] ], "normalized": [] }, { "id": "PMID-20676141_T9", "type": "Simple_chemical", "text": [ "Suberoylanilide hydroxamic acid" ], "offsets": [ [ 215, 246 ] ], "normalized": [] }, { "id": "PMID-20676141_T10", "type": "Simple_chemical", "text": [ "SAHA" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "PMID-20676141_T11", "type": "Cancer", "text": [ "T cell lymphoma" ], "offsets": [ [ 301, 316 ] ], "normalized": [] }, { "id": "PMID-20676141_T12", "type": "Organism", "text": [ "Adenovirus 5" ], "offsets": [ [ 415, 427 ] ], "normalized": [] }, { "id": "PMID-20676141_T13", "type": "Gene_or_gene_product", "text": [ "early region 1A" ], "offsets": [ [ 428, 443 ] ], "normalized": [] }, { "id": "PMID-20676141_T14", "type": "Gene_or_gene_product", "text": [ "E1A" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "PMID-20676141_T15", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "PMID-20676141_T16", "type": 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[]

[ { "id": "PMID-12823209__text", "type": "abstract", "text": [ "Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of the esophagus.\nThe most common genetic alterations found in a wide variety of cancers are p53 tumor suppressor gene mutations. p53 appears to be a nuclear transcription factor that plays a role in the control of cell proliferation, apoptosis, and the maintenance of genetic stability. Angiogenesis is a critical process in solid tumor growth and metastasis. Vascular endothelial growth factor (VEGF), a recently identified growth factor with significant angiogenic properties, may be a major tumor angiogenesis regulator. Few studies have investigated the association between p53 and VEGF expressions and prognosis in esophageal carcinoma. Forty-seven specimens resected from patients with stage II and III squamous cell carcinoma (SCC) of the esophagus were studied using immunohistochemical staining. VEGF and p53 expressions were observed in 40% and 53% of the tumors, respectively. The p53 and VEGF staining statuses were coincident in only 21% of the tumors, and no significant correlation was found between p53 and VEGF statuses. No clinicopathologic factors were significantly correlated with p53 or VEGF expression. No significant association between p53 and VEGF expressions and poor prognosis was found. In conclusion, p53 and VEGF were not correlated with prognosis in patients with stage II and III SCC of the esophagus.\n" ], "offsets": [ [ 0, 1465 ] ] } ]

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"role": "Theme", "ref_id": "PMID-12823209_T31" } ] } ]

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[]

[ { "id": "PMID-10487573__text", "type": "abstract", "text": [ "External beam radiotherapy for subretinal neovascularization in age-related macular degeneration: is this treatment efficient?\nPURPOSE: Control of the natural course of subretinal neovascularization (SRNV) in age-related macular degeneration (AMD) is difficult. Only a subset of patients is suitable for laser coagulation. This prospective study aimed to determine the efficacy and individual benefit of external beam radiotherapy (EBRT). METHODS AND MATERIALS: The prospective trial included 287 patients with subfoveal neovascularization due to AMD which was verified by fluorescein angiography. Patients have been treated between January 1996 and October 1997. All patients received a total dose of 16 Gy in 2-Gy daily fractions with 5-6 MeV photons based on computerized treatment planning in individual head mask fixation. This first analysis is based on 73 patients (50 women, 23 men, median age 74.3 years), with a median follow-up of 13.3 months and a minimum follow-up of 11 months. RESULTS: All patients completed therapy and tolerability was good. First clinical control with second angiography was performed 6 weeks after irradiation, then in 3-month intervals. Eighteen patients with SRNV refusing radiotherapy served as a control group and were matched with 18 irradiated patients. After 7 months median visual acuity (VA) was 20/160 for the irradiated and 20/400 for the untreated patients. One year after radiotherapy final median VA was 20/400 in both groups. CONCLUSION: These results suggest that 16 Gy of conventionally fractionated external beam irradiation slows down the visual loss in exudative AMD for only a few months. Patients' reading vision could not be saved for a long-term run.\n" ], "offsets": [ [ 0, 1711 ] ] } ]

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[]

[]

[ { "id": "PMID-21135106__text", "type": "abstract", "text": [ "The disintegrin-like and cysteine-rich domains of ADAM-9 mediate interactions between melanoma cells and fibroblasts. \nA characteristic of malignant cells is their capacity to invade their surrounding and to metastasize to distant organs. During these processes, proteolytic activities of tumor and stromal cells modify the extracellular matrix to produce a microenvironment suitable for their growth and migration. In recent years the family of ADAM proteases has been ascribed important roles in these processes. ADAM-9 is expressed in human melanoma at the tumor-stroma border where direct or indirect interactions between tumor cells and fibroblasts occur. To analyze the role of ADAM-9 for the interaction between melanoma cells and stromal fibroblasts, we produced the recombinant disintegrin-like and cysteine-rich domain of ADAM-9 (DC-9). Melanoma cells and human fibroblasts adhered to immobilized DC-9 in a Mn(2+)-dependent fashion suggesting an integrin-mediated process. Inhibition studies showed that adhesion of fibroblasts was mediated by several beta1 integrin receptors independent of the RGD and ECD recognition motif. Furthermore, interaction of fibroblasts and high invasive melanoma cells with soluble recombinant DC-9 resulted in enhanced expression of MMP-1 and MMP-2. Silencing of ADAM-9 in melanoma cells significantly reduced cell adhesion to fibroblasts. Ablation of ADAM-9 in fibroblasts almost completely abolished these cellular interactions and melanoma cell invasion in vitro. In summary, these results suggest that ADAM-9 expression plays an important role in mediating cell-cell contacts between fibroblasts and melanoma cells and that these interactions contribute to proteolytic activities required during invasion of melanoma cells.\n" ], "offsets": [ [ 0, 1770 ] ] } ]

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"normalized": [] }, { "id": "PMID-21135106_T17", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 642, 653 ] ], "normalized": [] }, { "id": "PMID-21135106_T18", "type": "Gene_or_gene_product", "text": [ "ADAM-9" ], "offsets": [ [ 684, 690 ] ], "normalized": [] }, { "id": "PMID-21135106_T19", "type": "Cell", "text": [ "melanoma cells" ], "offsets": [ [ 719, 733 ] ], "normalized": [] }, { "id": "PMID-21135106_T20", "type": "Cell", "text": [ "stromal fibroblasts" ], "offsets": [ [ 738, 757 ] ], "normalized": [] }, { "id": "PMID-21135106_T21", "type": "Gene_or_gene_product", "text": [ "disintegrin" ], "offsets": [ [ 787, 798 ] ], "normalized": [] }, { "id": "PMID-21135106_T22", "type": "Amino_acid", "text": [ "cysteine" ], "offsets": [ [ 808, 816 ] ], "normalized": [] }, { "id": "PMID-21135106_T23", "type": "Gene_or_gene_product", "text": [ "ADAM-9" ], "offsets": [ [ 832, 838 ] ], "normalized": [] }, { "id": "PMID-21135106_T24", "type": "Cell", "text": [ "Melanoma cells" ], 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invasive melanoma cells" ], "offsets": [ [ 1181, 1209 ] ], "normalized": [] }, { "id": "PMID-21135106_T33", "type": "Gene_or_gene_product", "text": [ "MMP-1" ], "offsets": [ [ 1275, 1280 ] ], "normalized": [] }, { "id": "PMID-21135106_T34", "type": "Gene_or_gene_product", "text": [ "MMP-2" ], "offsets": [ [ 1285, 1290 ] ], "normalized": [] }, { "id": "PMID-21135106_T35", "type": "Gene_or_gene_product", "text": [ "ADAM-9" ], "offsets": [ [ 1305, 1311 ] ], "normalized": [] }, { "id": "PMID-21135106_T36", "type": "Cell", "text": [ "melanoma cells" ], "offsets": [ [ 1315, 1329 ] ], "normalized": [] }, { "id": "PMID-21135106_T37", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1352, 1356 ] ], "normalized": [] }, { "id": "PMID-21135106_T38", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1369, 1380 ] ], "normalized": [] }, { "id": "PMID-21135106_T39", "type": "Gene_or_gene_product", "text": [ "ADAM-9" ], "offsets": [ [ 1394, 1400 ] ], "normalized": [] }, { "id": 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"PMID-21135106_T48", "type": "Cell", "text": [ "melanoma cells" ], "offsets": [ [ 1754, 1768 ] ], "normalized": [] } ]

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"ref_id": "PMID-21135106_T20" } ] }, { "id": "PMID-21135106_E15", "type": "Planned_process", "trigger": { "text": [ "produced" ], "offsets": [ [ 762, 770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T23" } ] }, { "id": "PMID-21135106_E16", "type": "Binding", "trigger": { "text": [ "adhered" ], "offsets": [ [ 884, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T24" } ] }, { "id": "PMID-21135106_E17", "type": "Binding", "trigger": { "text": [ "adhered" ], "offsets": [ [ 884, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T26" } ] }, { "id": "PMID-21135106_E18", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 924, 933 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_T27" }, { "role": "Theme", "ref_id": "PMID-21135106_E17" } ] }, { "id": "PMID-21135106_E19", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 924, 933 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_T27" }, { "role": "Theme", "ref_id": "PMID-21135106_E16" } ] }, { "id": "PMID-21135106_E20", "type": "Binding", "trigger": { "text": [ "adhesion" ], "offsets": [ [ 1014, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T29" } ] }, { "id": "PMID-21135106_E21", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1042, 1050 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E20" } ] }, { "id": "PMID-21135106_E22", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1150, 1161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T31" }, { "role": "Theme", "ref_id": "PMID-21135106_T32" } ] }, { "id": "PMID-21135106_E23", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1240, 1248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E25" } ] }, { "id": "PMID-21135106_E24", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1240, 1248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E26" } ] }, { "id": "PMID-21135106_E25", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1252, 1260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E27" } ] }, { "id": "PMID-21135106_E26", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1252, 1260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E28" } ] }, { "id": "PMID-21135106_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1261, 1271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T33" } ] }, { "id": "PMID-21135106_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1261, 1271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T34" } ] }, { "id": "PMID-21135106_E29", "type": "Negative_regulation", "trigger": { "text": [ "Silencing" ], "offsets": [ [ 1292, 1301 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T35" } ] }, { "id": "PMID-21135106_E30", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1344, 1351 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_E29" }, { "role": "Theme", "ref_id": "PMID-21135106_E31" } ] }, { "id": "PMID-21135106_E31", "type": "Binding", "trigger": { "text": [ "adhesion" ], "offsets": [ [ 1357, 1365 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T38" }, { "role": "Theme", "ref_id": "PMID-21135106_T36" } ] }, { "id": "PMID-21135106_E32", "type": "Negative_regulation", "trigger": { "text": [ "Ablation" ], "offsets": [ [ 1382, 1390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T39" } ] }, { "id": "PMID-21135106_E33", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1434, 1443 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_E32" }, { "role": "Theme", "ref_id": "PMID-21135106_E35" } ] }, { "id": "PMID-21135106_E34", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1434, 1443 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_E32" }, { "role": "Theme", "ref_id": "PMID-21135106_E36" } ] }, { "id": "PMID-21135106_E35", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1459, 1471 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T41" }, { "role": "Theme", "ref_id": "PMID-21135106_T40" } ] }, { "id": "PMID-21135106_E36", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 1490, 1498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T42" } ] }, { "id": "PMID-21135106_E37", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1555, 1565 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T43" } ] }, { "id": "PMID-21135106_E38", "type": "Regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 1593, 1602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_E39" }, { "role": "Cause", "ref_id": "PMID-21135106_E37" } ] }, { "id": "PMID-21135106_E39", "type": "Binding", "trigger": { "text": [ "contacts" ], "offsets": [ [ 1613, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T46" }, { "role": "Theme", "ref_id": "PMID-21135106_T47" } ] }, { "id": "PMID-21135106_E40", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1676, 1688 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T46" }, { "role": "Theme", "ref_id": "PMID-21135106_T47" } ] }, { "id": "PMID-21135106_E41", "type": "Positive_regulation", "trigger": { "text": [ "contribute" ], "offsets": [ [ 1689, 1699 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21135106_E40" }, { "role": "Theme", "ref_id": "PMID-21135106_E42" } ] }, { "id": "PMID-21135106_E42", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 1742, 1750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21135106_T48" } ] } ]

[]

[]

[ { "id": "PMID-15327827__text", "type": "abstract", "text": [ "Convergence of p53 and TGF-beta signaling networks. \np53 is a protein with many talents. One of the most fundamental is the ability to act as essential growth checkpoint that protects cells against cellular transformation. p53 does so through the induction of genes leading to growth arrest or apoptosis. Most of the studies focusing on the mechanisms of p53 activity have been performed in cultured cells upon treatment with well-established p53-activating inputs, such as high doses of radiations, DNA-damaging drugs and activated oncogenes. However, how the tumor suppressive functions of p53 become concerted with the extracellular cues arriving at the cell surface during tissue homeostasis, remains largely unknown. Intriguingly, two recent papers have shed new light into this unexplored field, indicating that p53 plays a key role in TGF-beta-induced growth arrest and, unexpectedly, in the developmental effects of TGF-beta in early embryos. Here we review and comment on these findings and on their implications for cancer biology.\n" ], "offsets": [ [ 0, 1042 ] ] } ]

[ { "id": "PMID-15327827_T1", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 15, 18 ] ], "normalized": [] }, { "id": "PMID-15327827_T2", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 23, 31 ] ], "normalized": [] }, { "id": "PMID-15327827_T3", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 53, 56 ] ], "normalized": [] }, { "id": "PMID-15327827_T4", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 184, 189 ] ], "normalized": [] }, { "id": "PMID-15327827_T5", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 198, 206 ] ], "normalized": [] }, { "id": "PMID-15327827_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 223, 226 ] ], "normalized": [] }, { "id": "PMID-15327827_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 355, 358 ] ], "normalized": [] }, { "id": "PMID-15327827_T8", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 400, 405 ] ], "normalized": [] }, { "id": "PMID-15327827_T9", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 443, 446 ] ], "normalized": [] }, { "id": "PMID-15327827_T10", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 500, 503 ] ], "normalized": [] }, { "id": "PMID-15327827_T11", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 561, 566 ] ], "normalized": [] }, { "id": "PMID-15327827_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 592, 595 ] ], "normalized": [] }, { "id": "PMID-15327827_T13", "type": "Immaterial_anatomical_entity", "text": [ "extracellular" ], "offsets": [ [ 622, 635 ] ], "normalized": [] }, { "id": "PMID-15327827_T14", "type": "Cellular_component", "text": [ "cell surface" ], "offsets": [ [ 657, 669 ] ], "normalized": [] }, { "id": "PMID-15327827_T15", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 677, 683 ] ], "normalized": [] }, { "id": "PMID-15327827_T16", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 818, 821 ] ], "normalized": [] }, { "id": "PMID-15327827_T17", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 842, 850 ] ], "normalized": [] }, { "id": "PMID-15327827_T18", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 924, 932 ] ], "normalized": [] }, { "id": "PMID-15327827_T19", "type": "Developing_anatomical_structure", "text": [ "embryos" ], "offsets": [ [ 942, 949 ] ], "normalized": [] }, { "id": "PMID-15327827_T20", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 1026, 1032 ] ], "normalized": [] } ]

[ { "id": "PMID-15327827_E1", "type": "Pathway", "trigger": { "text": [ "signaling networks" ], "offsets": [ [ 32, 50 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15327827_T2" } ] }, { "id": "PMID-15327827_E2", "type": "Pathway", "trigger": { "text": [ "signaling networks" ], "offsets": [ [ 32, 50 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15327827_T1" } ] }, { "id": "PMID-15327827_E3", "type": "Negative_regulation", "trigger": { "text": [ "protects" ], "offsets": [ [ 175, 183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_E4" }, { "role": "Cause", "ref_id": "PMID-15327827_T3" } ] }, { "id": "PMID-15327827_E4", "type": "Cell_transformation", "trigger": { "text": [ "transformation" ], "offsets": [ [ 207, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T5" } ] }, { "id": "PMID-15327827_E5", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 266, 273 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_E6" }, { "role": "Cause", "ref_id": "PMID-15327827_T6" } ] }, { "id": "PMID-15327827_E6", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 294, 303 ] ] }, "arguments": [] }, { "id": "PMID-15327827_E7", "type": "Planned_process", "trigger": { "text": [ "cultured" ], "offsets": [ [ 391, 399 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T8" } ] }, { "id": "PMID-15327827_E8", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 411, 420 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T8" } ] }, { "id": "PMID-15327827_E9", "type": "Breakdown", "trigger": { "text": [ "damaging" ], "offsets": [ [ 504, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T10" } ] }, { "id": "PMID-15327827_E10", "type": "Negative_regulation", "trigger": { "text": [ "suppressive" ], "offsets": [ [ 567, 578 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15327827_T12" }, { "role": "Theme", "ref_id": "PMID-15327827_T11" } ] }, { "id": "PMID-15327827_E11", "type": "Localization", "trigger": { "text": [ "arriving" ], "offsets": [ [ 641, 649 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T12" }, { "role": "ToLoc", "ref_id": "PMID-15327827_T14" } ] }, { "id": "PMID-15327827_E12", "type": "Regulation", "trigger": { "text": [ "plays a key role" ], "offsets": [ [ 822, 838 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15327827_T16" }, { "role": "Theme", "ref_id": "PMID-15327827_T17" } ] }, { "id": "PMID-15327827_E13", "type": "Regulation", "trigger": { "text": [ "plays a key role" ], "offsets": [ [ 822, 838 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15327827_T16" }, { "role": "Theme", "ref_id": "PMID-15327827_E15" } ] }, { "id": "PMID-15327827_E14", "type": "Development", "trigger": { "text": [ "developmental" ], "offsets": [ [ 899, 912 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_T19" } ] }, { "id": "PMID-15327827_E15", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 913, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15327827_E14" }, { "role": "Cause", "ref_id": "PMID-15327827_T18" } ] } ]

[]

[]

[ { "id": "PMID-1505125__text", "type": "abstract", "text": [ "NIH3T3 transfectant containing human K-ras oncogene shows enhanced metastatic activity after in vivo tumor growth or co-culture with fibroblasts. \nA clone of NIH3T3 transformant (H-3), obtained by transfecting genomic DNA of a human colon carcinoma cell line, contains human K-ras oncogene and yields metastatic pulmonary nodules after intravenous injection of the cells into nude mice. This metastatic ability was enhanced remarkably after in vivo tumor growth (subcutaneous tumor formation in nude mice) accompanied by increased mRNA expression and gene amplification of the human-derived K-ras oncogene, while it declined gradually as the passage number increased in vitro, with corresponding decreases of gene amplification and mRNA expression. Six subclones were randomly selected from H-3 cells which had been subcultured to passage 22. All of the clones in culture showed almost the same low level of metastatic ability and exhibited little K-ras oncogene amplification with correspondingly low mRNA expression. However, after they formed tumors in nude mice, every clone acquired high metastatic ability and the gene amplification increased, with elevated mRNA expression. These experimental facts indicated that acquisition of metastatic ability coupled with the function of K-ras oncogene was conditional in nature, being strongly affected by in vivo tumor circumstances. The low metastatic and G-418-resistant H-3 cells were co-cultured with BALB/c3T3 fibroblasts for 2-4 weeks. After removal of fibroblasts by exposure to G-418, the tumor cells exhibited increased metastatic ability and human K-ras oncogene mRNA, suggesting an intimate interaction between H-3 cells and fibroblasts influencing the function of transfected human K-ras oncogene. Fibroblasts of the host animal may thus have an important role in generating enhanced metastatic activity of H-3 cells.\n" ], "offsets": [ [ 0, 1878 ] ] } ]

[ { "id": "PMID-1505125_T1", "type": "Cell", "text": [ "NIH3T3 transfectant" ], "offsets": [ [ 0, 19 ] ], "normalized": [] }, { "id": "PMID-1505125_T2", "type": "Organism", "text": [ "human" ], "offsets": [ [ 31, 36 ] ], "normalized": [] }, { "id": "PMID-1505125_T3", "type": "Gene_or_gene_product", "text": [ "K-ras" ], "offsets": [ [ 37, 42 ] ], "normalized": [] }, { "id": "PMID-1505125_T4", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 101, 106 ] ], "normalized": [] }, { "id": "PMID-1505125_T5", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 133, 144 ] ], "normalized": [] }, { "id": "PMID-1505125_T6", "type": "Cell", "text": [ "clone" ], "offsets": [ [ 149, 154 ] ], "normalized": [] }, { "id": "PMID-1505125_T7", "type": "Cell", "text": [ "NIH3T3 transformant" ], "offsets": [ [ 158, 177 ] ], "normalized": [] }, { "id": "PMID-1505125_T8", "type": "Cell", "text": [ "H-3" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "PMID-1505125_T9", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 218, 221 ] ], "normalized": [] }, { "id": "PMID-1505125_T10", "type": "Organism", "text": [ "human" ], "offsets": [ [ 227, 232 ] ], "normalized": [] }, { "id": "PMID-1505125_T11", "type": "Cell", "text": [ "colon carcinoma cell line" ], "offsets": [ [ 233, 258 ] ], "normalized": [] }, { "id": "PMID-1505125_T12", "type": "Organism", "text": [ "human" ], "offsets": [ [ 269, 274 ] ], "normalized": [] }, { "id": "PMID-1505125_T13", "type": "Gene_or_gene_product", "text": [ "K-ras" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-1505125_T14", "type": "Pathological_formation", "text": [ "pulmonary nodules" ], "offsets": [ [ 312, 329 ] ], "normalized": [] }, { "id": "PMID-1505125_T15", "type": "Immaterial_anatomical_entity", "text": [ "intravenous" ], "offsets": [ [ 336, 347 ] ], "normalized": [] }, { "id": "PMID-1505125_T16", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "PMID-1505125_T17", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 376, 385 ] ], "normalized": [] }, { "id": "PMID-1505125_T18", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 449, 454 ] ], "normalized": [] }, { "id": "PMID-1505125_T19", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 476, 481 ] ], "normalized": [] }, { "id": "PMID-1505125_T20", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 495, 504 ] ], "normalized": [] }, { "id": "PMID-1505125_T21", "type": "Organism", "text": [ "human" ], "offsets": [ [ 577, 582 ] ], "normalized": [] }, { "id": "PMID-1505125_T22", "type": "Gene_or_gene_product", "text": [ "K-ras" ], "offsets": [ [ 591, 596 ] ], "normalized": [] }, { "id": "PMID-1505125_T23", "type": "Cell", "text": [ "subclones" ], "offsets": [ [ 753, 762 ] ], "normalized": [] }, { "id": "PMID-1505125_T24", "type": "Cell", "text": [ "H-3 cells" ], "offsets": [ [ 791, 800 ] ], "normalized": [] }, { "id": "PMID-1505125_T25", "type": "Cell", 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[]

[ { "id": "PMID-11587364__text", "type": "abstract", "text": [ "Oncogenic mechanisms of Evi-1 protein. \nAlthough Evi-1 is thought to promote growth or block differentiation in some cell types, its biological functions have not been elucidated. To explore the mechanisms underlying Evi-1-induced oncogenesis, we investigated whether Evi-1 affects the signaling of transforming growth factor beta (TGF-beta), which inhibits proliferation of a wide range of cell types and is one of the most studied growth regulatory factors. We demonstrated that Evi-1 represses TGF-beta signaling and antagonizes its growth-inhibitory effects. Two separate regions of Evi-1 are responsible for this repression, one of which is the first zinc-finger domain. Through this domain, Evi-1 physically interacts with Smad3, an intracellular mediator of TGF-beta signaling, thereby suppressing the transcriptional activity of Smad3. These results define a novel function of Evi-1 as a repressor of signaling components of TGF-beta. We also demonstrated that Evi-1 represses Smad-induced transcriptional activation by recruiting CtBP as a corepressor. Evi-1 associates with CtBP1 through one of the CtBP-binding consensus motifs within the region from amino acid 544 to 607, and this association is required for the efficient inhibition of TGF-beta signaling. A specific histone deacetylase (HDAc) inhibitor, trichostatin A (TSA), alleviates Evi-1-mediated repression of TGF-beta signaling, suggesting that HDAc is involved in transcriptional repression by Evi-1. This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms involved in Evi-1-induced leukemogenesis. These results indicate that specific HDAc inhibitors may be useful in the treatment of Evi-1-induced neoplastic tumors, including myeloid leukemias.\n" ], "offsets": [ [ 0, 1824 ] ] } ]

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[ [ 391, 401 ] ], "normalized": [] }, { "id": "PMID-11587364_T9", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "PMID-11587364_T10", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 497, 505 ] ], "normalized": [] }, { "id": "PMID-11587364_T11", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 587, 592 ] ], "normalized": [] }, { "id": "PMID-11587364_T12", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 697, 702 ] ], "normalized": [] }, { "id": "PMID-11587364_T13", "type": "Gene_or_gene_product", "text": [ "Smad3" ], "offsets": [ [ 729, 734 ] ], "normalized": [] }, { "id": "PMID-11587364_T14", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 739, 752 ] ], "normalized": [] }, { "id": "PMID-11587364_T15", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 765, 773 ] ], "normalized": [] }, { "id": "PMID-11587364_T16", "type": "Gene_or_gene_product", "text": [ "Smad3" ], "offsets": [ [ 837, 842 ] ], "normalized": [] }, { "id": "PMID-11587364_T17", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 885, 890 ] ], "normalized": [] }, { "id": "PMID-11587364_T18", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 933, 941 ] ], "normalized": [] }, { "id": "PMID-11587364_T19", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 969, 974 ] ], "normalized": [] }, { "id": "PMID-11587364_T20", "type": "Gene_or_gene_product", "text": [ "Smad" ], "offsets": [ [ 985, 989 ] ], "normalized": [] }, { "id": "PMID-11587364_T21", "type": "Gene_or_gene_product", "text": [ "CtBP" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "PMID-11587364_T22", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1062, 1067 ] ], "normalized": [] }, { "id": "PMID-11587364_T23", "type": "Gene_or_gene_product", "text": [ "CtBP1" ], "offsets": [ [ 1084, 1089 ] ], "normalized": [] }, { "id": "PMID-11587364_T24", "type": "Gene_or_gene_product", "text": [ "CtBP" ], "offsets": [ [ 1109, 1113 ] ], "normalized": [] }, { "id": "PMID-11587364_T25", "type": "Amino_acid", "text": [ "amino acid 544" ], "offsets": [ [ 1162, 1176 ] ], "normalized": [] }, { "id": "PMID-11587364_T26", "type": "Amino_acid", "text": [ "607" ], "offsets": [ [ 1180, 1183 ] ], "normalized": [] }, { "id": "PMID-11587364_T27", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 1250, 1258 ] ], "normalized": [] }, { "id": "PMID-11587364_T28", "type": "Gene_or_gene_product", "text": [ "histone deacetylase" ], "offsets": [ [ 1281, 1300 ] ], "normalized": [] }, { "id": "PMID-11587364_T29", "type": "Gene_or_gene_product", "text": [ "HDAc" ], "offsets": [ [ 1302, 1306 ] ], "normalized": [] }, { "id": "PMID-11587364_T30", "type": "Simple_chemical", "text": [ "trichostatin A" ], "offsets": [ [ 1319, 1333 ] ], "normalized": [] }, { "id": "PMID-11587364_T31", "type": "Simple_chemical", "text": [ "TSA" ], "offsets": [ [ 1335, 1338 ] ], "normalized": [] }, { "id": "PMID-11587364_T32", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1352, 1357 ] ], "normalized": [] }, { "id": "PMID-11587364_T33", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 1381, 1389 ] ], "normalized": [] }, { "id": "PMID-11587364_T34", "type": "Gene_or_gene_product", "text": [ "HDAc" ], "offsets": [ [ 1417, 1421 ] ], "normalized": [] }, { "id": "PMID-11587364_T35", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1467, 1472 ] ], "normalized": [] }, { "id": "PMID-11587364_T36", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1510, 1515 ] ], "normalized": [] }, { "id": "PMID-11587364_T37", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1645, 1650 ] ], "normalized": [] }, { "id": "PMID-11587364_T38", "type": "Gene_or_gene_product", "text": [ "HDAc" ], "offsets": [ [ 1712, 1716 ] ], "normalized": [] }, { "id": "PMID-11587364_T39", "type": "Gene_or_gene_product", "text": [ "Evi-1" ], "offsets": [ [ 1762, 1767 ] ], "normalized": [] }, { "id": "PMID-11587364_T40", "type": "Cancer", "text": [ "neoplastic tumors" ], "offsets": [ [ 1776, 1793 ] ], "normalized": [] }, { "id": "PMID-11587364_T41", "type": "Cancer", "text": [ "myeloid leukemias" ], "offsets": [ [ 1805, 1822 ] ], "normalized": [] }, { "id": "PMID-11587364_T60", "type": "Protein_domain_or_region", "text": [ "zinc-finger domain" ], "offsets": [ [ 656, 674 ] ], "normalized": [] }, { "id": "PMID-11587364_T70", "type": "Protein_domain_or_region", "text": [ "amino acid 544 to 607" ], "offsets": [ [ 1162, 1183 ] ], "normalized": [] } ]

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"Participant", "ref_id": "PMID-11587364_T33" } ] }, { "id": "PMID-11587364_E36", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1425, 1433 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11587364_T34" }, { "role": "Theme", "ref_id": "PMID-11587364_E37" } ] }, { "id": "PMID-11587364_E37", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1453, 1463 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11587364_T35" }, { "role": "Theme", "ref_id": "PMID-11587364_E35" } ] }, { "id": "PMID-11587364_E38", "type": "Binding", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 1580, 1591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11587364_T36" } ] }, { "id": "PMID-11587364_E39", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1651, 1658 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11587364_T37" }, { "role": "Theme", "ref_id": "PMID-11587364_E40" } ] }, { "id": "PMID-11587364_E40", "type": "Carcinogenesis", "trigger": { "text": [ "leukemogenesis" ], "offsets": [ [ 1659, 1673 ] ] }, "arguments": [] }, { "id": "PMID-11587364_E41", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1749, 1758 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11587364_T40" }, { "role": "Theme", "ref_id": "PMID-11587364_T41" } ] }, { "id": "PMID-11587364_E42", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1768, 1775 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11587364_T39" }, { "role": "Theme", "ref_id": "PMID-11587364_T40" } ] }, { "id": "PMID-11587364_E43", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1768, 1775 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11587364_T39" }, { "role": "Theme", "ref_id": "PMID-11587364_T41" } ] } ]

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[]

[ { "id": "PMID-10978899__text", "type": "abstract", "text": [ "Urokinase receptor: a molecular organizer in cellular communication.\nIn a variety of cell types, the glycolipid-anchored urokinase receptor (uPAR) is colocalized pericellularly with components of the plasminogen activation system and endocytosis receptors. uPAR is also coexpressed with caveolin and members of the integrin adhesion receptor superfamily. The formation of functional units with these various proteins allows the uPAR to mediate the focused proteolysis required for cell migration and invasion and to contribute both directly and indirectly to cell adhesive processes in a non-proteolytic fashion. This dual activity, together with the initiation of signal transduction pathways by uPAR, is believed to influence cellular behaviour in angiogenesis, inflammation, wound repair and tumor progression/metastasis and open up the way for uPAR-based therapeutic approaches.\n" ], "offsets": [ [ 0, 883 ] ] } ]

[ { "id": "PMID-10978899_T1", "type": "Gene_or_gene_product", "text": [ "Urokinase receptor" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "PMID-10978899_T2", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 45, 53 ] ], "normalized": [] }, { "id": "PMID-10978899_T3", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 85, 89 ] ], "normalized": [] }, { "id": "PMID-10978899_T4", "type": "Gene_or_gene_product", "text": [ "glycolipid-anchored urokinase receptor" ], "offsets": [ [ 101, 139 ] ], "normalized": [] }, { "id": "PMID-10978899_T5", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 141, 145 ] ], "normalized": [] }, { "id": "PMID-10978899_T6", "type": "Gene_or_gene_product", "text": [ "plasminogen" ], "offsets": [ [ 200, 211 ] ], "normalized": [] }, { "id": "PMID-10978899_T7", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 257, 261 ] ], "normalized": [] }, { "id": "PMID-10978899_T8", "type": "Gene_or_gene_product", "text": [ "caveolin" ], "offsets": [ [ 287, 295 ] ], "normalized": [] }, { "id": "PMID-10978899_T9", "type": "Gene_or_gene_product", "text": [ "integrin adhesion receptor" ], "offsets": [ [ 315, 341 ] ], "normalized": [] }, { "id": "PMID-10978899_T10", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 428, 432 ] ], "normalized": [] }, { "id": "PMID-10978899_T11", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 481, 485 ] ], "normalized": [] }, { "id": "PMID-10978899_T12", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-10978899_T13", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 697, 701 ] ], "normalized": [] }, { "id": "PMID-10978899_T14", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 728, 736 ] ], "normalized": [] }, { "id": "PMID-10978899_T15", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "PMID-10978899_T16", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 795, 800 ] ], "normalized": [] }, { "id": "PMID-10978899_T17", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 848, 852 ] ], "normalized": [] } ]

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[ { "id": "PMID-10978899_1", "entity_ids": [ "PMID-10978899_T4", "PMID-10978899_T5" ] } ]

[]

[ { "id": "PMID-2314900__text", "type": "abstract", "text": [ "Overexpression confers an oncogenic potential upon the eph gene. \nThe eph gene encodes a putative receptor tyrosine kinase for an as yet unknown ligand. Some human cancer cells have been found to overexpress eph mRNAs without gene amplification. We show here that NIH3T3 cells acquire tumorigenic ability in nude mice and make colonies in soft agar with a viral LTR (Long Terminal Repeat)-driven artificial expression of the eph gene to a high level. This result supports the alleged contribution of overexpressed receptor tyrosine kinases to cell transformation.\n" ], "offsets": [ [ 0, 564 ] ] } ]

[ { "id": "PMID-2314900_T1", "type": "Gene_or_gene_product", "text": [ "eph" ], "offsets": [ [ 55, 58 ] ], "normalized": [] }, { "id": "PMID-2314900_T2", "type": "Gene_or_gene_product", "text": [ "eph" ], "offsets": [ [ 70, 73 ] ], "normalized": [] }, { "id": "PMID-2314900_T3", "type": "Gene_or_gene_product", "text": [ "receptor tyrosine kinase" ], "offsets": [ [ 98, 122 ] ], "normalized": [] }, { "id": "PMID-2314900_T4", "type": "Organism", "text": [ "human" ], "offsets": [ [ 158, 163 ] ], "normalized": [] }, { "id": "PMID-2314900_T5", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 164, 176 ] ], "normalized": [] }, { "id": "PMID-2314900_T6", "type": "Gene_or_gene_product", "text": [ "eph" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-2314900_T7", "type": "Cell", "text": [ "NIH3T3 cells" ], "offsets": [ [ 264, 276 ] ], "normalized": [] }, { "id": "PMID-2314900_T8", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "PMID-2314900_T9", "type": "Gene_or_gene_product", "text": [ "eph" ], "offsets": [ [ 425, 428 ] ], "normalized": [] }, { "id": "PMID-2314900_T10", "type": "Gene_or_gene_product", "text": [ "receptor tyrosine kinases" ], "offsets": [ [ 514, 539 ] ], "normalized": [] }, { "id": "PMID-2314900_T11", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 543, 547 ] ], "normalized": [] } ]

[ { "id": "PMID-2314900_E1", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_T1" } ] }, { "id": "PMID-2314900_E2", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_E1" } ] }, { "id": "PMID-2314900_E3", "type": "Transcription", "trigger": { "text": [ "overexpress" ], "offsets": [ [ 196, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_T6" } ] }, { "id": "PMID-2314900_E4", "type": "Positive_regulation", "trigger": { "text": [ "overexpress" ], "offsets": [ [ 196, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_E3" } ] }, { "id": "PMID-2314900_E5", "type": "Mutation", "trigger": { "text": [ "gene amplification" ], "offsets": [ [ 226, 244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_T6" } ] }, { "id": "PMID-2314900_E6", "type": "Carcinogenesis", "trigger": { "text": [ "tumorigenic" ], "offsets": [ [ 285, 296 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-2314900_T7" } ] }, { "id": "PMID-2314900_E7", "type": "Planned_process", "trigger": { "text": [ "expression" ], "offsets": [ [ 407, 417 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-2314900_T9" }, { "role": "Theme", "ref_id": "PMID-2314900_T7" } ] }, { "id": "PMID-2314900_E8", "type": "Regulation", "trigger": { "text": [ "contribution" ], "offsets": [ [ 484, 496 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2314900_T10" }, { "role": "Theme", "ref_id": "PMID-2314900_E11" } ] }, { "id": "PMID-2314900_E9", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 500, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_T10" } ] }, { "id": "PMID-2314900_E10", "type": "Positive_regulation", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 500, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_E9" } ] }, { "id": "PMID-2314900_E11", "type": "Cell_transformation", "trigger": { "text": [ "transformation" ], "offsets": [ [ 548, 562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2314900_T11" } ] } ]

[]

[]

[ { "id": "PMID-16398404__text", "type": "abstract", "text": [ "The differential regulation of human telomerase reverse transcriptase and vascular endothelial growth factor may contribute to the clinically more aggressive behavior of p63-positive breast carcinomas.\np63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.\n" ], "offsets": [ [ 0, 1701 ] ] } ]

[ { "id": "PMID-16398404_T1", "type": "Organism", "text": [ "human" ], "offsets": [ [ 31, 36 ] ], "normalized": [] }, { "id": "PMID-16398404_T2", "type": "Gene_or_gene_product", "text": [ "telomerase reverse transcriptase" ], "offsets": [ [ 37, 69 ] ], "normalized": [] }, { "id": "PMID-16398404_T3", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 74, 108 ] ], "normalized": [] }, { "id": "PMID-16398404_T4", "type": "Cancer", "text": [ "p63-positive breast carcinomas" ], "offsets": [ [ 170, 200 ] ], "normalized": [] }, { "id": "PMID-16398404_T5", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 170, 173 ] ], "normalized": [] }, { "id": "PMID-16398404_T6", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 202, 205 ] ], "normalized": [] }, { "id": "PMID-16398404_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 209, 212 ] ], "normalized": [] }, { "id": "PMID-16398404_T8", "type": "Cell", "text": [ "myoepithelial cell" ], "offsets": [ [ 229, 247 ] ], "normalized": [] }, { "id": "PMID-16398404_T9", "type": "Organ", "text": [ "mammary gland" ], "offsets": [ [ 269, 282 ] ], "normalized": [] }, { "id": "PMID-16398404_T10", "type": "Cell", "text": [ "p63-positive neoplastic cells" ], "offsets": [ [ 287, 316 ] ], "normalized": [] }, { "id": "PMID-16398404_T11", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 287, 290 ] ], "normalized": [] }, { "id": "PMID-16398404_T12", "type": "Cancer", "text": [ "invasive breast carcinomas" ], "offsets": [ [ 346, 372 ] ], "normalized": [] }, { "id": "PMID-16398404_T13", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 425, 428 ] ], "normalized": [] }, { "id": "PMID-16398404_T14", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 485, 490 ] ], "normalized": [] }, { "id": "PMID-16398404_T15", "type": "Cancer", "text": [ "breast pathology" ], "offsets": [ [ 527, 543 ] ], "normalized": [] }, { "id": "PMID-16398404_T16", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 576, 580 ] ], "normalized": [] }, { "id": "PMID-16398404_T17", "type": "Gene_or_gene_product", "text": [ "metalloproteinases" ], "offsets": [ [ 627, 645 ] ], "normalized": [] }, { "id": "PMID-16398404_T18", "type": "Cancer", "text": [ "invasive ductal carcinomas" ], "offsets": [ [ 781, 807 ] ], "normalized": [] }, { "id": "PMID-16398404_T19", "type": "Cell", "text": [ "p63-positive cells" ], "offsets": [ [ 809, 827 ] ], "normalized": [] }, { "id": "PMID-16398404_T20", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 809, 812 ] ], "normalized": [] }, { "id": "PMID-16398404_T21", "type": "Cancer", "text": [ "carcinomas" ], "offsets": [ [ 849, 859 ] ], "normalized": [] }, { "id": "PMID-16398404_T22", "type": "Cancer", "text": [ "p63-positive carcinomas" ], "offsets": [ [ 861, 884 ] ], "normalized": [] }, { "id": "PMID-16398404_T23", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 861, 864 ] ], "normalized": [] }, { "id": "PMID-16398404_T24", "type": "Cancer", "text": [ "neoplasms" ], "offsets": [ [ 939, 948 ] ], "normalized": [] }, { "id": "PMID-16398404_T25", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 981, 984 ] ], "normalized": [] }, { "id": "PMID-16398404_T26", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "PMID-16398404_T27", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1069, 1074 ] ], "normalized": [] }, { "id": "PMID-16398404_T28", "type": "Gene_or_gene_product", "text": [ "telomerase reverse transcriptase" ], "offsets": [ [ 1075, 1107 ] ], "normalized": [] }, { "id": "PMID-16398404_T29", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1109, 1114 ] ], "normalized": [] }, { "id": "PMID-16398404_T30", "type": "Gene_or_gene_product", "text": [ "tissue inhibitor of matrix metalloproteinase 1" ], "offsets": [ [ 1117, 1163 ] ], "normalized": [] }, { "id": "PMID-16398404_T31", "type": "Gene_or_gene_product", "text": [ "TIMP1" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "PMID-16398404_T32", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1176, 1210 ] ], "normalized": [] }, { "id": "PMID-16398404_T33", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "PMID-16398404_T34", "type": "Gene_or_gene_product", "text": [ "TIMP1" ], "offsets": [ [ 1237, 1242 ] ], "normalized": [] }, { "id": "PMID-16398404_T35", "type": "Cancer", "text": [ "p63-positive carcinomas" ], "offsets": [ [ 1309, 1332 ] ], "normalized": [] }, { "id": "PMID-16398404_T36", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 1309, 1312 ] ], "normalized": [] }, { "id": "PMID-16398404_T37", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1334, 1339 ] ], "normalized": [] }, { "id": "PMID-16398404_T38", "type": "Multi-tissue_structure", "text": [ "nodal" ], "offsets": [ [ 1368, 1373 ] ], "normalized": [] }, { "id": "PMID-16398404_T39", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 1389, 1397 ] ], "normalized": [] }, { "id": "PMID-16398404_T40", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1413, 1417 ] ], "normalized": [] }, { "id": "PMID-16398404_T41", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1494, 1499 ] ], "normalized": [] }, { "id": "PMID-16398404_T42", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1574, 1579 ] ], "normalized": [] }, { "id": "PMID-16398404_T43", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1584, 1588 ] ], "normalized": [] }, { "id": "PMID-16398404_T44", "type": "Cancer", "text": [ "p63-positive breast carcinomas" ], "offsets": [ [ 1592, 1622 ] ], "normalized": [] }, { "id": "PMID-16398404_T45", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 1592, 1595 ] ], "normalized": [] }, { "id": "PMID-16398404_T46", "type": "Cancer", "text": [ "neoplasms" ], "offsets": [ [ 1690, 1699 ] ], "normalized": [] } ]

[ { "id": "PMID-16398404_E1", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T2" } ] }, { "id": "PMID-16398404_E2", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T3" } ] }, { "id": "PMID-16398404_E3", "type": "Localization", "trigger": { "text": [ "found" ], "offsets": [ [ 324, 329 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16398404_T12" }, { "role": "Theme", "ref_id": "PMID-16398404_T6" } ] }, { "id": "PMID-16398404_E4", "type": "Localization", "trigger": { "text": [ "found" ], "offsets": [ [ 324, 329 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16398404_T12" }, { "role": "Theme", "ref_id": "PMID-16398404_T7" } ] }, { "id": "PMID-16398404_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 429, 439 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T13" } ] }, { "id": "PMID-16398404_E6", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 599, 608 ] ] }, "arguments": [] }, { "id": "PMID-16398404_E7", "type": "Localization", "trigger": { "text": [ "found" ], "offsets": [ [ 833, 838 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T19" }, { "role": "AtLoc", "ref_id": "PMID-16398404_T21" } ] }, { "id": "PMID-16398404_E8", "type": "Cell_differentiation", "trigger": { "text": [ "differentiated" ], "offsets": [ [ 897, 911 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16398404_T22" } ] }, { "id": "PMID-16398404_E9", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 961, 974 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T24" } ] }, { "id": "PMID-16398404_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1055, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T28" } ] }, { "id": "PMID-16398404_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1055, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T30" } ] }, { "id": "PMID-16398404_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1055, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T32" } ] }, { "id": "PMID-16398404_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1223, 1233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T34" } ] }, { "id": "PMID-16398404_E14", "type": "Metastasis", "trigger": { "text": [ "metastases" ], "offsets": [ [ 1374, 1384 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-16398404_T38" } ] }, { "id": "PMID-16398404_E15", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1398, 1411 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T39" } ] }, { "id": "PMID-16398404_E16", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1418, 1427 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16398404_T40" }, { "role": "Theme", "ref_id": "PMID-16398404_E17" } ] }, { "id": "PMID-16398404_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1428, 1440 ] ] }, "arguments": [] }, { "id": "PMID-16398404_E18", "type": "Positive_regulation", "trigger": { "text": [ "fundamental" ], "offsets": [ [ 1458, 1469 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16398404_E17" }, { "role": "Theme", "ref_id": "PMID-16398404_E20" } ] }, { "id": "PMID-16398404_E19", "type": "Positive_regulation", "trigger": { "text": [ "fundamental" ], "offsets": [ [ 1458, 1469 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16398404_E17" }, { "role": "Theme", "ref_id": "PMID-16398404_E21" } ] }, { "id": "PMID-16398404_E20", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 1500, 1506 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T41" } ] }, { "id": "PMID-16398404_E21", "type": "Metastasis", "trigger": { "text": [ "metastatic dissemination" ], "offsets": [ [ 1511, 1535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T41" } ] }, { "id": "PMID-16398404_E22", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1560, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T44" }, { "role": "Cause", "ref_id": "PMID-16398404_T42" } ] }, { "id": "PMID-16398404_E23", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1560, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16398404_T44" }, { "role": "Cause", "ref_id": "PMID-16398404_T43" } ] } ]

[ { "id": "PMID-16398404_1", "entity_ids": [ "PMID-16398404_T29", "PMID-16398404_T28" ] }, { "id": "PMID-16398404_2", "entity_ids": [ "PMID-16398404_T30", "PMID-16398404_T31" ] }, { "id": "PMID-16398404_3", "entity_ids": [ "PMID-16398404_T32", "PMID-16398404_T33" ] } ]

[]

[ { "id": "PMID-19236257__text", "type": "abstract", "text": [ "Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors.\nBACKGROUND: Aberrant angiogenesis is a landmark feature in cancer, which is important for proliferation, growth and metastasis, and is mediated by various pro-angiogenic factors. The VEGF pathway is one of the most important and best-studied angiogenic pathways. Inhibition of this pathway may provide clinical benefits to cancer patients. OBJECTIVES: Strategies to inhibit the VEGF pathway, including antibodies to VEGF, antibodies to the extracellular domain of VEGFR-1 or VEGFR-2, decoy receptors for VEGF and tyrosine kinase inhibitors of VEGFRs, are summarized. METHODS: This review outlines and compares the latest development of these strategies, with emphasis on aflibercept, a novel decoy fusion protein of domain 2 of VEGFR-1 and domain 3 of VEGFR-2 with the Fc fragment of IgG1. RESULTS: Aflibercept was shown to have early clinical activity. Multiple studies are ongoing to determine the clinical benefits of aflibercept in cancer patients.\n" ], "offsets": [ [ 0, 1075 ] ] } ]

[ { "id": "PMID-19236257_T1", "type": "Simple_chemical", "text": [ "Aflibercept" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "PMID-19236257_T2", "type": "Simple_chemical", "text": [ "AVE0005" ], "offsets": [ [ 13, 20 ] ], "normalized": [] }, { "id": "PMID-19236257_T3", "type": "Cancer", "text": [ "tumour" ], "offsets": [ [ 62, 68 ] ], "normalized": [] }, { "id": "PMID-19236257_T4", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factors" ], "offsets": [ [ 85, 120 ] ], "normalized": [] }, { "id": "PMID-19236257_T5", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 181, 187 ] ], "normalized": [] }, { "id": "PMID-19236257_T6", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 305, 309 ] ], "normalized": [] }, { "id": "PMID-19236257_T7", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 445, 451 ] ], "normalized": [] }, { "id": "PMID-19236257_T8", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 452, 460 ] ], "normalized": [] }, { "id": "PMID-19236257_T9", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 500, 504 ] ], "normalized": [] }, { "id": "PMID-19236257_T10", "type": "Gene_or_gene_product", "text": [ "antibodies to VEGF" ], "offsets": [ [ 524, 542 ] ], "normalized": [] }, { "id": "PMID-19236257_T11", "type": "Gene_or_gene_product", "text": [ "antibodies to the extracellular domain of VEGFR-1" ], "offsets": [ [ 544, 593 ] ], "normalized": [] }, { "id": "PMID-19236257_T12", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 597, 604 ] ], "normalized": [] }, { "id": "PMID-19236257_T13", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 626, 630 ] ], "normalized": [] }, { "id": "PMID-19236257_T14", "type": "Simple_chemical", "text": [ "tyrosine kinase inhibitors" ], "offsets": [ [ 635, 661 ] ], "normalized": [] }, { "id": "PMID-19236257_T15", "type": "Gene_or_gene_product", "text": [ "VEGFRs" ], "offsets": [ [ 665, 671 ] ], "normalized": [] }, { "id": "PMID-19236257_T16", "type": "Simple_chemical", "text": [ "aflibercept" ], "offsets": [ [ 793, 804 ] ], "normalized": [] }, { "id": "PMID-19236257_T17", "type": "Gene_or_gene_product", "text": [ "VEGFR-1" ], "offsets": [ [ 850, 857 ] ], "normalized": [] }, { "id": "PMID-19236257_T18", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 874, 881 ] ], "normalized": [] }, { "id": "PMID-19236257_T19", "type": "Gene_or_gene_product", "text": [ "IgG1" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "PMID-19236257_T20", "type": "Simple_chemical", "text": [ "Aflibercept" ], "offsets": [ [ 921, 932 ] ], "normalized": [] }, { "id": "PMID-19236257_T21", "type": "Simple_chemical", "text": [ "aflibercept" ], "offsets": [ [ 1043, 1054 ] ], "normalized": [] }, { "id": "PMID-19236257_T22", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 1058, 1064 ] ], "normalized": [] }, { "id": "PMID-19236257_T23", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1065, 1073 ] ], "normalized": [] }, { "id": "PMID-19236257_T38", "type": "Protein_domain_or_region", "text": [ "Fc fragment" ], "offsets": [ [ 891, 902 ] ], "normalized": [] } ]

[ { "id": "PMID-19236257_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 51, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E2" }, { "role": "Cause", "ref_id": "PMID-19236257_T4" } ] }, { "id": "PMID-19236257_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 69, 81 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19236257_T3" } ] }, { "id": "PMID-19236257_E3", "type": "Regulation", "trigger": { "text": [ "Aberrant" ], "offsets": [ [ 134, 142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E4" } ] }, { "id": "PMID-19236257_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 143, 155 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E5", "type": "Positive_regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 198, 207 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19236257_E4" }, { "role": "Theme", "ref_id": "PMID-19236257_E7" } ] }, { "id": "PMID-19236257_E6", "type": "Positive_regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 198, 207 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19236257_E4" }, { "role": "Theme", "ref_id": "PMID-19236257_E8" } ] }, { "id": "PMID-19236257_E7", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 227, 233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_T5" } ] }, { "id": "PMID-19236257_E8", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 238, 248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_T5" } ] }, { "id": "PMID-19236257_E9", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 257, 265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E4" } ] }, { "id": "PMID-19236257_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 281, 291 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E11", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 310, 317 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19236257_T6" } ] }, { "id": "PMID-19236257_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 364, 374 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E13", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 385, 395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E11" } ] }, { "id": "PMID-19236257_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 488, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E19" }, { "role": "Cause", "ref_id": "PMID-19236257_T10" } ] }, { "id": "PMID-19236257_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 488, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E19" }, { "role": "Cause", "ref_id": "PMID-19236257_T11" } ] }, { "id": "PMID-19236257_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 488, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E19" }, { "role": "Cause", "ref_id": "PMID-19236257_T12" } ] }, { "id": "PMID-19236257_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 488, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E19" } ] }, { "id": "PMID-19236257_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 488, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E19" }, { "role": "Cause", "ref_id": "PMID-19236257_T14" } ] }, { "id": "PMID-19236257_E19", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 505, 512 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19236257_T9" } ] } ]

[ { "id": "PMID-19236257_1", "entity_ids": [ "PMID-19236257_T1", "PMID-19236257_T2" ] } ]

[]

[ { "id": "PMID-9778569__text", "type": "abstract", "text": [ "Glucose and lactate metabolism in C6 glioma cells: evidence for the preferential utilization of lactate for cell oxidative metabolism.\n13C and 1H nuclear magnetic resonance spectroscopy (NMR) was used to investigate the metabolism of L-lactate and D-glucose in C6 glioma cells. The 13C enrichment of cell metabolites was examined after a 4-h incubation in media containing 5.5 mM glucose and 11 mM lactate, each metabolite being alternatively labelled with either [1-13C]D-glucose or [3-13C]L-lactate. The results indicated that exogenous lactate was the major substrate for oxidative metabolism. They were consistent with the concept of the existence of 2 pools of both lactate and pyruvate, of which 1 pool was closely connected with exogenous lactate and oxidative metabolism, and the other pool was closely related to glycolysis and disconnected from oxidative metabolism. The molecular basis of this behaviour could be related to different locations for the lactate dehydrogenase isoenzymes, as suggested by their immunohistochemical labelling.\n" ], "offsets": [ [ 0, 1050 ] ] } ]

[ { "id": "PMID-9778569_T1", "type": "Simple_chemical", "text": [ "Glucose" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-9778569_T2", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 12, 19 ] ], "normalized": [] }, { "id": "PMID-9778569_T3", "type": "Cell", "text": [ "C6 glioma cells" ], "offsets": [ [ 34, 49 ] ], "normalized": [] }, { "id": "PMID-9778569_T4", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 96, 103 ] ], "normalized": [] }, { "id": "PMID-9778569_T5", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 108, 112 ] ], "normalized": [] }, { "id": "PMID-9778569_T6", "type": "Simple_chemical", "text": [ "13C" ], "offsets": [ [ 135, 138 ] ], "normalized": [] }, { "id": "PMID-9778569_T7", "type": "Simple_chemical", "text": [ "1H" ], "offsets": [ [ 143, 145 ] ], "normalized": [] }, { "id": "PMID-9778569_T8", "type": "Simple_chemical", "text": [ "L-lactate" ], "offsets": [ [ 234, 243 ] ], "normalized": [] }, { "id": "PMID-9778569_T9", "type": "Simple_chemical", "text": [ "D-glucose" ], "offsets": [ [ 248, 257 ] ], "normalized": [] }, { "id": "PMID-9778569_T10", "type": "Cell", "text": [ "C6 glioma cells" ], "offsets": [ [ 261, 276 ] ], "normalized": [] }, { "id": "PMID-9778569_T11", "type": "Simple_chemical", "text": [ "13C" ], "offsets": [ [ 282, 285 ] ], "normalized": [] }, { "id": "PMID-9778569_T12", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 300, 304 ] ], "normalized": [] }, { "id": "PMID-9778569_T13", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 380, 387 ] ], "normalized": [] }, { "id": "PMID-9778569_T14", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 398, 405 ] ], "normalized": [] }, { "id": "PMID-9778569_T15", "type": "Simple_chemical", "text": [ "[1-13C]D-glucose" ], "offsets": [ [ 464, 480 ] ], "normalized": [] }, { "id": "PMID-9778569_T16", "type": "Simple_chemical", "text": [ "[3-13C]L-lactate" ], "offsets": [ [ 484, 500 ] ], "normalized": [] }, { "id": "PMID-9778569_T17", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 539, 546 ] ], "normalized": [] }, { "id": "PMID-9778569_T18", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 671, 678 ] ], "normalized": [] }, { "id": "PMID-9778569_T19", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 683, 691 ] ], "normalized": [] }, { "id": "PMID-9778569_T20", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 746, 753 ] ], "normalized": [] }, { "id": "PMID-9778569_T21", "type": "Gene_or_gene_product", "text": [ "lactate dehydrogenase isoenzymes" ], "offsets": [ [ 963, 995 ] ], "normalized": [] } ]

[ { "id": "PMID-9778569_E1", "type": "Metabolism", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 20, 30 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T1" } ] }, { "id": "PMID-9778569_E2", "type": "Metabolism", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 20, 30 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T2" } ] }, { "id": "PMID-9778569_E3", "type": "Metabolism", "trigger": { "text": [ "utilization" ], "offsets": [ [ 81, 92 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T4" } ] }, { "id": "PMID-9778569_E4", "type": "Metabolism", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 220, 230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T8" } ] }, { "id": "PMID-9778569_E5", "type": "Metabolism", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 220, 230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T9" } ] }, { "id": "PMID-9778569_E6", "type": "Planned_process", "trigger": { "text": [ "enrichment" ], "offsets": [ [ 286, 296 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-9778569_T11" } ] }, { "id": "PMID-9778569_E7", "type": "Planned_process", "trigger": { "text": [ "incubation" ], "offsets": [ [ 342, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T12" }, { "role": "Instrument", "ref_id": "PMID-9778569_T13" }, { "role": "Instrument", "ref_id": "PMID-9778569_T14" } ] }, { "id": "PMID-9778569_E8", "type": "Planned_process", "trigger": { "text": [ "labelled" ], "offsets": [ [ 443, 451 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T15" } ] }, { "id": "PMID-9778569_E9", "type": "Planned_process", "trigger": { "text": [ "labelled" ], "offsets": [ [ 443, 451 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T16" } ] }, { "id": "PMID-9778569_E10", "type": "Metabolism", "trigger": { "text": [ "oxidative metabolism" ], "offsets": [ [ 575, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T17" } ] }, { "id": "PMID-9778569_E11", "type": "Metabolism", "trigger": { "text": [ "oxidative metabolism" ], "offsets": [ [ 758, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9778569_T20" } ] }, { "id": "PMID-9778569_E12", "type": "Glycolysis", "trigger": { "text": [ "glycolysis" ], "offsets": [ [ 822, 832 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-17960624__text", "type": "abstract", "text": [ "Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion.\nThe role of the pro-inflammatory peptide, LL-37, and its pro-form, human cationic antimicrobial protein 18 (hCAP-18), in cancer development and progression is poorly understood. In damaged and inflamed tissue, LL-37 functions as a chemoattractant, mitogen and pro-angiogenic factor suggesting that the peptide may potentiate tumor progression. The aim of this study was to characterize the distribution of hCAP-18/LL-37 in normal and cancerous ovarian tissue and to examine the effects of LL-37 on ovarian cancer cells. Expression of hCAP-18/LL-37 was localized to immune and granulosa cells of normal ovarian tissue. By contrast, ovarian tumors displayed significantly higher levels of hCAP-18/LL-37 where expression was observed in tumor and stromal cells. Protein expression was statistically compared to the degree of immune cell infiltration and microvessel density in epithelial-derived ovarian tumors and a significant correlation was observed for both. It was demonstrated that ovarian tumor tissue lysates and ovarian cancer cell lines express hCAP-18/LL-37. Treatment of ovarian cancer cell lines with recombinant LL-37 stimulated proliferation, chemotaxis, invasion and matrix metalloproteinase expression. These data demonstrate for the first time that hCAP-18/LL-37 is significantly overexpressed in ovarian tumors and suggest LL-37 may contribute to ovarian tumorigenesis through direct stimulation of tumor cells, initiation of angiogenesis and recruitment of immune cells. These data provide further evidence of the existing relationship between pro-inflammatory molecules and ovarian cancer progression.\n" ], "offsets": [ [ 0, 1766 ] ] } ]

[ { "id": "PMID-17960624_T1", "type": "Cancer", "text": [ "Ovarian cancers" ], "offsets": [ [ 0, 15 ] ], "normalized": [] }, { "id": "PMID-17960624_T2", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 54, 61 ] ], "normalized": [] }, { "id": "PMID-17960624_T3", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 81, 86 ] ], "normalized": [] }, { "id": "PMID-17960624_T4", "type": "Cell", "text": [ "ovarian cancer cell" ], "offsets": [ [ 97, 116 ] ], "normalized": [] }, { "id": "PMID-17960624_T5", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 187, 192 ] ], "normalized": [] }, { "id": "PMID-17960624_T6", "type": "Gene_or_gene_product", "text": [ "human cationic antimicrobial protein 18" ], "offsets": [ [ 212, 251 ] ], "normalized": [] }, { "id": "PMID-17960624_T7", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 253, 260 ] ], "normalized": [] }, { "id": "PMID-17960624_T8", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 266, 272 ] ], "normalized": [] }, { "id": "PMID-17960624_T9", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 347, 353 ] ], "normalized": [] }, { "id": "PMID-17960624_T10", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 355, 360 ] ], "normalized": [] }, { "id": "PMID-17960624_T11", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 470, 475 ] ], "normalized": [] }, { "id": "PMID-17960624_T12", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 551, 558 ] ], "normalized": [] }, { "id": "PMID-17960624_T13", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 559, 564 ] ], "normalized": [] }, { "id": "PMID-17960624_T14", "type": "Tissue", "text": [ "ovarian tissue" ], "offsets": [ [ 589, 603 ] ], "normalized": [] }, { "id": "PMID-17960624_T15", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 634, 639 ] ], "normalized": [] }, { "id": "PMID-17960624_T16", "type": "Cell", "text": [ "ovarian cancer cells" ], "offsets": [ [ 643, 663 ] ], "normalized": [] }, { "id": "PMID-17960624_T17", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 679, 686 ] ], "normalized": [] }, { "id": "PMID-17960624_T18", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "PMID-17960624_T19", "type": "Cell", "text": [ "immune" ], "offsets": [ [ 710, 716 ] ], "normalized": [] }, { "id": "PMID-17960624_T20", "type": "Cell", "text": [ "granulosa cells" ], "offsets": [ [ 721, 736 ] ], "normalized": [] }, { "id": "PMID-17960624_T21", "type": "Tissue", "text": [ "normal ovarian tissue" ], "offsets": [ [ 740, 761 ] ], "normalized": [] }, { "id": "PMID-17960624_T22", "type": "Cancer", "text": [ "ovarian tumors" ], "offsets": [ [ 776, 790 ] ], "normalized": [] }, { "id": "PMID-17960624_T23", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 832, 839 ] ], "normalized": [] }, { "id": "PMID-17960624_T24", 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[ { "id": "PMID-17662274__text", "type": "abstract", "text": [ "Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: implications for oral carcinogenesis. \nIn oral cancers, cytoplasmic BAG-1 overexpression is a marker of poor prognosis. BAG-1 regulates cellular growth, differentiation and survival through interactions with diverse proteins, including the vitamin D receptor (VDR), a key regulator of keratinocyte growth and differentiation. BAG-1 is expressed ubiquitously in human cells as three major isoforms of 50 kDa (BAG-1L), 46 kDa (BAG-1M) and 36 kDa (BAG-1S) from a single mRNA. In oral keratinocytes BAG-1L, but not BAG-1M and BAG-1S, enhanced VDR transactivation in response to 1alpha,25-dihydroxyvitamin D3. BAG-1L was nucleoplasmic and nucleolar, whereas BAG-1S and BAG-1M were cytoplasmic and nucleoplasmic in localisation. Having identified the nucleolar localisation sequence in BAG-1L, we showed that mutation of this sequence did not prevent BAG-1L from potentiating VDR activity. BAG-1L also potentiated transactivation of known vitamin-D-responsive gene promoters, osteocalcin and 24-hydroxylase, and enhanced VDR-dependent transcription and protein expression of the keratinocyte differentiation marker, involucrin. These results demonstrate endogenous gene regulation by BAG-1L by potentiating nuclear hormone receptor function and suggest a role for BAG-1L in 24-hydroxylase regulation of vitamin D metabolism and the cellular response of oral keratinocytes to 1alpha,25-dihydroxyvitamin D3. By contrast to the cytoplasmic BAG-1 isoforms, BAG-1L may act to suppress tumorigenesis.\n" ], "offsets": [ [ 0, 1638 ] ] } ]

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[ { "id": "PMID-17662274_1", "entity_ids": [ "PMID-17662274_T11", "PMID-17662274_T12" ] } ]

[]

[ { "id": "PMID-9840923__text", "type": "abstract", "text": [ "Tumors of the retinal pigment epithelium metastasize to inguinal lymph nodes and spleen in tyrosinase-related protein 1/SV40 T antigen transgenic mice. \nThe pigment epithelium of the retina (RPE) is derived from the optic cup and is essential for function and development of the eye. We produced a transgenic mouse line that expresses simian virus (SV40) transforming sequences under control of the 1.4 kb tyrosinase-related protein 1 (TRP-1) promoter, targeting expression of T antigen (Tag) to the RPE. In transgenic embryos, RPE cells proliferated in the anterior part of the eye and near the optic nerve. This resulted in formation of tumors, which were pigmented and of epithelial origin. In 3 months-old mice, pigmented cells were detected in spleen and inguinal lymph nodes. In spleen, tyrosinase, TRP-1 and SV40 Tag were expressed and tyrosinase was enzymatically active. Pigmented regions were positive for an epithelial marker, cytokeratin. Cell lines were established from tumor and metastases and kept in culture for more than 2 months. These were pigmented, and maintained expression of tyrosinase, TRP-1, cytokeratin and SV40 Tag. This demonstrates that RPE tumor cells metastasize to lymph node and spleen. In conclusion, the metastasis from TRP-1/Tag RPE tumors towards spleen and lymph nodes serves as potential tool to investigate biology and metastasis of tumors derived from the pigment epithelium.\n" ], "offsets": [ [ 0, 1419 ] ] } ]

[ { "id": "PMID-9840923_T1", "type": "Cancer", "text": [ "Tumors" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-9840923_T2", "type": "Tissue", "text": [ "retinal pigment epithelium" ], "offsets": [ [ 14, 40 ] ], "normalized": [] }, { "id": "PMID-9840923_T3", "type": "Multi-tissue_structure", "text": [ "lymph nodes" ], "offsets": [ [ 65, 76 ] ], "normalized": [] }, { "id": "PMID-9840923_T4", "type": "Organ", "text": [ "spleen" ], "offsets": [ [ 81, 87 ] ], "normalized": [] }, { "id": "PMID-9840923_T5", "type": "Gene_or_gene_product", "text": [ "tyrosinase-related protein 1" ], "offsets": [ [ 91, 119 ] ], "normalized": [] }, { "id": "PMID-9840923_T6", "type": "Organism", "text": [ "tyrosinase-related protein 1/SV40 T antigen transgenic mice" ], "offsets": [ [ 91, 150 ] ], "normalized": [] }, { "id": "PMID-9840923_T7", "type": "Gene_or_gene_product", "text": [ "SV40 T antigen" ], "offsets": [ [ 120, 134 ] ], "normalized": [] }, { "id": "PMID-9840923_T8", "type": "Tissue", "text": [ "pigment epithelium" ], "offsets": [ [ 157, 175 ] ], "normalized": [] }, { "id": "PMID-9840923_T9", "type": "Multi-tissue_structure", "text": [ "retina" ], "offsets": [ [ 183, 189 ] ], "normalized": [] }, { "id": "PMID-9840923_T10", "type": "Tissue", "text": [ "RPE" ], "offsets": [ [ 191, 194 ] ], "normalized": [] }, { "id": "PMID-9840923_T11", "type": "Multi-tissue_structure", "text": [ "optic cup" ], "offsets": [ [ 216, 225 ] ], "normalized": [] }, { "id": "PMID-9840923_T12", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 279, 282 ] ], "normalized": [] }, { "id": "PMID-9840923_T13", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 309, 314 ] ], "normalized": [] }, { "id": "PMID-9840923_T14", "type": "Organism", "text": [ "simian virus" ], "offsets": [ [ 335, 347 ] ], "normalized": [] }, { "id": "PMID-9840923_T15", "type": "Organism", "text": [ "SV40" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "PMID-9840923_T16", "type": "Gene_or_gene_product", "text": [ "tyrosinase-related protein 1" ], "offsets": [ [ 406, 434 ] ], "normalized": [] }, { "id": "PMID-9840923_T17", "type": "Gene_or_gene_product", "text": [ "TRP-1" ], "offsets": [ [ 436, 441 ] ], "normalized": [] }, { "id": "PMID-9840923_T18", "type": "Gene_or_gene_product", "text": [ "T antigen" ], "offsets": [ [ 477, 486 ] ], "normalized": [] }, { "id": "PMID-9840923_T19", "type": "Gene_or_gene_product", "text": [ "Tag" ], "offsets": [ [ 488, 491 ] ], "normalized": [] }, { "id": "PMID-9840923_T20", "type": "Tissue", "text": [ "RPE" ], "offsets": [ [ 500, 503 ] ], "normalized": [] }, { "id": "PMID-9840923_T21", "type": "Developing_anatomical_structure", "text": [ "embryos" ], "offsets": [ [ 519, 526 ] ], "normalized": [] }, { "id": "PMID-9840923_T22", "type": "Cell", "text": [ "RPE cells" ], "offsets": [ [ 528, 537 ] ], "normalized": [] }, { "id": "PMID-9840923_T23", "type": "Multi-tissue_structure", "text": [ "anterior part" ], "offsets": [ [ 558, 571 ] ], "normalized": [] }, 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[]

[ { "id": "PMID-3492269__text", "type": "abstract", "text": [ "Growth state-dependent regulation of protein kinase C in normal and transformed murine cells. \nWe determined whether growth state can influence the action of protein kinase C by measuring protein kinase C activity in growing and stationary cultures of normal and transformed cells. Two approaches were used to measure protein kinase C: assay of intact cells for inhibition of epidermal growth factor (EGF) binding in response to phorbol dibutyrate (PDBu); and assay of detergent extracts for total calcium, phospholipid-dependent kinase activity. In extracts of growing and stationary Swiss 3T3 cells, the total amount of protein kinase C activity was similar, indicating that growth state does not alter the level of enzyme in the cell. The short-term response of Swiss 3T3 cells to an activator of protein kinase C also appeared to be independent of growth state, since the 50% effective dose for PDBu inhibition of EGF binding to its receptor was approximately 7 nM for both growth conditions. In contrast, the response of cells to long-term treatment with PDBu was significantly different depending upon the initial growth state of the cells. In both growth states, PDBu caused loss of protein kinase C activity, which reflected a loss in protein mass as determined by immunoblotting with antiserum to protein kinase C. However, the maximum decrease approached 100% in stationary cultures versus approximately 75% in growing cells. Protein kinase C levels in several transformed cell lines were subject to down modulation in a similar growth state-dependent manner. Further, the inhibition of EGF binding by tumor promoters following long-term treatment of Swiss 3T3 cells with PDBu also varied with growth state. In down modulated growing cells, PDBu caused almost complete inhibition of EGF binding, whereas in down modulated stationary cells, minimal inhibition of EGF binding by PDBu was observed. These results suggest that prolonged treatment with tumor promoters alters the sensitivity of cells to activators of protein kinase C in a growth state-dependent manner.\n" ], "offsets": [ [ 0, 2076 ] ] } ]

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"normalized": [] }, { "id": "PMID-3492269_T9", "type": "Gene_or_gene_product", "text": [ "epidermal growth factor" ], "offsets": [ [ 376, 399 ] ], "normalized": [] }, { "id": "PMID-3492269_T10", "type": "Gene_or_gene_product", "text": [ "EGF" ], "offsets": [ [ 401, 404 ] ], "normalized": [] }, { "id": "PMID-3492269_T11", "type": "Simple_chemical", "text": [ "phorbol dibutyrate" ], "offsets": [ [ 429, 447 ] ], "normalized": [] }, { "id": "PMID-3492269_T12", "type": "Simple_chemical", "text": [ "PDBu" ], "offsets": [ [ 449, 453 ] ], "normalized": [] }, { "id": "PMID-3492269_T13", "type": "Organism_substance", "text": [ "extracts" ], "offsets": [ [ 479, 487 ] ], "normalized": [] }, { "id": "PMID-3492269_T14", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 498, 505 ] ], "normalized": [] }, { "id": "PMID-3492269_T15", "type": "Simple_chemical", "text": [ "phospholipid" ], "offsets": [ [ 507, 519 ] ], "normalized": [] }, { "id": "PMID-3492269_T16", "type": "Organism_substance", "text": [ "extracts" ], "offsets": [ [ 550, 558 ] ], "normalized": [] }, { "id": "PMID-3492269_T17", "type": "Cell", "text": [ "Swiss 3T3 cells" ], "offsets": [ [ 585, 600 ] ], "normalized": [] }, { "id": "PMID-3492269_T18", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 622, 638 ] ], "normalized": [] }, { "id": "PMID-3492269_T19", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 732, 736 ] ], "normalized": [] }, { "id": "PMID-3492269_T20", "type": "Cell", "text": [ "Swiss 3T3 cells" ], "offsets": [ [ 765, 780 ] ], "normalized": [] }, { "id": "PMID-3492269_T21", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 800, 816 ] ], "normalized": [] }, { "id": "PMID-3492269_T22", "type": "Simple_chemical", "text": [ "PDBu" ], "offsets": [ [ 899, 903 ] ], "normalized": [] }, { "id": "PMID-3492269_T23", "type": "Gene_or_gene_product", "text": [ "EGF" ], "offsets": [ [ 918, 921 ] ], "normalized": [] }, { "id": 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[]

[ { "id": "PMID-10890377__text", "type": "abstract", "text": [ "The value of serum S-100beta and interleukins as tumour markers in advanced melanoma. \nRecently serum S-100beta has shown promise as a tumour marker in melanoma; however, its use as a prognostic marker in the advanced stage needs to be confirmed. Interleukins (ILs) may mediate regression or progression of cancer. In order to study their relation to the metastatic profile and survival, we evaluated the association between pretreatment serum levels of S-100beta, IL-6, IL-10 and IL-12 and metastatic site and survival in 50 patients with advanced melanoma who were to receive chemoimmunotherapy. Patients with liver and/or bone metastases had significantly higher median concentrations of S-100beta, IL-6 and IL-10 than those with only skin, nodal and/or lung involvement. The differences in IL-12 levels were unremarkable. Using univariate analysis, the S-100beta level and metastatic profile were found to be statistically significant prognostic factors for survival. Using multivariate analysis the S-100beta level was the most powerful prognostic indicator, while the metastatic profile was found to be significant after exclusion of S-100beta. The findings suggest that elevated serum levels of S-100beta, IL-6 and IL-10 reflect concurrent liver or bone metastases in melanoma. S-100beta is also an independent prognostic marker. Pretreatment IL levels were not associated with outcome.\n" ], "offsets": [ [ 0, 1394 ] ] } ]

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[] }, { "id": "PMID-10890377_T9", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 152, 160 ] ], "normalized": [] }, { "id": "PMID-10890377_T10", "type": "Gene_or_gene_product", "text": [ "Interleukins" ], "offsets": [ [ 247, 259 ] ], "normalized": [] }, { "id": "PMID-10890377_T11", "type": "Gene_or_gene_product", "text": [ "ILs" ], "offsets": [ [ 261, 264 ] ], "normalized": [] }, { "id": "PMID-10890377_T12", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 307, 313 ] ], "normalized": [] }, { "id": "PMID-10890377_T13", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 438, 443 ] ], "normalized": [] }, { "id": "PMID-10890377_T14", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 454, 463 ] ], "normalized": [] }, { "id": "PMID-10890377_T15", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 465, 469 ] ], "normalized": [] }, { "id": "PMID-10890377_T16", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 471, 476 ] ], "normalized": [] }, { "id": "PMID-10890377_T17", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "PMID-10890377_T18", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 526, 534 ] ], "normalized": [] }, { "id": "PMID-10890377_T19", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 549, 557 ] ], "normalized": [] }, { "id": "PMID-10890377_T20", "type": "Organism", "text": [ "Patients" ], "offsets": [ [ 598, 606 ] ], "normalized": [] }, { "id": "PMID-10890377_T21", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 612, 617 ] ], "normalized": [] }, { "id": "PMID-10890377_T22", "type": "Organ", "text": [ "bone" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMID-10890377_T23", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 691, 700 ] ], "normalized": [] }, { "id": "PMID-10890377_T24", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-10890377_T25", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "PMID-10890377_T26", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "PMID-10890377_T27", "type": "Multi-tissue_structure", "text": [ "nodal" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "PMID-10890377_T28", "type": "Organ", "text": [ "lung" ], "offsets": [ [ 757, 761 ] ], "normalized": [] }, { "id": "PMID-10890377_T29", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 794, 799 ] ], "normalized": [] }, { "id": "PMID-10890377_T30", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 857, 866 ] ], "normalized": [] }, { "id": "PMID-10890377_T31", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 1004, 1013 ] ], "normalized": [] }, { "id": "PMID-10890377_T32", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 1140, 1149 ] ], "normalized": [] }, { "id": "PMID-10890377_T33", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1186, 1191 ] ], "normalized": [] }, { "id": "PMID-10890377_T34", "type": "Gene_or_gene_product", "text": [ "S-100beta" ], "offsets": [ [ 1202, 1211 ] ], "normalized": [] }, { "id": "PMID-10890377_T35", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "PMID-10890377_T36", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 1222, 1227 ] ], "normalized": [] }, { "id": "PMID-10890377_T37", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 1247, 1252 ] ], "normalized": [] }, { "id": "PMID-10890377_T38", "type": "Organ", "text": [ "bone" ], "offsets": [ [ 1256, 1260 ] ], "normalized": [] }, { "id": "PMID-10890377_T39", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 1275, 1283 ] ], "normalized": [] }, { "id": "PMID-10890377_T40", "type": 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[]

[ { "id": "PMID-8633524__text", "type": "abstract", "text": [ "Pancreatic somatostatin-secreting gangliocytic paraganglioma with lymph node metastases. \nGangliocytic paraganglioma (GPG) with local lymph node metastasis was found in the pancreas of a 74-yr-old female who presented with diarrhea, steatorrhea, vomiting, nausea, and abdominal pain. A Whipple procedure led to a complete resolution of these symptoms and a return of an elevated stomatostatin level to normal. This is the first description of GPG in this location and the first endocrinologically active GPG.\n" ], "offsets": [ [ 0, 509 ] ] } ]

[ { "id": "PMID-8633524_T1", "type": "Organ", "text": [ "Pancreatic" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-8633524_T2", "type": "Gene_or_gene_product", "text": [ "somatostatin" ], "offsets": [ [ 11, 23 ] ], "normalized": [] }, { "id": "PMID-8633524_T3", "type": "Cancer", "text": [ "gangliocytic paraganglioma" ], "offsets": [ [ 34, 60 ] ], "normalized": [] }, { "id": "PMID-8633524_T4", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 66, 76 ] ], "normalized": [] }, { "id": "PMID-8633524_T5", "type": "Cancer", "text": [ "Gangliocytic paraganglioma" ], "offsets": [ [ 90, 116 ] ], "normalized": [] }, { "id": "PMID-8633524_T6", "type": "Cancer", "text": [ "GPG" ], "offsets": [ [ 118, 121 ] ], "normalized": [] }, { "id": "PMID-8633524_T7", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 134, 144 ] ], "normalized": [] }, { "id": "PMID-8633524_T8", "type": "Organ", "text": [ "pancreas" ], "offsets": [ [ 173, 181 ] ], "normalized": [] }, { "id": "PMID-8633524_T9", "type": "Organism", "text": [ "female" ], "offsets": [ [ 197, 203 ] ], "normalized": [] }, { "id": "PMID-8633524_T10", "type": "Organism_subdivision", "text": [ "abdominal" ], "offsets": [ [ 268, 277 ] ], "normalized": [] }, { "id": "PMID-8633524_T11", "type": "Gene_or_gene_product", "text": [ "stomatostatin" ], "offsets": [ [ 379, 392 ] ], "normalized": [] }, { "id": "PMID-8633524_T12", "type": "Cancer", "text": [ "GPG" ], "offsets": [ [ 443, 446 ] ], "normalized": [] }, { "id": "PMID-8633524_T13", "type": "Cancer", "text": [ "GPG" ], "offsets": [ [ 504, 507 ] ], "normalized": [] } ]

[ { "id": "PMID-8633524_E1", "type": "Localization", "trigger": { "text": [ "secreting" ], "offsets": [ [ 24, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8633524_T2" } ] }, { "id": "PMID-8633524_E2", "type": "Metastasis", "trigger": { "text": [ "metastases" ], "offsets": [ [ 77, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8633524_T3" }, { "role": "ToLoc", "ref_id": "PMID-8633524_T4" } ] }, { "id": "PMID-8633524_E3", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 145, 155 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-8633524_T7" }, { "role": "Theme", "ref_id": "PMID-8633524_T5" } ] }, { "id": "PMID-8633524_E4", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 370, 378 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8633524_T11" } ] } ]

[ { "id": "PMID-8633524_1", "entity_ids": [ "PMID-8633524_T5", "PMID-8633524_T6" ] } ]

[]

[ { "id": "PMID-3027568__text", "type": "abstract", "text": [ "Elevated levels of diacylglycerol and decreased phorbol ester sensitivity in ras-transformed fibroblasts. \nDiacylglycerol (DG) plays a central role in phospholipid metabolism and is an endogenous activator of protein kinase C. We have suggested that constitutive activation of this kinase is one mechanism by which oncogenes transform cells. The ras-encoded proteins are similar to regulatory G-proteins and are candidates for the unknown G-protein that modulates phosphatidylinositol (PI) turnover. Differences in polyphosphoinositide metabolism have been reported for ras-transformed cells. But because these experiments were performed on confluent cultures of established cell lines, the differences are difficult to attribute to ras transformation. Here we show that exponentially growing NIH 3T3 fibroblasts recently transformed by Ha-ras or Ki-ras possess elevated DG concentrations without significant alterations in the levels of other polyphosphoinositide metabolites. The basal phosphorylation of protein kinase C substrate of relative molecular mass (Mr) 80,000 (80K) is significantly increased in all the ras-transformed cell lines. Surprisingly, however, further phosphorylation of this protein on addition of phorbol ester was greatly reduced. Ha-ras cells also show less binding of phorbol ester than control cells, suggesting that elevation of DG causes partial down-regulation in addition to activation of protein kinase C.\n" ], "offsets": [ [ 0, 1441 ] ] } ]

[ { "id": "PMID-3027568_T1", "type": "Simple_chemical", "text": [ "diacylglycerol" ], "offsets": [ [ 19, 33 ] ], "normalized": [] }, { "id": "PMID-3027568_T2", "type": "Simple_chemical", "text": [ "phorbol ester" ], "offsets": [ [ 48, 61 ] ], "normalized": [] }, { "id": "PMID-3027568_T3", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 77, 80 ] ], "normalized": [] }, { "id": "PMID-3027568_T4", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 93, 104 ] ], "normalized": [] }, { "id": "PMID-3027568_T5", "type": "Simple_chemical", "text": [ "Diacylglycerol" ], "offsets": [ [ 107, 121 ] ], "normalized": [] }, { "id": "PMID-3027568_T6", "type": "Simple_chemical", "text": [ "DG" ], "offsets": [ [ 123, 125 ] ], "normalized": [] }, { "id": "PMID-3027568_T7", "type": "Simple_chemical", "text": [ "phospholipid" ], "offsets": [ [ 151, 163 ] ], "normalized": [] }, { "id": "PMID-3027568_T8", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 209, 225 ] ], "normalized": [] }, { "id": "PMID-3027568_T9", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 335, 340 ] ], "normalized": [] }, { "id": "PMID-3027568_T10", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 346, 349 ] ], "normalized": [] }, { "id": "PMID-3027568_T11", "type": "Gene_or_gene_product", "text": [ "G-proteins" ], "offsets": [ [ 393, 403 ] ], "normalized": [] }, { "id": "PMID-3027568_T12", "type": "Gene_or_gene_product", "text": [ "G-protein" ], "offsets": [ [ 439, 448 ] ], "normalized": [] }, { "id": "PMID-3027568_T13", "type": "Simple_chemical", "text": [ "phosphatidylinositol" ], "offsets": [ [ 464, 484 ] ], "normalized": [] }, { "id": "PMID-3027568_T14", "type": "Simple_chemical", "text": [ "PI" ], "offsets": [ [ 486, 488 ] ], "normalized": [] }, { "id": "PMID-3027568_T15", "type": "Simple_chemical", "text": [ "polyphosphoinositide" ], "offsets": [ [ 515, 535 ] ], "normalized": [] }, { "id": "PMID-3027568_T16", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 570, 573 ] ], "normalized": [] }, { "id": "PMID-3027568_T17", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "PMID-3027568_T18", "type": "Cell", "text": [ "cell lines" ], "offsets": [ [ 675, 685 ] ], "normalized": [] }, { "id": "PMID-3027568_T19", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 733, 736 ] ], "normalized": [] }, { "id": "PMID-3027568_T20", "type": "Cell", "text": [ "NIH 3T3 fibroblasts" ], "offsets": [ [ 793, 812 ] ], "normalized": [] }, { "id": "PMID-3027568_T21", "type": "Gene_or_gene_product", "text": [ "Ha-ras" ], "offsets": [ [ 837, 843 ] ], "normalized": [] }, { "id": "PMID-3027568_T22", "type": "Gene_or_gene_product", "text": [ "Ki-ras" ], "offsets": [ [ 847, 853 ] ], "normalized": [] }, { "id": "PMID-3027568_T23", "type": "Simple_chemical", "text": [ "DG" ], "offsets": [ [ 871, 873 ] ], "normalized": [] }, { "id": "PMID-3027568_T24", "type": "Simple_chemical", "text": [ "polyphosphoinositide" ], "offsets": [ [ 944, 964 ] ], "normalized": [] }, { "id": "PMID-3027568_T25", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1007, 1023 ] ], "normalized": [] }, { "id": "PMID-3027568_T26", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 1117, 1120 ] ], "normalized": [] }, { "id": "PMID-3027568_T27", "type": "Cell", "text": [ "cell lines" ], "offsets": [ [ 1133, 1143 ] ], "normalized": [] }, { "id": "PMID-3027568_T28", "type": "Simple_chemical", "text": [ "phorbol ester" ], "offsets": [ [ 1223, 1236 ] ], "normalized": [] }, { "id": "PMID-3027568_T29", "type": "Gene_or_gene_product", "text": [ "Ha-ras" ], "offsets": [ [ 1258, 1264 ] ], "normalized": [] }, { "id": "PMID-3027568_T30", "type": "Cell", "text": [ "Ha-ras cells" ], "offsets": [ [ 1258, 1270 ] ], "normalized": [] }, { "id": "PMID-3027568_T31", "type": "Simple_chemical", "text": [ "phorbol ester" ], "offsets": [ [ 1297, 1310 ] ], "normalized": [] }, { "id": "PMID-3027568_T32", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1324, 1329 ] ], "normalized": [] }, { "id": "PMID-3027568_T33", "type": "Simple_chemical", "text": [ "DG" ], "offsets": [ [ 1360, 1362 ] ], "normalized": [] }, { "id": "PMID-3027568_T34", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1423, 1439 ] ], "normalized": [] } ]

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[ { "id": "PMID-3027568_1", "entity_ids": [ "PMID-3027568_T5", "PMID-3027568_T6" ] }, { "id": "PMID-3027568_2", "entity_ids": [ "PMID-3027568_T13", "PMID-3027568_T14" ] } ]

[]

[ { "id": "PMID-16740157__text", "type": "abstract", "text": [ "Hyperfibrinogenemia is associated with lymphatic as well as hematogenous metastasis and worse clinical outcome in T2 gastric cancer. \nBACKGROUND: Abnormal hemostasis in cancer patients has previously been described, however the correlation between the plasma fibrinogen level and cancer metastasis and prognosis has not been reported in a large-scale clinical study. METHODS: Preoperative plasma fibrinogen levels were retrospectively examined in 405 patients who underwent surgery for advanced gastric cancer. The association of fibrinogen levels with clinical/pathological findings and clinical outcome was evaluated. RESULTS: There was a positive correlation between plasma fibrinogen levels and the depth of invasion (p < 0.05). Hyperfibrinogenemia (>310 mg/dl) was independently associated with lymph node (Odds Ratio; 2.342, P = 0.0032) and liver (Odds Ratio; 2.933, P = 0.0147) metastasis, not with peritoneal metastasis in this series. Patients with hyperfibrinogenemia showed worse clinical outcome in T2 gastric cancer, however, there was no correlation of plasma fibrinogen level with prognosis in T3/T4 gastric cancer. CONCLUSION: Our results might support the idea that hyperfibrinogenemia can augment lymphatic and hematogeneous metastasis of advanced gastric cancer, which is major determinant of the prognosis in T2 gastric cancer. Therefore, in the situation without peritoneal involvement, hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome in T2 gastric cancer.\n" ], "offsets": [ [ 0, 1534 ] ] } ]

[ { "id": "PMID-16740157_T1", "type": "Multi-tissue_structure", "text": [ "lymphatic" ], "offsets": [ [ 39, 48 ] ], "normalized": [] }, { "id": "PMID-16740157_T2", "type": "Cancer", "text": [ "T2 gastric cancer" ], "offsets": [ [ 114, 131 ] ], "normalized": [] }, { "id": "PMID-16740157_T3", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 169, 175 ] ], "normalized": [] }, { "id": "PMID-16740157_T4", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 176, 184 ] ], "normalized": [] }, { "id": "PMID-16740157_T5", "type": "Organism_substance", "text": [ "plasma" ], "offsets": [ [ 252, 258 ] ], "normalized": [] }, { "id": "PMID-16740157_T6", "type": "Gene_or_gene_product", "text": [ "fibrinogen" ], "offsets": [ [ 259, 269 ] ], "normalized": [] }, { "id": "PMID-16740157_T7", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 280, 286 ] ], "normalized": [] }, { "id": "PMID-16740157_T8", "type": "Organism_substance", "text": [ "plasma" ], "offsets": [ [ 389, 395 ] ], "normalized": [] }, { "id": "PMID-16740157_T9", "type": "Gene_or_gene_product", "text": [ "fibrinogen" ], "offsets": [ [ 396, 406 ] ], "normalized": [] }, { "id": "PMID-16740157_T10", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 451, 459 ] ], "normalized": [] }, { "id": "PMID-16740157_T11", "type": "Cancer", "text": [ "gastric cancer" ], "offsets": [ [ 495, 509 ] ], "normalized": [] }, { "id": "PMID-16740157_T12", "type": "Gene_or_gene_product", "text": [ "fibrinogen" ], "offsets": [ [ 530, 540 ] ], "normalized": [] }, { "id": "PMID-16740157_T13", "type": "Organism_substance", "text": [ "plasma" ], "offsets": [ [ 670, 676 ] ], "normalized": [] }, { "id": "PMID-16740157_T14", "type": "Gene_or_gene_product", "text": [ "fibrinogen" ], "offsets": [ [ 677, 687 ] ], "normalized": [] }, { "id": "PMID-16740157_T15", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 800, 810 ] ], "normalized": [] }, { "id": "PMID-16740157_T16", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 847, 852 ] ], "normalized": [] }, { "id": "PMID-16740157_T17", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 906, 916 ] ], "normalized": [] }, { "id": "PMID-16740157_T18", "type": "Organism", "text": [ "Patients" ], "offsets": [ [ 944, 952 ] ], "normalized": [] }, { "id": "PMID-16740157_T19", "type": "Cancer", "text": [ "T2 gastric cancer" ], "offsets": [ [ 1011, 1028 ] ], "normalized": [] }, { "id": "PMID-16740157_T20", "type": "Organism_substance", "text": [ "plasma" ], "offsets": [ [ 1067, 1073 ] ], "normalized": [] }, { "id": "PMID-16740157_T21", "type": "Gene_or_gene_product", "text": [ "fibrinogen" ], "offsets": [ [ 1074, 1084 ] ], "normalized": [] }, { "id": "PMID-16740157_T22", "type": "Cancer", "text": [ "T3/T4 gastric cancer" ], "offsets": [ [ 1109, 1129 ] ], "normalized": [] }, { "id": "PMID-16740157_T23", "type": "Cell", "text": [ "lymphatic" ], "offsets": [ [ 1215, 1224 ] ], "normalized": [] }, { "id": "PMID-16740157_T24", "type": "Cancer", "text": [ "gastric cancer" ], "offsets": [ [ 1266, 1280 ] ], "normalized": [] }, { "id": "PMID-16740157_T25", "type": "Cancer", "text": [ "T2 gastric cancer" ], "offsets": [ [ 1329, 1346 ] ], "normalized": [] }, { "id": "PMID-16740157_T26", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 1384, 1394 ] ], "normalized": [] }, { "id": "PMID-16740157_T27", "type": "Cancer", "text": [ "T2 gastric cancer" ], "offsets": [ [ 1515, 1532 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-16893130__text", "type": "abstract", "text": [ "[Autologous bone marrow stem cell or peripheral blood endothelial progenitor cell therapy in patients with peripheral limb ischaemia]\nNo effective medical therapies have been developed sofar to enhance blood flow in the legs of patients with peripheral arterial disease (PAD). For patients with limb threatening ischaemia the only option for relief of rest pain or gangraena is amputation. There is evidence in experimental and clinical studies that adult bone marrow-derived stem cells and endothelial progenitor cells participate in the development of new blood vessels, called neoangiogenesis or neovascularization. Clinical results induced by autologous bone marrow stem cells or angiogenic growth/differentiation factors in end-stage patients with PAD are summarized. Considering the relatively few number of patients treated by angiogenic therapy, the interpretation of clinical results needs cautiousness.\n" ], "offsets": [ [ 0, 913 ] ] } ]

[ { "id": "PMID-16893130_T1", "type": "Cell", "text": [ "bone marrow stem cell" ], "offsets": [ [ 12, 33 ] ], "normalized": [] }, { "id": "PMID-16893130_T2", "type": "Cell", "text": [ "peripheral blood endothelial progenitor cell" ], "offsets": [ [ 37, 81 ] ], "normalized": [] }, { "id": "PMID-16893130_T3", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 93, 101 ] ], "normalized": [] }, { "id": "PMID-16893130_T4", "type": "Organism_subdivision", "text": [ "limb" ], "offsets": [ [ 118, 122 ] ], "normalized": [] }, { "id": "PMID-16893130_T5", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 202, 207 ] ], "normalized": [] }, { "id": "PMID-16893130_T6", "type": "Organism_subdivision", "text": [ "legs" ], "offsets": [ [ 220, 224 ] ], "normalized": [] }, { "id": "PMID-16893130_T7", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 228, 236 ] ], "normalized": [] }, { "id": "PMID-16893130_T8", "type": "Multi-tissue_structure", "text": [ "peripheral arterial" ], "offsets": [ [ 242, 261 ] ], "normalized": [] }, { "id": "PMID-16893130_T9", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 281, 289 ] ], "normalized": [] }, { "id": "PMID-16893130_T10", "type": "Organism_subdivision", "text": [ "limb" ], "offsets": [ [ 295, 299 ] ], "normalized": [] }, { "id": "PMID-16893130_T11", "type": "Cell", "text": [ "bone marrow-derived stem cells" ], "offsets": [ [ 456, 486 ] ], "normalized": [] }, { "id": "PMID-16893130_T12", "type": "Cell", "text": [ "endothelial progenitor cells" ], "offsets": [ [ 491, 519 ] ], "normalized": [] }, { "id": "PMID-16893130_T13", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 558, 571 ] ], "normalized": [] }, { "id": "PMID-16893130_T14", "type": "Cell", "text": [ "bone marrow stem cells" ], "offsets": [ [ 658, 680 ] ], "normalized": [] }, { "id": "PMID-16893130_T15", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 739, 747 ] ], "normalized": [] }, { "id": "PMID-16893130_T16", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 814, 822 ] ], "normalized": [] } ]

[ { "id": "PMID-16893130_E1", "type": "Planned_process", "trigger": { "text": [ "therapy" ], "offsets": [ [ 82, 89 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16893130_T3" }, { "role": "Instrument", "ref_id": "PMID-16893130_T2" } ] }, { "id": "PMID-16893130_E2", "type": "Planned_process", "trigger": { "text": [ "therapy" ], "offsets": [ [ 82, 89 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16893130_T3" }, { "role": "Instrument", "ref_id": "PMID-16893130_T1" } ] }, { "id": "PMID-16893130_E3", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 539, 550 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16893130_T13" } ] }, { "id": "PMID-16893130_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 580, 595 ] ] }, "arguments": [] }, { "id": "PMID-16893130_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 599, 617 ] ] }, "arguments": [] }, { "id": "PMID-16893130_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 684, 694 ] ] }, "arguments": [] }, { "id": "PMID-16893130_E7", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 823, 830 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16893130_T16" } ] }, { "id": "PMID-16893130_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 834, 844 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-19050907__text", "type": "abstract", "text": [ "Evaluation of electrical stimulation for ischemic wound therapy: a feasibility study using the lapine wound model.\nChronic wounds are a major secondary complication for many people with impaired mobility. Electrical stimulation (ES) has been recommended as a adjunctive therapy, however optimal treatment paradigms have not been established. Our group seeks to determine the basic mechanisms underlying ES wound therapy, an area where understanding is currently limited. A feasibility study was carried out to develop the Ahn/Mustoe lapine wound model for systematic investigation of the effects of electrical stimulation on ischemic wound therapy. A standardized surgical procedure incorporated a hybrid stimulation system comprising an implantable mini-stimulator and surface electrodes, with creation of repeatable ischemic wounds. Twenty mature male New Zealand white rabbits (3 kg weight) were employed to evaluate the effects of two empirically selected stimulation paradigms applied continuously for 7-21 days, using each animal as its own control. Outcomes measures included transcutaneous blood gas levels, histology, total RNA content and analysis of alpha2 (I) collagen (COL-I), type IV collagen (COL-IV), alpha1 (V) collagen (COL-V), and vascular endothelial growth factor (VEGF) expression using real-time quantitative PCR. All markers for stimulated wounds showed increased activity relative to non-stimulated control wounds between 7 and 14 days following injury, with peak activity at 14 days. By 21 days post-injury, all activity had returned to near baseline level. VEGF and COL-IV levels were found to be significantly higher for pattern A (110 mus pulse width) compared to pattern B (5 mus pulse width) at 14 days, implying that pattern A may be more effective at promoting angiogenesis. All wounds were fully re-epithelialized by 10 days post-injury. Both COL-I and COL-V showed statistically significant (P less than 0.05) increased activity between day 7 and day 14 for pattern A, potentially indicating a continued effect on matrix remodeling. The early closure of all wounds implies that the rabbit ear model may not be valid for chronic wound studies.\n" ], "offsets": [ [ 0, 2180 ] ] } ]

[ { "id": "PMID-19050907_T1", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 50, 55 ] ], "normalized": [] }, { "id": "PMID-19050907_T2", "type": "Organism", "text": [ "lapine" ], "offsets": [ [ 95, 101 ] ], "normalized": [] }, { "id": "PMID-19050907_T3", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 102, 107 ] ], "normalized": [] }, { "id": "PMID-19050907_T4", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 123, 129 ] ], "normalized": [] }, { "id": "PMID-19050907_T5", "type": "Organism", "text": [ "people" ], "offsets": [ [ 174, 180 ] ], "normalized": [] }, { "id": "PMID-19050907_T6", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 406, 411 ] ], "normalized": [] }, { "id": "PMID-19050907_T7", "type": "Organism", "text": [ "lapine" ], "offsets": [ [ 533, 539 ] ], "normalized": [] }, { "id": "PMID-19050907_T8", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 540, 545 ] ], "normalized": [] }, { "id": "PMID-19050907_T9", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 634, 639 ] ], "normalized": [] }, { "id": "PMID-19050907_T10", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 827, 833 ] ], "normalized": [] }, { "id": "PMID-19050907_T11", "type": "Organism", "text": [ "rabbits" ], "offsets": [ [ 872, 879 ] ], "normalized": [] }, { "id": "PMID-19050907_T12", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 1098, 1103 ] ], "normalized": [] }, { "id": "PMID-19050907_T13", "type": "Gene_or_gene_product", "text": [ "alpha2 (I) collagen" ], "offsets": [ [ 1161, 1180 ] ], "normalized": [] }, { "id": "PMID-19050907_T14", "type": "Gene_or_gene_product", "text": [ "COL-I" ], "offsets": [ [ 1182, 1187 ] ], "normalized": [] }, { "id": "PMID-19050907_T15", "type": "Gene_or_gene_product", "text": [ "type IV collagen" ], "offsets": [ [ 1190, 1206 ] ], "normalized": [] }, { "id": "PMID-19050907_T16", "type": "Gene_or_gene_product", "text": [ "COL-IV" ], "offsets": [ [ 1208, 1214 ] ], "normalized": [] }, { "id": "PMID-19050907_T17", "type": "Gene_or_gene_product", "text": [ "alpha1 (V) collagen" ], "offsets": [ [ 1217, 1236 ] ], "normalized": [] }, { "id": "PMID-19050907_T18", "type": "Gene_or_gene_product", "text": [ "COL-V" ], "offsets": [ [ 1238, 1243 ] ], "normalized": [] }, { "id": "PMID-19050907_T19", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1250, 1284 ] ], "normalized": [] }, { "id": "PMID-19050907_T20", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1286, 1290 ] ], "normalized": [] }, { "id": "PMID-19050907_T21", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 1364, 1370 ] ], "normalized": [] }, { "id": "PMID-19050907_T22", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 1432, 1438 ] ], "normalized": [] }, { "id": "PMID-19050907_T23", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1584, 1588 ] ], "normalized": [] }, { "id": "PMID-19050907_T24", "type": "Gene_or_gene_product", "text": [ "COL-IV" ], "offsets": [ [ 1593, 1599 ] ], "normalized": [] }, { "id": "PMID-19050907_T25", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 1812, 1818 ] ], "normalized": [] }, { "id": "PMID-19050907_T26", "type": "Gene_or_gene_product", "text": [ "COL-I" ], "offsets": [ [ 1877, 1882 ] ], "normalized": [] }, { "id": "PMID-19050907_T27", "type": "Gene_or_gene_product", "text": [ "COL-V" ], "offsets": [ [ 1887, 1892 ] ], "normalized": [] }, { "id": "PMID-19050907_T28", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 2051, 2057 ] ], "normalized": [] }, { "id": "PMID-19050907_T29", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 2095, 2101 ] ], "normalized": [] }, { "id": "PMID-19050907_T30", "type": "Organism", "text": [ "rabbit" ], "offsets": [ [ 2119, 2125 ] ], "normalized": [] }, { "id": "PMID-19050907_T31", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 2126, 2129 ] ], "normalized": [] }, { "id": "PMID-19050907_T32", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 2165, 2170 ] ], "normalized": [] } ]

[ { "id": "PMID-19050907_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1292, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T19" } ] }, { "id": "PMID-19050907_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1292, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T17" } ] }, { "id": "PMID-19050907_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1292, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T15" } ] }, { "id": "PMID-19050907_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1292, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T13" } ] }, { "id": "PMID-19050907_E5", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 1784, 1793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_E6" } ] }, { "id": "PMID-19050907_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1794, 1806 ] ] }, "arguments": [] }, { "id": "PMID-19050907_E7", "type": "Positive_regulation", "trigger": { "text": [ "activity" ], "offsets": [ [ 1957, 1965 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T27" } ] }, { "id": "PMID-19050907_E8", "type": "Positive_regulation", "trigger": { "text": [ "activity" ], "offsets": [ [ 1957, 1965 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T26" } ] }, { "id": "PMID-19050907_E9", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 2041, 2047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_E11" }, { "role": "Cause", "ref_id": "PMID-19050907_T27" } ] }, { "id": "PMID-19050907_E10", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 2041, 2047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_E11" }, { "role": "Cause", "ref_id": "PMID-19050907_T26" } ] }, { "id": "PMID-19050907_E11", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 2058, 2068 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19050907_T28" } ] } ]

[ { "id": "PMID-19050907_1", "entity_ids": [ "PMID-19050907_T13", "PMID-19050907_T14" ] }, { "id": "PMID-19050907_2", "entity_ids": [ "PMID-19050907_T15", "PMID-19050907_T16" ] }, { "id": "PMID-19050907_3", "entity_ids": [ "PMID-19050907_T17", "PMID-19050907_T18" ] }, { "id": "PMID-19050907_4", "entity_ids": [ "PMID-19050907_T19", "PMID-19050907_T20" ] } ]

[]

[ { "id": "PMID-19422607__text", "type": "abstract", "text": [ "Met amplification and tumor progression in Cdkn2a-deficient melanocytes. \nWhile many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen-activated protein kinase signaling pathway. In this study, we used a Cdkn2a-deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a-deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency.\n" ], "offsets": [ [ 0, 1076 ] ] } ]

[ { "id": "PMID-19422607_T1", "type": "Gene_or_gene_product", "text": [ "Met" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-19422607_T2", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 22, 27 ] ], "normalized": [] }, { "id": "PMID-19422607_T3", "type": "Gene_or_gene_product", "text": [ "Cdkn2a" ], "offsets": [ [ 43, 49 ] ], "normalized": [] }, { "id": "PMID-19422607_T4", "type": "Cell", "text": [ "Cdkn2a-deficient melanocytes" ], "offsets": [ [ 43, 71 ] ], "normalized": [] }, { "id": "PMID-19422607_T5", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 129, 137 ] ], "normalized": [] }, { "id": "PMID-19422607_T6", "type": "Organism", "text": [ "human" ], "offsets": [ [ 244, 249 ] ], "normalized": [] }, { "id": "PMID-19422607_T7", "type": "Cancer", "text": [ "melanomas" ], "offsets": [ [ 250, 259 ] ], "normalized": [] }, { "id": "PMID-19422607_T8", "type": "Gene_or_gene_product", "text": [ "CDKN2A" ], "offsets": [ [ 294, 300 ] ], "normalized": [] }, { "id": "PMID-19422607_T9", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 350, 382 ] ], "normalized": [] }, { "id": "PMID-19422607_T10", "type": "Gene_or_gene_product", "text": [ "Cdkn2a" ], "offsets": [ [ 427, 433 ] ], "normalized": [] }, { "id": "PMID-19422607_T11", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 444, 449 ] ], "normalized": [] }, { "id": "PMID-19422607_T12", "type": "Cell", "text": [ "melanocyte cell line" ], "offsets": [ [ 450, 470 ] ], "normalized": [] }, { "id": "PMID-19422607_T13", "type": "Cancer", "text": [ "melanoma tumor" ], "offsets": [ [ 513, 527 ] ], "normalized": [] }, { "id": "PMID-19422607_T14", "type": "Cellular_component", "text": [ "intrachromosomal" ], "offsets": [ [ 561, 577 ] ], "normalized": [] }, { "id": "PMID-19422607_T15", "type": "Gene_or_gene_product", "text": [ "Met" ], "offsets": [ [ 600, 603 ] ], "normalized": [] }, { "id": "PMID-19422607_T16", "type": "Amino_acid", "text": [ "tyrosine" ], "offsets": [ [ 616, 624 ] ], "normalized": [] }, { "id": "PMID-19422607_T17", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 646, 654 ] ], "normalized": [] }, { "id": "PMID-19422607_T18", "type": "Gene_or_gene_product", "text": [ "Cdkn2a" ], "offsets": [ [ 686, 692 ] ], "normalized": [] }, { "id": "PMID-19422607_T19", "type": "Cancer", "text": [ "Cdkn2a-deficient tumors" ], "offsets": [ [ 686, 709 ] ], "normalized": [] }, { "id": "PMID-19422607_T20", "type": "Gene_or_gene_product", "text": [ "Met" ], "offsets": [ [ 738, 741 ] ], "normalized": [] }, { "id": "PMID-19422607_T21", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 751, 762 ] ], "normalized": [] }, { "id": "PMID-19422607_T22", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 798, 803 ] ], "normalized": [] }, { "id": "PMID-19422607_T23", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 845, 850 ] ], "normalized": [] }, { "id": "PMID-19422607_T24", "type": "Gene_or_gene_product", "text": [ "MET" ], "offsets": [ [ 852, 855 ] ], "normalized": [] }, { "id": "PMID-19422607_T25", "type": "Organism", "text": [ "human" ], "offsets": [ [ 897, 902 ] ], "normalized": [] }, { "id": "PMID-19422607_T26", "type": "Cancer", "text": [ "melanoma" ], "offsets": [ [ 903, 911 ] ], "normalized": [] }, { "id": "PMID-19422607_T27", "type": "Cancer", "text": [ "metastatic disease" ], "offsets": [ [ 942, 960 ] ], "normalized": [] }, { "id": "PMID-19422607_T28", "type": "Gene_or_gene_product", "text": [ "Met" ], "offsets": [ [ 994, 997 ] ], "normalized": [] }, { "id": "PMID-19422607_T29", "type": "Cancer", "text": [ "melanoma tumor" ], "offsets": [ [ 1012, 1026 ] ], "normalized": [] }, { "id": "PMID-19422607_T30", "type": "Gene_or_gene_product", "text": [ "Cdkn2a" ], "offsets": [ [ 1057, 1063 ] ], "normalized": [] } ]

[ { "id": "PMID-19422607_E1", "type": "Mutation", "trigger": { "text": [ "amplification" ], "offsets": [ [ 4, 17 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T1" } ] }, { "id": "PMID-19422607_E2", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 28, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T2" } ] }, { "id": "PMID-19422607_E3", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 50, 59 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T3" } ] }, { "id": "PMID-19422607_E4", "type": "Mutation", "trigger": { "text": [ "genetic alterations" ], "offsets": [ [ 85, 104 ] ] }, "arguments": [] }, { "id": "PMID-19422607_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 276, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T8" } ] }, { "id": "PMID-19422607_E6", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 322, 332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_E7" } ] }, { "id": "PMID-19422607_E7", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 383, 400 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19422607_T9" } ] }, { "id": "PMID-19422607_E8", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 434, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T10" } ] }, { "id": "PMID-19422607_E9", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 528, 539 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T13" } ] }, { "id": "PMID-19422607_E10", "type": "Mutation", "trigger": { "text": [ "gene amplification" ], "offsets": [ [ 578, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T15" } ] }, { "id": "PMID-19422607_E11", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 655, 666 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T17" } ] }, { "id": "PMID-19422607_E12", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 693, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T18" } ] }, { "id": "PMID-19422607_E13", "type": "Planned_process", "trigger": { "text": [ "RNA interference" ], "offsets": [ [ 711, 727 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19422607_T20" }, { "role": "Theme", "ref_id": "PMID-19422607_T21" } ] }, { "id": "PMID-19422607_E14", "type": "Negative_regulation", "trigger": { "text": [ "delay" ], "offsets": [ [ 789, 794 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_E15" } ] }, { "id": "PMID-19422607_E15", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 804, 810 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T22" } ] }, { "id": "PMID-19422607_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 856, 866 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T24" } ] }, { "id": "PMID-19422607_E17", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 985, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_E19" }, { "role": "Cause", "ref_id": "PMID-19422607_E18" } ] }, { "id": "PMID-19422607_E18", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 998, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T28" } ] }, { "id": "PMID-19422607_E19", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 1027, 1038 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T29" } ] }, { "id": "PMID-19422607_E20", "type": "Gene_expression", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 1064, 1074 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19422607_T30" } ] } ]

[]

[]

[ { "id": "PMID-7566959__text", "type": "abstract", "text": [ "Bicistronic retroviral vector reveals capacity of v-erbA to induce erythroleukemia and to co-operate with v-myb. \nPrevious studies have shown that v-erbA and v-myb can induce the proliferation of avian erythroid cells in culture. To study the combined effects of v-erbA and v-myb, the two oncogenes were engineered into a retrovirus bicistronic vector with an internal ribosomal entry site (IRES) or into a vector with a splice acceptor (SPL). This allowed coexpression of the two proteins and a comparison with the same vector containing either v-erbA or v-myb only. Both the erbA IRES and the erbA/myb IRES virus constructs transformed erythroid cells after infection of bone marrow or blastoderm cultures. The erbA/myb IRES virus exhibited a 5-10-fold higher transformed colony forming efficiency than the erbA IRES virus in the blastoderm assay. Surprisingly, when injected into chicken embryos in the presence of helper virus, both viruses induced an erythroleukemia in about half of the animals. In contrast, no leukemia was observed with a myb IRES virus, with spliced vectors containing v-erbA alone or v-erbA in combination with v-myb, nor with erbA IRES and erbA/myb IRES viruses produced in the absence of helper virus. The average latency of leukemia induction was shorter for the erbA/myb IRES virus (3.5 weeks) than for the erbA IRES virus (5 weeks). Nevertheless, for both viruses the leukemic blasts retained full factor dependence for growth. These results show that v-erbA is capable of inducing an erythroleukemia when expressed by a high titer bicistronic retrovirus under conditions of virus spreading and that its in vitro and in vivo transforming potential can be enhanced by v-myb.\n" ], "offsets": [ [ 0, 1706 ] ] } ]

[ { "id": "PMID-7566959_T1", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 50, 56 ] ], "normalized": [] }, { "id": "PMID-7566959_T2", "type": "Cancer", "text": [ "erythroleukemia" ], "offsets": [ [ 67, 82 ] ], "normalized": [] }, { "id": "PMID-7566959_T3", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 106, 111 ] ], "normalized": [] }, { "id": "PMID-7566959_T4", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 147, 153 ] ], "normalized": [] }, { "id": "PMID-7566959_T5", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 158, 163 ] ], "normalized": [] }, { "id": "PMID-7566959_T6", "type": "Cell", "text": [ "erythroid cells" ], "offsets": [ [ 202, 217 ] ], "normalized": [] }, { "id": "PMID-7566959_T7", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 263, 269 ] ], "normalized": [] }, { "id": "PMID-7566959_T8", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 274, 279 ] ], "normalized": [] }, { "id": "PMID-7566959_T9", "type": "Cellular_component", "text": [ "ribosomal" ], "offsets": [ [ 369, 378 ] ], "normalized": [] }, { "id": "PMID-7566959_T10", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 546, 552 ] ], "normalized": [] }, { "id": "PMID-7566959_T11", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 556, 561 ] ], "normalized": [] }, { "id": "PMID-7566959_T12", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 577, 581 ] ], "normalized": [] }, { "id": "PMID-7566959_T13", "type": "Organism", "text": [ "erbA IRES" ], "offsets": [ [ 577, 586 ] ], "normalized": [] }, { "id": "PMID-7566959_T14", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 595, 599 ] ], "normalized": [] }, { "id": "PMID-7566959_T15", "type": "Organism", "text": [ "erbA/myb IRES virus" ], "offsets": [ [ 595, 614 ] ], "normalized": [] }, { "id": "PMID-7566959_T16", "type": "Gene_or_gene_product", "text": [ "myb" ], "offsets": [ [ 600, 603 ] ], "normalized": [] }, { "id": "PMID-7566959_T17", "type": "Cell", "text": [ "erythroid cells" ], "offsets": [ [ 638, 653 ] ], "normalized": [] }, { "id": "PMID-7566959_T18", "type": "Multi-tissue_structure", "text": [ "bone marrow" ], "offsets": [ [ 673, 684 ] ], "normalized": [] }, { "id": "PMID-7566959_T19", "type": "Cell", "text": [ "blastoderm cultures" ], "offsets": [ [ 688, 707 ] ], "normalized": [] }, { "id": "PMID-7566959_T20", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 713, 717 ] ], "normalized": [] }, { "id": "PMID-7566959_T21", "type": "Organism", "text": [ "erbA/myb IRES virus" ], "offsets": [ [ 713, 732 ] ], "normalized": [] }, { "id": "PMID-7566959_T22", "type": "Gene_or_gene_product", "text": [ "myb" ], "offsets": [ [ 718, 721 ] ], "normalized": [] }, { "id": "PMID-7566959_T23", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "PMID-7566959_T24", "type": "Organism", "text": [ "erbA IRES virus" ], "offsets": [ [ 809, 824 ] ], "normalized": [] }, { "id": "PMID-7566959_T25", "type": "Cell", "text": [ "blastoderm" ], "offsets": [ [ 832, 842 ] ], "normalized": [] }, { "id": "PMID-7566959_T26", "type": "Organism", "text": [ "chicken" ], "offsets": [ [ 883, 890 ] ], "normalized": [] }, { "id": "PMID-7566959_T27", "type": "Developing_anatomical_structure", "text": [ "embryos" ], "offsets": [ [ 891, 898 ] ], "normalized": [] }, { "id": "PMID-7566959_T28", "type": "Cancer", "text": [ "erythroleukemia" ], "offsets": [ [ 956, 971 ] ], "normalized": [] }, { "id": "PMID-7566959_T29", "type": "Cancer", "text": [ "leukemia" ], "offsets": [ [ 1018, 1026 ] ], "normalized": [] }, { "id": "PMID-7566959_T30", "type": "Gene_or_gene_product", "text": [ "myb" ], "offsets": [ [ 1047, 1050 ] ], "normalized": [] }, { "id": "PMID-7566959_T31", "type": "Organism", "text": [ "myb IRES virus" ], "offsets": [ [ 1047, 1061 ] ], "normalized": [] }, { "id": "PMID-7566959_T32", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 1095, 1101 ] ], "normalized": [] }, { "id": "PMID-7566959_T33", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 1111, 1117 ] ], "normalized": [] }, { "id": "PMID-7566959_T34", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 1138, 1143 ] ], "normalized": [] }, { "id": "PMID-7566959_T35", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 1154, 1158 ] ], "normalized": [] }, { "id": "PMID-7566959_T36", "type": "Organism", "text": [ "erbA IRES" ], "offsets": [ [ 1154, 1163 ] ], "normalized": [] }, { "id": "PMID-7566959_T37", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 1168, 1172 ] ], "normalized": [] }, { "id": "PMID-7566959_T38", "type": "Organism", "text": [ "erbA/myb IRES viruses" ], "offsets": [ [ 1168, 1189 ] ], "normalized": [] }, { "id": "PMID-7566959_T39", "type": "Gene_or_gene_product", "text": [ "myb" ], "offsets": [ [ 1173, 1176 ] ], "normalized": [] }, { "id": "PMID-7566959_T40", "type": "Cancer", "text": [ "leukemia" ], "offsets": [ [ 1254, 1262 ] ], "normalized": [] }, { "id": "PMID-7566959_T41", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 1293, 1297 ] ], "normalized": [] }, { "id": "PMID-7566959_T42", "type": "Organism", "text": [ "erbA/myb IRES virus" ], "offsets": [ [ 1293, 1312 ] ], "normalized": [] }, { "id": "PMID-7566959_T43", "type": "Gene_or_gene_product", "text": [ "myb" ], "offsets": [ [ 1298, 1301 ] ], "normalized": [] }, { "id": "PMID-7566959_T44", "type": "Gene_or_gene_product", "text": [ "erbA" ], "offsets": [ [ 1338, 1342 ] ], "normalized": [] }, { "id": "PMID-7566959_T45", "type": "Organism", "text": [ "erbA IRES virus" ], "offsets": [ [ 1338, 1353 ] ], "normalized": [] }, { "id": "PMID-7566959_T46", "type": "Cell", "text": [ "leukemic blasts" ], "offsets": [ [ 1400, 1415 ] ], "normalized": [] }, { "id": "PMID-7566959_T47", "type": "Gene_or_gene_product", "text": [ "v-erbA" ], "offsets": [ [ 1484, 1490 ] ], "normalized": [] }, { "id": "PMID-7566959_T48", "type": "Cancer", "text": [ "erythroleukemia" ], "offsets": [ [ 1517, 1532 ] ], "normalized": [] }, { "id": "PMID-7566959_T49", "type": "Gene_or_gene_product", "text": [ "v-myb" ], "offsets": [ [ 1699, 1704 ] ], "normalized": [] } ]

[ { "id": "PMID-7566959_E1", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 60, 66 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7566959_T1" }, { "role": "Theme", "ref_id": "PMID-7566959_T2" } ] }, { "id": "PMID-7566959_E2", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 168, 174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E4" }, { "role": "Cause", "ref_id": "PMID-7566959_T5" } ] }, { "id": "PMID-7566959_E3", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 168, 174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E4" }, { "role": "Cause", "ref_id": "PMID-7566959_T4" } ] }, { "id": "PMID-7566959_E4", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 179, 192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T6" } ] }, { "id": "PMID-7566959_E5", "type": "Planned_process", "trigger": { "text": [ "engineered" ], "offsets": [ [ 304, 314 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-7566959_T8" }, { "role": "Instrument", "ref_id": "PMID-7566959_T7" } ] }, { "id": "PMID-7566959_E6", "type": "Gene_expression", "trigger": { "text": [ "coexpression" ], "offsets": [ [ 457, 469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T7" }, { "role": "Theme", "ref_id": "PMID-7566959_T8" } ] }, { "id": "PMID-7566959_E7", "type": "Cell_transformation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 626, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T17" } ] }, { "id": "PMID-7566959_E8", "type": "Positive_regulation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 626, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E7" }, { "role": "Cause", "ref_id": "PMID-7566959_T15" } ] }, { "id": "PMID-7566959_E9", "type": "Positive_regulation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 626, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E7" }, { "role": "Cause", "ref_id": "PMID-7566959_T13" } ] }, { "id": "PMID-7566959_E10", "type": "Infection", "trigger": { "text": [ "infection" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T18" }, { "role": "Participant", "ref_id": "PMID-7566959_T15" } ] }, { "id": "PMID-7566959_E11", "type": "Infection", "trigger": { "text": [ "infection" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T19" }, { "role": "Participant", "ref_id": "PMID-7566959_T15" } ] }, { "id": "PMID-7566959_E12", "type": "Infection", "trigger": { "text": [ "infection" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T18" }, { "role": "Participant", "ref_id": "PMID-7566959_T13" } ] }, { "id": "PMID-7566959_E13", "type": "Infection", "trigger": { "text": [ "infection" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T19" }, { "role": "Participant", "ref_id": "PMID-7566959_T13" } ] }, { "id": "PMID-7566959_E14", "type": "Cell_transformation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 762, 773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T25" } ] }, { "id": "PMID-7566959_E15", "type": "Positive_regulation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 762, 773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E14" }, { "role": "Cause", "ref_id": "PMID-7566959_T21" } ] }, { "id": "PMID-7566959_E16", "type": "Positive_regulation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 762, 773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_E14" }, { "role": "Cause", "ref_id": "PMID-7566959_T24" } ] }, { "id": "PMID-7566959_E17", "type": "Planned_process", "trigger": { "text": [ "injected" ], "offsets": [ [ 869, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T27" } 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"Positive_regulation", "trigger": { "text": [ "capable" ], "offsets": [ [ 1494, 1501 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7566959_T47" }, { "role": "Theme", "ref_id": "PMID-7566959_E27" } ] }, { "id": "PMID-7566959_E27", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 1505, 1513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T48" } ] }, { "id": "PMID-7566959_E28", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1538, 1547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7566959_T47" } ] }, { "id": "PMID-7566959_E29", "type": "Cell_transformation", "trigger": { "text": [ "transforming" ], "offsets": [ [ 1657, 1669 ] ] }, "arguments": [] }, { "id": "PMID-7566959_E30", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1687, 1695 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7566959_T49" }, { "role": "Theme", "ref_id": 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[ { "id": "PMID-12724285__text", "type": "abstract", "text": [ "Possible role of cyclooxygenase II in the acquisition of ovarian luteal function in rodents.\nThe development of the corpus luteum (CL), which involves angiogenesis, is essential for the establishment of early pregnancy. We investigated the roles of the prostaglandin synthases cyclooxygenase (COX) I and COX-II in angiogenesis and progesterone production in the newly formed CL, using inhibitors of the COX enzymes and the gonadotropin-induced pseudopregnant rat as a model. Injection of indomethacin, a nonselective COX inhibitor, on the day of ovulation and the following day decreased serum levels of progesterone, as did injection of the selective COX-II inhibitor NS-398. In contrast, a selective COX-I inhibitor, SC-560, had no effect on serum progesterone concentrations. None of the inhibitors had any effect on the weight of the superovulated ovaries or on the synthesis of progesterone by cultured luteal cells. To determine whether changes in angiogenesis are responsible for the decrease in progesterone synthesis, we measured hemoglobin and CD34 levels in luteinized ovaries following injection of COX inhibitors and measured the relative frequency of cells positive for platelet-endothelial cell adhesion molecule as a specific marker for endothelial cells. All of these parameters were reduced by the COX-II inhibitors, suggesting that changes in the vasculature are responsible for the decrease in serum progesterone. Histological examination of ovarian corrosion casts indicated that NS-398 inhibited the establishment of luteal capillary vessels following the injection of hCG. The results are consistent with the hypothesis that the activity of COX-II is associated with the formation of functional CL via its stimulation of angiogenesis.\n" ], "offsets": [ [ 0, 1758 ] ] } ]

[ { "id": "PMID-12724285_T1", "type": "Gene_or_gene_product", "text": [ "cyclooxygenase II" ], "offsets": [ [ 17, 34 ] ], "normalized": [] }, { "id": "PMID-12724285_T2", "type": "Multi-tissue_structure", "text": [ "ovarian luteal" ], "offsets": [ [ 57, 71 ] ], "normalized": [] }, { "id": "PMID-12724285_T3", "type": "Multi-tissue_structure", "text": [ "corpus luteum" ], "offsets": [ [ 116, 129 ] ], "normalized": [] }, { "id": "PMID-12724285_T4", "type": "Multi-tissue_structure", "text": [ "CL" ], "offsets": [ [ 131, 133 ] ], "normalized": [] }, { "id": "PMID-12724285_T5", "type": "Simple_chemical", "text": [ "prostaglandin" ], "offsets": [ [ 253, 266 ] ], "normalized": [] }, { "id": "PMID-12724285_T6", "type": "Gene_or_gene_product", "text": [ "cyclooxygenase (COX) I" ], "offsets": [ [ 277, 299 ] ], "normalized": [] }, { "id": "PMID-12724285_T7", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 304, 310 ] ], "normalized": [] }, { "id": "PMID-12724285_T8", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 331, 343 ] ], "normalized": [] }, { "id": "PMID-12724285_T9", "type": "Multi-tissue_structure", "text": [ "CL" ], "offsets": [ [ 375, 377 ] ], "normalized": [] }, { "id": "PMID-12724285_T10", "type": "Gene_or_gene_product", "text": [ "COX enzymes" ], "offsets": [ [ 403, 414 ] ], "normalized": [] }, { "id": "PMID-12724285_T11", "type": "Gene_or_gene_product", "text": [ "gonadotropin" ], "offsets": [ [ 423, 435 ] ], "normalized": [] }, { "id": "PMID-12724285_T12", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 459, 462 ] ], "normalized": [] }, { "id": "PMID-12724285_T13", "type": "Simple_chemical", "text": [ "indomethacin" ], "offsets": [ [ 488, 500 ] ], "normalized": [] }, { "id": "PMID-12724285_T14", "type": "Gene_or_gene_product", "text": [ "COX" ], "offsets": [ [ 517, 520 ] ], "normalized": [] }, { "id": "PMID-12724285_T15", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 588, 593 ] ], "normalized": [] }, { "id": "PMID-12724285_T16", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 604, 616 ] ], "normalized": [] }, { "id": "PMID-12724285_T17", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 652, 658 ] ], "normalized": [] }, { "id": "PMID-12724285_T18", "type": "Simple_chemical", "text": [ "NS-398" ], "offsets": [ [ 669, 675 ] ], "normalized": [] }, { "id": "PMID-12724285_T19", "type": "Gene_or_gene_product", "text": [ "COX-I" ], "offsets": [ [ 702, 707 ] ], "normalized": [] }, { "id": "PMID-12724285_T20", "type": "Simple_chemical", "text": [ "SC-560" ], "offsets": [ [ 719, 725 ] ], "normalized": [] }, { "id": "PMID-12724285_T21", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "PMID-12724285_T22", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 750, 762 ] ], "normalized": [] }, { "id": "PMID-12724285_T23", "type": "Organ", "text": [ "superovulated ovaries" ], "offsets": [ [ 838, 859 ] ], "normalized": [] }, { "id": "PMID-12724285_T24", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 883, 895 ] ], "normalized": [] }, { "id": "PMID-12724285_T25", "type": "Cell", "text": [ "cultured luteal cells" ], "offsets": [ [ 899, 920 ] ], "normalized": [] }, { "id": "PMID-12724285_T26", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 1003, 1015 ] ], "normalized": [] }, { "id": "PMID-12724285_T27", "type": "Gene_or_gene_product", "text": [ "hemoglobin" ], "offsets": [ [ 1039, 1049 ] ], "normalized": [] }, { "id": "PMID-12724285_T28", "type": "Gene_or_gene_product", "text": [ "CD34" ], "offsets": [ [ 1054, 1058 ] ], "normalized": [] }, { "id": "PMID-12724285_T29", "type": "Organ", "text": [ "ovaries" ], "offsets": [ [ 1080, 1087 ] ], "normalized": [] }, { "id": "PMID-12724285_T30", "type": "Gene_or_gene_product", "text": [ "COX" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] }, { "id": "PMID-12724285_T31", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "PMID-12724285_T32", "type": "Gene_or_gene_product", "text": [ "platelet-endothelial cell adhesion molecule" ], "offsets": [ [ 1184, 1227 ] ], "normalized": [] }, { "id": "PMID-12724285_T33", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1253, 1270 ] ], "normalized": [] }, { "id": "PMID-12724285_T34", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 1316, 1322 ] ], "normalized": [] }, { "id": "PMID-12724285_T35", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 1366, 1377 ] ], "normalized": [] }, { "id": "PMID-12724285_T36", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1414, 1419 ] ], "normalized": [] }, { "id": "PMID-12724285_T37", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 1420, 1432 ] ], "normalized": [] }, { "id": "PMID-12724285_T38", "type": "Organ", "text": [ "ovarian" ], "offsets": [ [ 1462, 1469 ] ], "normalized": [] }, { "id": "PMID-12724285_T39", "type": "Simple_chemical", "text": [ "NS-398" ], "offsets": [ [ 1501, 1507 ] ], "normalized": [] }, { "id": "PMID-12724285_T40", "type": "Multi-tissue_structure", "text": [ "luteal capillary vessels" ], "offsets": [ [ 1539, 1563 ] ], "normalized": [] }, { "id": "PMID-12724285_T41", "type": "Gene_or_gene_product", "text": [ "hCG" ], "offsets": [ [ 1591, 1594 ] ], "normalized": [] }, { "id": "PMID-12724285_T42", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 1664, 1670 ] ], "normalized": [] }, { "id": "PMID-12724285_T43", "type": "Multi-tissue_structure", "text": [ "CL" ], "offsets": [ [ 1718, 1720 ] ], "normalized": [] } ]

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"Cause", "ref_id": "PMID-12724285_E18" }, { "role": "Theme", "ref_id": "PMID-12724285_E21" } ] }, { "id": "PMID-12724285_E21", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 991, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12724285_E22" } ] }, { "id": "PMID-12724285_E22", "type": "Synthesis", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1016, 1025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12724285_T26" } ] }, { "id": "PMID-12724285_E23", "type": "Development", "trigger": { "text": [ "luteinized" ], "offsets": [ [ 1069, 1079 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12724285_T29" } ] }, { "id": "PMID-12724285_E24", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1351, 1358 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12724285_T35" } ] }, { "id": "PMID-12724285_E25", "type": "Regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 1382, 1393 ] ] }, 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[]

[ { "id": "PMID-6312919__text", "type": "abstract", "text": [ "The genetics of transformation by SV 40. \nExperiments using the tsA 58 allele of the SV 40-A gene have demonstrated that the SV 40 large T-antigen is strictly required both for immortalization and induction anchorage independence of cells. It has been suggested that the immortalized phenotype is mediated by an extra cellular factor. The synthesis and/or the excretion of this factor in a medium is controlled by the A gene.\n" ], "offsets": [ [ 0, 426 ] ] } ]

[ { "id": "PMID-6312919_T1", "type": "Organism", "text": [ "SV 40" ], "offsets": [ [ 34, 39 ] ], "normalized": [] }, { "id": "PMID-6312919_T2", "type": "Gene_or_gene_product", "text": [ "tsA 58" ], "offsets": [ [ 64, 70 ] ], "normalized": [] }, { "id": "PMID-6312919_T3", "type": "Organism", "text": [ "SV 40" ], "offsets": [ [ 85, 90 ] ], "normalized": [] }, { "id": "PMID-6312919_T4", "type": "Gene_or_gene_product", "text": [ "A" ], "offsets": [ [ 91, 92 ] ], "normalized": [] }, { "id": "PMID-6312919_T5", "type": "Organism", "text": [ "SV 40" ], "offsets": [ [ 125, 130 ] ], "normalized": [] }, { "id": "PMID-6312919_T6", "type": "Gene_or_gene_product", "text": [ "large T-antigen" ], "offsets": [ [ 131, 146 ] ], "normalized": [] }, { "id": "PMID-6312919_T7", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 233, 238 ] ], "normalized": [] }, { "id": "PMID-6312919_T8", "type": "Immaterial_anatomical_entity", "text": [ "extra cellular" ], "offsets": [ [ 312, 326 ] ], "normalized": [] }, { "id": "PMID-6312919_T9", "type": "Gene_or_gene_product", "text": [ "factor" ], "offsets": [ [ 327, 333 ] ], "normalized": [] }, { "id": "PMID-6312919_T10", "type": "Gene_or_gene_product", "text": [ "factor" ], "offsets": [ [ 378, 384 ] ], "normalized": [] }, { "id": "PMID-6312919_T11", "type": "Gene_or_gene_product", "text": [ "A" ], "offsets": [ [ 418, 419 ] ], "normalized": [] } ]

[ { "id": "PMID-6312919_E1", "type": "Cell_transformation", "trigger": { "text": [ "transformation" ], "offsets": [ [ 16, 30 ] ] }, "arguments": [] }, { "id": "PMID-6312919_E2", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 159, 167 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-6312919_T6" }, { "role": "Theme", "ref_id": "PMID-6312919_E3" } ] }, { "id": "PMID-6312919_E3", "type": "Cell_transformation", "trigger": { "text": [ "immortalization" ], "offsets": [ [ 177, 192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6312919_T7" } ] }, { "id": "PMID-6312919_E4", "type": "Cell_transformation", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 271, 283 ] ] }, "arguments": [] }, { "id": "PMID-6312919_E5", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 297, 305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6312919_E4" }, { "role": "Cause", "ref_id": "PMID-6312919_T9" } ] }, { "id": "PMID-6312919_E6", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 339, 348 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6312919_T10" } ] }, { "id": "PMID-6312919_E7", "type": "Localization", "trigger": { "text": [ "excretion" ], "offsets": [ [ 360, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6312919_T10" } ] }, { "id": "PMID-6312919_E8", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 400, 410 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-6312919_T11" }, { "role": "Theme", "ref_id": "PMID-6312919_E7" } ] }, { "id": "PMID-6312919_E9", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 400, 410 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-6312919_T11" }, { "role": "Theme", "ref_id": "PMID-6312919_E6" } ] } ]

[]

[]

[ { "id": "PMID-19605361__text", "type": "abstract", "text": [ "MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover.\nThe formation of new blood vessels from pre-existing ones requires highly coordinated restructuring of endothelial cells (EC) and the surrounding extracellular matrix. Directed EC migration is a central step in this process and depends on cellular signaling cascades that initiate and control the structural rearrangements. On the basis of earlier findings that ERK5 deficiency in mouse EC results in massive defects in vessel architecture, we focused on the impact of the MEK5/ERK5 signaling pathway on EC migration. Using a retroviral gene transfer approach, we found that constitutive activation of MEK5/ERK5 signaling strongly inhibits EC migration and results in massive morphological changes. The area covered by spread EC was dramatically enlarged, accompanied by an increase in focal contacts and altered organization of actin filaments. Consequently, cells were more rigid and show reduced motility. This phenotype was most likely based on decreased focal contact turnover caused by reduced expression of p130Cas, a key player in directed cell migration. We demonstrate for the first time that ERK5 signaling not only is involved in EC survival and stress response but also controls migration and morphology of EC.\n" ], "offsets": [ [ 0, 1309 ] ] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E4" }, { "role": "Cause", "ref_id": "PMID-19605361_E8" } ] }, { "id": "PMID-19605361_E6", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 143, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E4" }, { "role": "Cause", "ref_id": "PMID-19605361_E7" } ] }, { "id": "PMID-19605361_E7", "type": "Remodeling", "trigger": { "text": [ "restructuring" ], "offsets": [ [ 171, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T6" } ] }, { "id": "PMID-19605361_E8", "type": "Remodeling", "trigger": { "text": [ "restructuring" ], "offsets": [ [ 171, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T8" } ] }, { "id": "PMID-19605361_E9", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 265, 274 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T9" } ] }, { "id": "PMID-19605361_E10", "type": "Gene_expression", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 452, 462 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T11" } ] }, { "id": "PMID-19605361_E11", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 475, 482 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19605361_E10" }, { "role": "Theme", "ref_id": "PMID-19605361_E12" } ] }, { "id": "PMID-19605361_E12", "type": "Negative_regulation", "trigger": { "text": [ "defects" ], "offsets": [ [ 494, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T14" } ] }, { "id": "PMID-19605361_E13", "type": "Regulation", "trigger": { "text": [ "impact" ], "offsets": [ [ 544, 550 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19605361_E14" }, { "role": "Theme", "ref_id": "PMID-19605361_E15" } ] }, { "id": "PMID-19605361_E14", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 568, 585 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19605361_T15" }, { "role": "Participant", "ref_id": "PMID-19605361_T16" } ] }, { "id": "PMID-19605361_E15", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 592, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T17" } ] }, { "id": "PMID-19605361_E16", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 673, 683 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E17" } ] }, { "id": "PMID-19605361_E17", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 697, 706 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19605361_T18" }, { "role": "Participant", "ref_id": "PMID-19605361_T19" } ] }, { "id": "PMID-19605361_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 716, 724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E19" }, { "role": "Cause", "ref_id": "PMID-19605361_E16" } ] }, { "id": "PMID-19605361_E19", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 728, 737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T20" } ] }, { "id": "PMID-19605361_E20", "type": "Localization", "trigger": { "text": [ "spread" ], "offsets": [ [ 804, 810 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T21" } ] }, { "id": "PMID-19605361_E21", "type": "Remodeling", "trigger": { "text": [ "organization" ], "offsets": [ [ 898, 910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T24" } ] }, { "id": "PMID-19605361_E22", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 976, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E23" } ] }, { "id": "PMID-19605361_E23", "type": "Localization", "trigger": { "text": [ "motility" ], "offsets": [ [ 984, 992 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T25" } ] }, { "id": "PMID-19605361_E24", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1077, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_E25" } ] }, { "id": "PMID-19605361_E25", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1085, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T27" } ] }, { "id": "PMID-19605361_E26", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1138, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T28" } ] }, { "id": "PMID-19605361_E27", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1193, 1202 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19605361_T29" } ] }, { "id": "PMID-19605361_E28", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1215, 1223 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19605361_E27" }, { "role": "Theme", "ref_id": "PMID-19605361_E29" } ] }, { "id": "PMID-19605361_E29", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1230, 1238 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T30" } ] }, { "id": "PMID-19605361_E30", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 1268, 1276 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19605361_E27" }, { "role": "Theme", "ref_id": "PMID-19605361_E32" } ] }, { "id": "PMID-19605361_E31", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 1268, 1276 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19605361_E27" }, { "role": "Theme", "ref_id": "PMID-19605361_T31" } ] }, { "id": "PMID-19605361_E32", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1277, 1286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19605361_T31" } ] } ]

[ { "id": "PMID-19605361_1", "entity_ids": [ "PMID-19605361_T6", "PMID-19605361_T7" ] } ]

[]

[ { "id": "PMID-12556444__text", "type": "abstract", "text": [ "Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing. \nTumors display a high rate of glucose uptake and glycolysis. We investigated how inhibition of glucose metabolism could affect death receptor-mediated apoptosis in human tumor cells of diverse origin. We show that both substitution of glucose for pyruvate and treatment with 2-deoxyglucose enhanced apoptosis induced by tumor necrosis factor (TNF)-alpha, CD95 agonistic antibody, and TNF-related apoptosis-inducing ligand (TRAIL). Inhibition of glucose metabolism enhanced killing of myeloid leukemia U937, cervical carcinoma HeLa, and breast carcinoma MCF-7 cells upon death receptor ligation. Caspase activation, mitochondrial depolarization, and cytochrome c release were increased under these conditions. Glucose deprivation-mediated sensitization to apoptosis was prevented in MCF-7 cells overexpressing BCL-2. Interestingly, the human B-lymphoblastoid cell line SKW6.4, a prototype for mitochondria-independent death receptor-induced apoptosis, was also sensitized to anti-CD95 and TRAIL-induced apoptosis under glucose-free conditions. Changes in c-FLIP(L) and cFLIPs levels were observed in some but not all the cell lines studied following glucose deprivation. Glucose deprivation enhanced death receptor-triggered formation of death-inducing signaling complex and early processing of procaspase-8. Altogether, these results suggest that the glycolytic pathway may be an important target for therapeutic intervention to sensitize tumor cells to selectively toxic soluble death ligands or death ligand-expressing cells of the immune system by facilitating the activation of initiator caspase-8.\n" ], "offsets": [ [ 0, 1800 ] ] } ]

[ { "id": "PMID-12556444_T1", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 14, 21 ] ], "normalized": [] }, { "id": "PMID-12556444_T2", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 44, 55 ] ], "normalized": [] }, { "id": "PMID-12556444_T3", "type": "Gene_or_gene_product", "text": [ "death-inducing signaling complex" ], "offsets": [ [ 117, 149 ] ], "normalized": [] }, { "id": "PMID-12556444_T4", "type": "Gene_or_gene_product", "text": [ "procaspase-8" ], "offsets": [ [ 171, 183 ] ], "normalized": [] }, { "id": "PMID-12556444_T5", "type": "Cancer", "text": [ "Tumors" ], "offsets": [ [ 197, 203 ] ], "normalized": [] }, { "id": "PMID-12556444_T6", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 227, 234 ] ], "normalized": [] }, { "id": "PMID-12556444_T7", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 292, 299 ] ], "normalized": [] }, { "id": "PMID-12556444_T8", "type": "Organism", "text": [ "human" ], "offsets": [ [ 361, 366 ] ], "normalized": [] }, { "id": "PMID-12556444_T9", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 367, 378 ] ], "normalized": [] }, { "id": "PMID-12556444_T10", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 432, 439 ] ], "normalized": [] }, { "id": "PMID-12556444_T11", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 444, 452 ] ], "normalized": [] }, { "id": "PMID-12556444_T12", "type": "Simple_chemical", "text": [ "2-deoxyglucose" ], "offsets": [ [ 472, 486 ] ], "normalized": [] }, { "id": "PMID-12556444_T13", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor (TNF)-alpha" ], "offsets": [ [ 517, 550 ] ], "normalized": [] }, { "id": "PMID-12556444_T14", "type": "Gene_or_gene_product", "text": [ "CD95" ], "offsets": [ [ 552, 556 ] ], "normalized": [] }, { "id": "PMID-12556444_T15", "type": "Gene_or_gene_product", "text": [ "TNF-related apoptosis-inducing ligand" ], "offsets": [ [ 581, 618 ] ], "normalized": [] }, { "id": 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[]

[ { "id": "PMID-14652292__text", "type": "abstract", "text": [ "Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2- and beta(2)-microglobulin-deficient mice. \nFolate supplementation may reduce the risk of colorectal dysplasia and cancer in subjects with chronic ulcerative colitis (UC). The interleukin (IL) 2- and beta(2)-microglobulin (beta(2)m)-deficient (IL-2(null) x beta(2)m(null)) mice spontaneously develop colon cancer in the setting of chronic UC. This study investigated the effects of dietary folate on the development of UC-associated colon cancer in the IL-2(null) x beta(2)m(null) mice. Weaning IL-2(null) x beta(2)m(null) mice were randomized to receive 0 (deficient; n = 40), 2 (basal requirement; control; n = 46), or 8 (supplemented; n = 36) mg folate/kg diet for 32 weeks. At necropsy, all macroscopic colonic tumors were identified and histologically classified as dysplasia or adenocarcinoma. The incidence of high-grade lesions (high-grade dysplasia/carcinoma in situ and invasive adenocarcinoma) in the folate-supplemented group was 46% lower than that in the control group (35.3% versus 65.1%, P = 0.009). The incidence of high-grade lesions in the folate-deficient group was also 49% lower than that in the control group (33.3% versus 65.1%, P = 0.007). The higher mortality rate in the folate-deficient group compared with the other two groups (25% versus 6.5% and 5.6%, P < 0.02) partially accounted for the low incidence of high-grade lesions in this group. These data indicate that dietary folate supplementation at 4x the basal dietary requirement significantly suppresses UC-associated colorectal carcinogenesis in the IL-2(null) x beta(2)m(null) mice. These data also suggest that folate deficiency may inhibit colorectal carcinogenesis in chronic UC. However, the high mortality observed in the folate-deficient group precludes a definitive conclusion concerning the effect of folate deficiency on UC-associated colorectal carcinogenesis in this model.\n" ], "offsets": [ [ 0, 1978 ] ] } ]

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[]

[ { "id": "PMID-16489021__text", "type": "abstract", "text": [ "Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. \nMembers of the Runx and MYC families have been implicated as collaborating oncogenes. The mechanism of this potent collaboration is elucidated in this study of Runx2/MYC mice. As shown previously, ectopic expression of Runx2 in the thymus leads to a preneoplastic state defined by an accumulation of cells with an immature phenotype and a low proliferative rate. We now show that c-MYC overexpression is sufficient to rescue proliferation and to release the differentiation block imposed by Runx2. Analysis of Runx2-expressing lymphomas reveals a consistently low rate of apoptosis, in contrast to lymphomas of MYC mice which are often highly apoptotic. The low apoptosis phenotype is dominant in Runx2/MYC tumors, indicating that Runx2 confers a potent survival advantage to MYC-expressing tumor cells. The role of the p53 pathway in Runx2/MYC tumors was explored on a p53 heterozygote background. Surprisingly, functional p53 was retained in vivo, even after transplantation, whereas explanted tumor cells displayed rapid allele loss in vitro. Our results show that Runx2 and MYC overcome distinct \"fail-safe\" responses and that their selection as collaborating genes is due to their ability to neutralize each other's negative growth effect. Furthermore, the Runx2/MYC combination overcomes the requirement for genetic inactivation of the p53 pathway in vivo.\n" ], "offsets": [ [ 0, 1475 ] ] } ]

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"Cell_death", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 755, 764 ] ] }, "arguments": [] }, { "id": "PMID-16489021_E21", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 774, 783 ] ] }, "arguments": [] }, { "id": "PMID-16489021_E22", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 866, 874 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_T24" } ] }, { "id": "PMID-16489021_E23", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 892, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_T23" } ] }, { "id": "PMID-16489021_E24", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 920, 924 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16489021_E25" }, { "role": "Theme", "ref_id": "PMID-16489021_T27" } ] }, { "id": "PMID-16489021_E25", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 936, 943 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16489021_T25" } ] }, { "id": "PMID-16489021_E26", "type": "Planned_process", "trigger": { "text": [ "explanted" ], "offsets": [ [ 1098, 1107 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_T32" } ] }, { "id": "PMID-16489021_E27", "type": "Mutation", "trigger": { "text": [ "allele loss" ], "offsets": [ [ 1136, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_T31" } ] }, { "id": "PMID-16489021_E28", "type": "Positive_regulation", "trigger": { "text": [ "requirement" ], "offsets": [ [ 1410, 1421 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_E29" } ] }, { "id": "PMID-16489021_E29", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 1434, 1446 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16489021_E30" } ] }, { "id": "PMID-16489021_E30", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1458, 1465 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16489021_T37" } ] } ]

[]

[]

[ { "id": "PMID-12454816__text", "type": "abstract", "text": [ "Topoisomerase I protein expression in primary colorectal cancer and lymph node metastases. \nTopoisomerase I (topo I) is an important target for the treatment of malignant disease, especially colorectal cancer. Because there is little information on the expression of topo I in colorectal tumors, this study evaluated and characterized topo I protein expression in primary colorectal cancer and lymph node metastases and studied the association between topo I protein expression and clinicopathologic data, p53 status, and proliferating cell nuclear antigen (PCNA) status. Immunohistochemistry assay was performed for topo I protein expression in 249 primary human colorectal cancer and 42 paired lymph node metastasis samples. Topo I expression was described as the percentage of cells staining positive for topo I, along with the intensity and localization of the staining. Clinicopathologic data (sex, age, Dukes' stage, differentiation grade, survival status), p53 status, and PCNA status were statistically analyzed for association with topo I protein expression. Topo I expression in paired primary lymph node metastases were studied for concordance. Topo I protein expression was detected in 127 (51%) samples, including 24.4% with >50% positive tumor cells. The majority had nuclear (70.1%) or nuclear and cytoplasmic staining (17.3%). A higher percentage of cells expressing topo I in primary colorectal cancer was significantly associated with advanced age (P =.040). Patients with rectal cancer had greater topo I expression than those with colon tumors (P =.029). No significant correlation was found between topo I protein expression and sex, Dukes' stage, differentiation grade, survival status, p53 status, and PCNA status. Concordance in topo I staining between primary and lymph node metastases was observed in 33 of 42 cases (P =.029). This suggests that the activity of topo I inhibitors will not differ across various tumor stages, pathology, and patient gender. p53 and PCNA status do not appear to influence topo I expression, and topo I has no apparent association with the acquisition of a metastatic phenotype. Topo I expression now needs to be evaluated in patients undergoing topo I-inhibitor therapy, to better define the role of this protein as a predictive marker.\n" ], "offsets": [ [ 0, 2294 ] ] } ]

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"topo I" ], "offsets": [ [ 267, 273 ] ], "normalized": [] }, { "id": "PMID-12454816_T9", "type": "Cancer", "text": [ "colorectal tumors" ], "offsets": [ [ 277, 294 ] ], "normalized": [] }, { "id": "PMID-12454816_T10", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 335, 341 ] ], "normalized": [] }, { "id": "PMID-12454816_T11", "type": "Cancer", "text": [ "colorectal cancer" ], "offsets": [ [ 372, 389 ] ], "normalized": [] }, { "id": "PMID-12454816_T12", "type": "Cancer", "text": [ "lymph node metastases" ], "offsets": [ [ 394, 415 ] ], "normalized": [] }, { "id": "PMID-12454816_T13", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 452, 458 ] ], "normalized": [] }, { "id": "PMID-12454816_T14", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 506, 509 ] ], "normalized": [] }, { "id": "PMID-12454816_T15", "type": "Gene_or_gene_product", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 522, 556 ] ], "normalized": [] }, { "id": "PMID-12454816_T16", "type": "Gene_or_gene_product", "text": [ "PCNA" ], "offsets": [ [ 558, 562 ] ], "normalized": [] }, { "id": "PMID-12454816_T17", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 617, 623 ] ], "normalized": [] }, { "id": "PMID-12454816_T18", "type": "Organism", "text": [ "human" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "PMID-12454816_T19", "type": "Cancer", "text": [ "colorectal cancer" ], "offsets": [ [ 664, 681 ] ], "normalized": [] }, { "id": "PMID-12454816_T20", "type": "Cancer", "text": [ "lymph node metastasis samples" ], "offsets": [ [ 696, 725 ] ], "normalized": [] }, { "id": "PMID-12454816_T21", "type": "Gene_or_gene_product", "text": [ "Topo I" ], "offsets": [ [ 727, 733 ] ], "normalized": [] }, { "id": "PMID-12454816_T22", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 780, 785 ] ], "normalized": [] }, { "id": "PMID-12454816_T23", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 808, 814 ] ], "normalized": [] }, { "id": "PMID-12454816_T24", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 964, 967 ] ], "normalized": [] }, { "id": "PMID-12454816_T25", "type": "Gene_or_gene_product", "text": [ "PCNA" ], "offsets": [ [ 980, 984 ] ], "normalized": [] }, { "id": "PMID-12454816_T26", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1041, 1047 ] ], "normalized": [] }, { "id": "PMID-12454816_T27", "type": "Gene_or_gene_product", "text": [ "Topo I" ], "offsets": [ [ 1068, 1074 ] ], "normalized": [] }, { "id": "PMID-12454816_T28", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 1104, 1114 ] ], "normalized": [] }, { "id": "PMID-12454816_T29", "type": "Gene_or_gene_product", "text": [ "Topo I" ], "offsets": [ [ 1156, 1162 ] ], "normalized": [] }, { "id": "PMID-12454816_T30", "type": "Cancer", "text": [ "samples" ], "offsets": [ [ 1208, 1215 ] ], "normalized": [] }, { "id": "PMID-12454816_T31", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 1252, 1263 ] ], "normalized": [] }, { "id": "PMID-12454816_T32", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1282, 1289 ] ], "normalized": [] }, { "id": "PMID-12454816_T33", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1301, 1308 ] ], "normalized": [] }, { "id": "PMID-12454816_T34", "type": "Organism_substance", "text": [ "cytoplasmic" ], "offsets": [ [ 1313, 1324 ] ], "normalized": [] }, { "id": "PMID-12454816_T35", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1366, 1371 ] ], "normalized": [] }, { "id": "PMID-12454816_T36", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1383, 1389 ] ], "normalized": [] }, { "id": "PMID-12454816_T37", "type": "Cancer", "text": [ "primary colorectal cancer" ], "offsets": [ [ 1393, 1418 ] ], "normalized": [] }, { "id": "PMID-12454816_T38", "type": "Organism", "text": [ "Patients" ], "offsets": [ [ 1477, 1485 ] ], "normalized": [] }, { "id": "PMID-12454816_T39", "type": "Cancer", "text": [ "rectal cancer" ], "offsets": [ [ 1491, 1504 ] ], "normalized": [] }, { "id": "PMID-12454816_T40", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1517, 1523 ] ], "normalized": [] }, { "id": "PMID-12454816_T41", "type": "Cancer", "text": [ "colon tumors" ], "offsets": [ [ 1551, 1563 ] ], "normalized": [] }, { "id": "PMID-12454816_T42", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1620, 1626 ] ], "normalized": [] }, { "id": "PMID-12454816_T43", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1709, 1712 ] ], "normalized": [] }, { "id": "PMID-12454816_T44", "type": "Gene_or_gene_product", "text": [ "PCNA" ], "offsets": [ [ 1725, 1729 ] ], "normalized": [] }, { "id": "PMID-12454816_T45", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1753, 1759 ] ], "normalized": [] }, { "id": "PMID-12454816_T46", "type": "Cancer", "text": [ "primary" ], "offsets": [ [ 1777, 1784 ] ], "normalized": [] }, { "id": "PMID-12454816_T47", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 1789, 1799 ] ], "normalized": [] }, { "id": "PMID-12454816_T48", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 1888, 1894 ] ], "normalized": [] }, { "id": "PMID-12454816_T49", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1937, 1942 ] ], "normalized": [] }, { "id": "PMID-12454816_T50", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1966, 1973 ] ], "normalized": [] }, { "id": "PMID-12454816_T51", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1982, 1985 ] ], "normalized": [] }, { "id": "PMID-12454816_T52", "type": "Gene_or_gene_product", "text": [ "PCNA" ], "offsets": [ [ 1990, 1994 ] ], "normalized": [] }, { "id": "PMID-12454816_T53", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 2029, 2035 ] ], "normalized": [] }, { "id": "PMID-12454816_T54", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 2052, 2058 ] ], "normalized": [] }, { "id": "PMID-12454816_T55", "type": "Gene_or_gene_product", "text": [ "Topo I" ], "offsets": [ [ 2135, 2141 ] ], "normalized": [] }, { "id": "PMID-12454816_T56", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 2182, 2190 ] ], "normalized": [] }, { "id": "PMID-12454816_T57", "type": "Gene_or_gene_product", "text": [ "topo I" ], "offsets": [ [ 2202, 2208 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-3365266__text", "type": "abstract", "text": [ "Glutamine and glucose as energy substrates for Ehrlich ascites tumour cells.\nEnergy metabolism of freshly harvested Ehrlich ascites tumour cells in the presence of 5 mM glucose and/or 0.5 mM glutamine was studied. The rate of oxygen utilization was not altered by the addition of 0.5 mM glutamine; 5 mM glucose induced an inhibition of respiration. In the presence of both glucose and glutamine, the Crabtree effect decreased. In these conditions, the rates of oxygen uptake, the CO2 evolution and the changes in the redox states of cytochromes indicate that glucose is preferred by Ehrlich ascites tumour cells as energy substrate. Glucose decreased the rate of glutamine utilization by 34%. On the other hand, glutaminolysis did not inhibit glycolysis.\n" ], "offsets": [ [ 0, 755 ] ] } ]

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[]

[]

[ { "id": "PMID-10403689__text", "type": "abstract", "text": [ "Immunohistochemical analysis of nm23-H1 gene product in node-positive lung cancer and lymph nodes. \nThe nm23-H1 gene product has been considered as an anti-metastatic protein and the level of its expression has been reported to correlate inversely with metastatic potential in some cancers. However, the expression of nm23-H1 gene product in the metastatic sites have not been studied in detail. We examined the expression of nm23-H1 gene product in surgically resected 46 pairs of primary lung cancers and metastatic lymph nodes by immunohistochemistry. The positive staining of nm23-H1 gene product in primary cancers and metastatic lymph nodes were observed in 56.5 and 67.4%, respectively. The heterogeneity of nm23-H1 gene product expression between primary cancers and metastatic lymph nodes was observed in 41.3%. No correlations were found between the nm23-H1 gene product expression in lung cancers and the patients survival. No significant association was also observed between nm23-H1 gene product expression in lymph nodes and the patients survival. There was, furthermore, no correlation between the heterogeneity of nm23-H1 gene product expression and the patients survival. In conclusion, the level of nm23-H1 gene product expression does not significantly reveal prognostic value in node-positive lung cancers. Expression of nm23-H1 gene product in metastatic lymph nodes was also unrelated to patients survival.\n" ], "offsets": [ [ 0, 1429 ] ] } ]

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[ { "id": "PMID-10403689_E1", "type": "Localization", "trigger": { "text": [ "positive" ], "offsets": [ [ 61, 69 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10403689_T2" }, { "role": "Theme", "ref_id": "PMID-10403689_T3" } ] }, { "id": "PMID-10403689_E2", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 156, 166 ] ] }, "arguments": [] }, { "id": "PMID-10403689_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 196, 206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T5" } ] }, { "id": "PMID-10403689_E4", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 253, 263 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T6" } ] }, { "id": "PMID-10403689_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 304, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T7" } ] }, { "id": "PMID-10403689_E6", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 346, 356 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10403689_T8" } ] }, { "id": "PMID-10403689_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 412, 422 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T9" } ] }, { "id": "PMID-10403689_E8", "type": "Planned_process", "trigger": { "text": [ "resected" ], "offsets": [ [ 461, 469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T10" } ] }, { "id": "PMID-10403689_E9", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 507, 517 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10403689_T11" } ] }, { "id": "PMID-10403689_E10", "type": "Gene_expression", "trigger": { "text": [ "positive staining" ], "offsets": [ [ 559, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T12" } ] }, { "id": "PMID-10403689_E11", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 624, 634 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10403689_T14" } ] }, { "id": "PMID-10403689_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 736, 746 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T15" } ] }, { "id": "PMID-10403689_E13", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 775, 785 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10403689_T17" } ] }, { "id": "PMID-10403689_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T18" } ] }, { "id": "PMID-10403689_E15", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 925, 933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T20" } ] }, { "id": "PMID-10403689_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1009, 1019 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T21" } ] }, { "id": "PMID-10403689_E17", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1052, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T23" } ] }, { "id": "PMID-10403689_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1151, 1161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T24" } ] }, { "id": "PMID-10403689_E19", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1179, 1187 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T25" } ] }, { "id": "PMID-10403689_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1238, 1248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T26" } ] }, { "id": "PMID-10403689_E21", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 1327, 1337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T28" } ] }, { "id": "PMID-10403689_E22", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 1365, 1375 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10403689_T29" } ] }, { "id": "PMID-10403689_E23", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1419, 1427 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10403689_T30" } ] } ]

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[ { "id": "PMID-3985123__text", "type": "abstract", "text": [ "Mast cells and tumors. The specific enhancement of tumor proliferation in vitro.\nMast cells were found to be unique among the peritoneal leukocytes by virtue of their capacity to enhance profoundly the proliferation of a variety of tumors in vitro. This phenomenon occurs at mast cell/tumor ratios which reflect the stoichiometry of host cell/tumor relationships in vivo. The growth factor was found to reside in mast cell granules and was identified as heparin by sequential purification and enzymatic degradation. This cellular interaction was tumor-specific, although isolated granules could enhance fibroblast proliferation. The findings are discussed in relation to previous morphologic studies, reports of in vitro mast-cell-mediated tumor cytotoxicity, and the role of mast cells in angiogenesis and connective tissue proliferation.\n" ], "offsets": [ [ 0, 840 ] ] } ]

[ { "id": "PMID-3985123_T1", "type": "Cell", "text": [ "Mast cells" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-3985123_T2", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 15, 21 ] ], "normalized": [] }, { "id": "PMID-3985123_T3", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 51, 56 ] ], "normalized": [] }, { "id": "PMID-3985123_T4", "type": "Cell", "text": [ "Mast cells" ], "offsets": [ [ 81, 91 ] ], "normalized": [] }, { "id": "PMID-3985123_T5", "type": "Cell", "text": [ "peritoneal leukocytes" ], "offsets": [ [ 126, 147 ] ], "normalized": [] }, { "id": "PMID-3985123_T6", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 232, 238 ] ], "normalized": [] }, { "id": "PMID-3985123_T7", "type": "Cell", "text": [ "mast cell" ], "offsets": [ [ 275, 284 ] ], "normalized": [] }, { "id": "PMID-3985123_T8", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 285, 290 ] ], "normalized": [] }, { "id": "PMID-3985123_T9", "type": "Cell", "text": [ "host cell" ], "offsets": [ [ 333, 342 ] ], "normalized": [] }, { "id": "PMID-3985123_T10", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 343, 348 ] ], "normalized": [] }, { "id": "PMID-3985123_T11", "type": "Cell", "text": [ "mast cell" ], "offsets": [ [ 413, 422 ] ], "normalized": [] }, { "id": "PMID-3985123_T12", "type": "Organism_substance", "text": [ "granules" ], "offsets": [ [ 423, 431 ] ], "normalized": [] }, { "id": "PMID-3985123_T13", "type": "Simple_chemical", "text": [ "heparin" ], "offsets": [ [ 454, 461 ] ], "normalized": [] }, { "id": "PMID-3985123_T14", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 521, 529 ] ], "normalized": [] }, { "id": "PMID-3985123_T15", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 546, 551 ] ], "normalized": [] }, { "id": "PMID-3985123_T16", "type": "Organism_substance", "text": [ "granules" ], "offsets": [ [ 580, 588 ] ], "normalized": [] }, { "id": "PMID-3985123_T17", "type": "Cell", "text": [ "fibroblast" ], "offsets": [ [ 603, 613 ] ], "normalized": [] }, { "id": "PMID-3985123_T18", "type": "Cell", "text": [ "mast-cell" ], "offsets": [ [ 721, 730 ] ], "normalized": [] }, { "id": "PMID-3985123_T19", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "PMID-3985123_T20", "type": "Cell", "text": [ "mast cells" ], "offsets": [ [ 776, 786 ] ], "normalized": [] }, { "id": "PMID-3985123_T21", "type": "Tissue", "text": [ "connective tissue" ], "offsets": [ [ 807, 824 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-14613080__text", "type": "abstract", "text": [ "Microvascular density and vascular endothelial growth factor immunoreactivity as predictors of regional lymph node metastasis from betel-associated oral squamous cell carcinoma. \nPURPOSE: Neovascularization has profound effects on tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a mitogen that acts exclusively on endothelial cells. The roles of miscrovascularity density (MVD) and VEGF expression in the progression of oral squamous cell carcinoma (OSCC) have been controversial. The purpose of the present study was to measure the MVD and VEGF expression in a cohort of patients with betel-associated OSCC and to evaluate for possible clinicopathologic correlations. PATIENTS AND METHODS: The paraffin sections from 49 subjects with OSCC were subjected to immunohistochemical studies to measure the highest MVD (h-MVD) and cytoplasmic immunoreactivity of VEGF. The findings in the tissue samples were analyzed with regard to the patients' risk factors and clinical course. RESULTS: The OSCC samples had an average h-MVD score of 27.7/mm(2). VEGF immunoreactivity was positive in 75.5% of samples. Both h-MVD and VEGF immunoreactivity were statistically associated with lymph node metastasis (P =.012 and.037, respectively). A marginally significant association was also noted between the h-MVD and patient survival (P =.056). The age and oral habits of patients, as well as the tumor site and size, did not appear to be correlated with h-MVD or VEGF immunoreactivity. CONCLUSION: The data suggest that both h-MVD and VEGF immunoreactivity may be useful predictors for the progression of a subset of OSCC associated mostly with betel use. Antiangiogenesis therapy might have a role in reducing regional metastasis.\n" ], "offsets": [ [ 0, 1742 ] ] } ]

[ { "id": "PMID-14613080_T1", "type": "Tissue", "text": [ "Microvascular" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "PMID-14613080_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 26, 60 ] ], "normalized": [] }, { "id": "PMID-14613080_T3", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 104, 114 ] ], "normalized": [] }, { "id": "PMID-14613080_T4", "type": "Organism_subdivision", "text": [ "betel" ], "offsets": [ [ 131, 136 ] ], "normalized": [] }, { "id": "PMID-14613080_T5", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 148, 176 ] ], "normalized": [] }, { "id": "PMID-14613080_T6", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 231, 236 ] ], "normalized": [] }, { "id": "PMID-14613080_T7", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 260, 294 ] ], "normalized": [] }, { "id": "PMID-14613080_T8", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "PMID-14613080_T9", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 340, 357 ] ], "normalized": [] }, { "id": "PMID-14613080_T10", "type": "Tissue", "text": [ "miscrovascularity" ], "offsets": [ [ 372, 389 ] ], "normalized": [] }, { "id": "PMID-14613080_T11", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 408, 412 ] ], "normalized": [] }, { "id": "PMID-14613080_T12", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 446, 474 ] ], "normalized": [] }, { "id": "PMID-14613080_T13", "type": "Cancer", "text": [ "OSCC" ], "offsets": [ [ 476, 480 ] ], "normalized": [] }, { "id": "PMID-14613080_T14", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 567, 571 ] ], "normalized": [] }, { "id": "PMID-14613080_T15", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 598, 606 ] ], "normalized": [] }, { "id": "PMID-14613080_T16", "type": "Organism_subdivision", "text": [ "betel" ], "offsets": [ [ 612, 617 ] ], "normalized": [] }, { "id": "PMID-14613080_T17", "type": "Cancer", "text": [ "OSCC" ], "offsets": [ [ 629, 633 ] ], "normalized": [] }, { "id": "PMID-14613080_T18", "type": "Cancer", "text": [ "paraffin sections" ], "offsets": [ [ 721, 738 ] ], "normalized": [] }, { "id": "PMID-14613080_T19", "type": "Organism", "text": [ "subjects" ], "offsets": [ [ 747, 755 ] ], "normalized": [] }, { "id": "PMID-14613080_T20", "type": "Cancer", "text": [ "OSCC" ], "offsets": [ [ 761, 765 ] ], "normalized": [] }, { "id": "PMID-14613080_T21", "type": "Organism_substance", "text": [ "cytoplasmic" ], "offsets": [ [ 851, 862 ] ], "normalized": [] }, { "id": "PMID-14613080_T22", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "PMID-14613080_T23", "type": "Cancer", "text": [ "tissue samples" ], "offsets": [ [ 909, 923 ] ], "normalized": [] }, { "id": "PMID-14613080_T24", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 957, 965 ] ], "normalized": [] }, { "id": "PMID-14613080_T25", "type": "Cancer", "text": [ "OSCC samples" ], "offsets": [ [ 1014, 1026 ] ], "normalized": [] }, { "id": "PMID-14613080_T26", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1069, 1073 ] ], "normalized": [] }, { "id": "PMID-14613080_T27", "type": "Cancer", "text": [ "samples" ], "offsets": [ [ 1116, 1123 ] ], "normalized": [] }, { "id": "PMID-14613080_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1140, 1144 ] ], "normalized": [] }, { "id": "PMID-14613080_T29", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 1197, 1207 ] ], "normalized": [] }, { "id": "PMID-14613080_T30", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1326, 1333 ] ], "normalized": [] }, { "id": "PMID-14613080_T31", "type": "Organism_subdivision", "text": [ "oral" ], "offsets": [ [ 1366, 1370 ] ], "normalized": [] }, { "id": "PMID-14613080_T32", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1381, 1389 ] ], "normalized": [] }, { "id": "PMID-14613080_T33", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1406, 1411 ] ], "normalized": [] }, { "id": "PMID-14613080_T34", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1473, 1477 ] ], "normalized": [] }, { "id": "PMID-14613080_T35", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1545, 1549 ] ], "normalized": [] }, { "id": "PMID-14613080_T36", "type": "Cancer", "text": [ "OSCC" ], "offsets": [ [ 1627, 1631 ] ], "normalized": [] }, { "id": "PMID-14613080_T37", "type": "Organism_subdivision", "text": [ "betel" ], "offsets": [ [ 1655, 1660 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-16720995__text", "type": "abstract", "text": [ "GDP and AGE receptors: mechanisms of peritoneal damage.\nLong-term peritoneal dialysis (PD) is limited by morphological changes of the peritoneal membrane. Structural changes were promoted by toxicity of glucose degradation products (GDPs) which are generated during heat sterilization in peritoneal dialysis fluids (PDFs). Besides their direct toxicity GDPs promote formation of advanced glycation endproducts (AGEs). RAGE (receptor for AGE) is the best characterized signal transduction receptor for AGEs and is expressed on mesothelial cells. The effects of PDFs with different amounts of GDPs were compared on morphological changes in the peritoneal membrane in a RAGE -/- mouse model. It could be demonstrated that RAGE plays a pivotal role in structural damage (e.g. inflammation, neoangiogenesis and fibrosis) of the peritoneal membrane. Further investigations of this pathway with regard to preventing peritoneal fibrosis should be performed to maintain the integrity of the peritoneal membrane in peritoneal dialysis patients.\n" ], "offsets": [ [ 0, 1035 ] ] } ]

[ { "id": "PMID-16720995_T1", "type": "Simple_chemical", "text": [ "GDP" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-16720995_T2", "type": "Simple_chemical", "text": [ "AGE" ], "offsets": [ [ 8, 11 ] ], "normalized": [] }, { "id": "PMID-16720995_T3", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 37, 47 ] ], "normalized": [] }, { "id": "PMID-16720995_T4", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 66, 76 ] ], "normalized": [] }, { "id": "PMID-16720995_T5", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 134, 153 ] ], "normalized": [] }, { "id": "PMID-16720995_T6", "type": "Simple_chemical", "text": [ "glucose degradation products" ], "offsets": [ [ 203, 231 ] ], "normalized": [] }, { "id": "PMID-16720995_T7", "type": "Simple_chemical", "text": [ "GDPs" ], "offsets": [ [ 233, 237 ] ], "normalized": [] }, { "id": "PMID-16720995_T8", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 288, 298 ] ], "normalized": [] }, { "id": "PMID-16720995_T9", "type": "Simple_chemical", "text": [ "GDPs" ], "offsets": [ [ 353, 357 ] ], "normalized": [] }, { "id": "PMID-16720995_T10", "type": "Simple_chemical", "text": [ "advanced glycation endproducts" ], "offsets": [ [ 379, 409 ] ], "normalized": [] }, { "id": "PMID-16720995_T11", "type": "Simple_chemical", "text": [ "AGEs" ], "offsets": [ [ 411, 415 ] ], "normalized": [] }, { "id": "PMID-16720995_T12", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 418, 422 ] ], "normalized": [] }, { "id": "PMID-16720995_T13", "type": "Gene_or_gene_product", "text": [ "receptor for AGE" ], "offsets": [ [ 424, 440 ] ], "normalized": [] }, { "id": "PMID-16720995_T14", "type": "Simple_chemical", "text": [ "AGEs" ], "offsets": [ [ 501, 505 ] ], "normalized": [] }, { "id": "PMID-16720995_T15", "type": "Cell", "text": [ "mesothelial cells" ], "offsets": [ [ 526, 543 ] ], "normalized": [] }, { "id": "PMID-16720995_T16", "type": "Simple_chemical", "text": [ "GDPs" ], "offsets": [ [ 591, 595 ] ], "normalized": [] }, { "id": "PMID-16720995_T17", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 642, 661 ] ], "normalized": [] }, { "id": "PMID-16720995_T18", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 667, 671 ] ], "normalized": [] }, { "id": "PMID-16720995_T19", "type": "Organism", "text": [ "RAGE -/- mouse" ], "offsets": [ [ 667, 681 ] ], "normalized": [] }, { "id": "PMID-16720995_T20", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 719, 723 ] ], "normalized": [] }, { "id": "PMID-16720995_T21", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 823, 842 ] ], "normalized": [] }, { "id": "PMID-16720995_T22", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 909, 919 ] ], "normalized": [] }, { "id": "PMID-16720995_T23", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 982, 1001 ] ], "normalized": [] }, { "id": "PMID-16720995_T24", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 1005, 1015 ] ], "normalized": [] }, { "id": "PMID-16720995_T25", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1025, 1033 ] ], "normalized": [] } ]

[ { "id": "PMID-16720995_E1", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 48, 54 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T3" } ] }, { "id": "PMID-16720995_E2", "type": "Remodeling", "trigger": { "text": [ "morphological changes" ], "offsets": [ [ 105, 126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T5" } ] }, { "id": "PMID-16720995_E3", "type": "Positive_regulation", "trigger": { "text": [ "promoted" ], "offsets": [ [ 179, 187 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_E2" }, { "role": "Cause", "ref_id": "PMID-16720995_T6" } ] }, { "id": "PMID-16720995_E4", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 358, 365 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_E5" }, { "role": "Cause", "ref_id": "PMID-16720995_T9" } ] }, { "id": "PMID-16720995_E5", "type": "Synthesis", "trigger": { "text": [ "formation" ], "offsets": [ [ 366, 375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T10" } ] }, { "id": "PMID-16720995_E6", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 513, 522 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T12" } ] }, { "id": "PMID-16720995_E7", "type": "Remodeling", "trigger": { "text": [ "morphological changes" ], "offsets": [ [ 613, 634 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T17" } ] }, { "id": "PMID-16720995_E8", "type": "Regulation", "trigger": { "text": [ "plays a pivotal role" ], "offsets": [ [ 724, 744 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16720995_T20" }, { "role": "Theme", "ref_id": "PMID-16720995_E10" } ] }, { "id": "PMID-16720995_E9", "type": "Regulation", "trigger": { "text": [ "plays a pivotal role" ], "offsets": [ [ 724, 744 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16720995_T20" }, { "role": "Theme", "ref_id": "PMID-16720995_E11" } ] }, { "id": "PMID-16720995_E10", "type": "Breakdown", "trigger": { "text": [ "structural damage" ], "offsets": [ [ 748, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T21" } ] }, { "id": "PMID-16720995_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 786, 801 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16720995_T21" } ] } ]

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[]

[ { "id": "PMID-17145768__text", "type": "abstract", "text": [ "p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. \nMutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18(-/-); Men1(+/-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18(-/-) and Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-) and Men1(+/-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that Men1 may regulate additional factor(s) that interact with p18 and p27 differently.\n" ], "offsets": [ [ 0, 1382 ] ] } ]

[ { "id": "PMID-17145768_T1", "type": "Gene_or_gene_product", "text": [ "p18Ink4c" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-17145768_T2", "type": "Gene_or_gene_product", "text": [ "p27Kip1" ], "offsets": [ [ 18, 25 ] ], "normalized": [] }, { "id": "PMID-17145768_T3", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 45, 49 ] ], "normalized": [] }, { "id": "PMID-17145768_T4", "type": "Cancer", "text": [ "neuroendocrine organ tumors" ], "offsets": [ [ 62, 89 ] ], "normalized": [] }, { "id": "PMID-17145768_T5", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 99, 103 ] ], "normalized": [] }, { "id": "PMID-17145768_T6", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase" ], "offsets": [ [ 117, 140 ] ], "normalized": [] }, { "id": "PMID-17145768_T7", "type": "Gene_or_gene_product", "text": [ "CDK" ], "offsets": [ [ 142, 145 ] ], "normalized": [] }, { "id": "PMID-17145768_T8", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 158, 161 ] ], "normalized": [] }, { "id": "PMID-17145768_T9", "type": "Gene_or_gene_product", "text": [ "Ink4c" ], "offsets": [ [ 162, 167 ] ], "normalized": [] }, { "id": "PMID-17145768_T10", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 173, 176 ] ], "normalized": [] }, { "id": "PMID-17145768_T11", "type": "Gene_or_gene_product", "text": [ "Kip1" ], "offsets": [ [ 177, 181 ] ], "normalized": [] }, { "id": "PMID-17145768_T12", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 193, 198 ] ], "normalized": [] }, { "id": "PMID-17145768_T13", "type": "Organism", "text": [ "human" ], "offsets": [ [ 223, 228 ] ], "normalized": [] }, { "id": "PMID-17145768_T14", "type": "Cancer", "text": [ "multiple endocrine neoplasia" ], "offsets": [ [ 229, 257 ] ], "normalized": [] }, { "id": "PMID-17145768_T15", "type": "Cancer", "text": [ "MEN" ], "offsets": [ [ 259, 262 ] ], "normalized": [] }, { "id": "PMID-17145768_T16", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 292, 295 ] ], "normalized": [] }, { "id": "PMID-17145768_T17", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 300, 303 ] ], "normalized": [] }, { "id": "PMID-17145768_T18", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 330, 334 ] ], "normalized": [] }, { "id": "PMID-17145768_T19", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 340, 345 ] ], "normalized": [] }, { "id": "PMID-17145768_T20", "type": "Cancer", "text": [ "MEN1" ], "offsets": [ [ 382, 386 ] ], "normalized": [] }, { "id": "PMID-17145768_T21", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 405, 408 ] ], "normalized": [] }, { "id": "PMID-17145768_T22", "type": "Organism", "text": [ "p18-Men1 and p27-Men1 double mutant mice" ], "offsets": [ [ 405, 445 ] ], "normalized": [] }, { "id": "PMID-17145768_T23", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 409, 413 ] ], "normalized": [] }, { "id": "PMID-17145768_T24", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 418, 421 ] ], "normalized": [] }, { "id": "PMID-17145768_T25", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-17145768_T26", "type": "Organism", "text": [ "single mutant littermates" ], "offsets": [ [ 481, 506 ] ], "normalized": [] }, { "id": "PMID-17145768_T27", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 512, 515 ] ], "normalized": [] }, { "id": "PMID-17145768_T28", "type": "Organism", "text": [ "p18(-/-); Men1(+/-) mice" ], "offsets": [ [ 512, 536 ] ], "normalized": [] }, { "id": "PMID-17145768_T29", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "PMID-17145768_T30", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 545, 551 ] ], "normalized": [] }, { "id": "PMID-17145768_T31", "type": "Organ", "text": [ "pituitary" ], "offsets": [ [ 614, 623 ] ], "normalized": [] }, { "id": "PMID-17145768_T32", "type": "Organ", "text": [ "thyroid" ], "offsets": [ [ 625, 632 ] ], "normalized": [] }, { "id": "PMID-17145768_T33", "type": "Organ", "text": [ "parathyroid" ], "offsets": [ [ 634, 645 ] ], "normalized": [] }, { "id": "PMID-17145768_T34", "type": "Organ", "text": [ "pancreas" ], "offsets": [ [ 651, 659 ] ], "normalized": [] }, { "id": "PMID-17145768_T35", "type": "Multi-tissue_structure", "text": [ "pituitary" ], "offsets": [ [ 668, 677 ] ], "normalized": [] }, { "id": "PMID-17145768_T36", "type": "Multi-tissue_structure", "text": [ "pancreatic islets" ], "offsets": [ [ 682, 699 ] ], "normalized": [] }, { "id": "PMID-17145768_T37", "type": "Gene_or_gene_product", "text": [ "retinoblastoma" ], "offsets": [ [ 724, 738 ] ], "normalized": [] }, { "id": "PMID-17145768_T38", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 740, 742 ] ], "normalized": [] }, { "id": "PMID-17145768_T39", "type": "Gene_or_gene_product", "text": [ "CDK2" ], "offsets": [ [ 760, 764 ] ], "normalized": [] }, { "id": "PMID-17145768_T40", "type": "Gene_or_gene_product", "text": [ "CDK4/6" ], "offsets": [ [ 769, 775 ] ], "normalized": [] }, { "id": "PMID-17145768_T41", "type": "Gene_or_gene_product", "text": [ "p18(-/-)" ], "offsets": [ [ 799, 807 ] ], "normalized": [] }, { "id": "PMID-17145768_T42", "type": "Cell", "text": [ "p18(-/-) and Men1(+/-) cells" ], "offsets": [ [ 799, 827 ] ], "normalized": [] }, { "id": "PMID-17145768_T43", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 812, 816 ] ], "normalized": [] }, { "id": "PMID-17145768_T44", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 857, 860 ] ], "normalized": [] }, { "id": "PMID-17145768_T45", "type": "Cell", "text": [ "p18(-/-); Men1(+/-) cells" ], "offsets": [ [ 857, 882 ] ], "normalized": [] }, { "id": "PMID-17145768_T46", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 867, 871 ] ], "normalized": [] }, { "id": "PMID-17145768_T47", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 908, 912 ] ], "normalized": [] }, { "id": "PMID-17145768_T48", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 937, 943 ] ], "normalized": [] }, { "id": "PMID-17145768_T49", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 949, 953 ] ], "normalized": [] }, { "id": "PMID-17145768_T50", "type": "Organism", "text": [ "Men1(+/-) mice" ], "offsets": [ [ 949, 963 ] ], "normalized": [] }, { "id": "PMID-17145768_T51", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 989, 995 ] ], "normalized": [] }, { "id": "PMID-17145768_T52", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "PMID-17145768_T53", "type": "Organism", "text": [ "p18(-/-); Men1(+/-) mice" ], "offsets": [ [ 1001, 1025 ] ], "normalized": [] }, { "id": "PMID-17145768_T54", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 1011, 1015 ] ], "normalized": [] }, { "id": "PMID-17145768_T55", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 1049, 1052 ] ], "normalized": [] }, { "id": "PMID-17145768_T56", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] }, { "id": "PMID-17145768_T57", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1140, 1142 ] ], "normalized": [] }, { "id": "PMID-17145768_T58", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1160, 1164 ] ], "normalized": [] }, { "id": "PMID-17145768_T59", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1184, 1189 ] ], "normalized": [] }, { "id": "PMID-17145768_T60", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 1269, 1272 ] ], "normalized": [] }, { "id": "PMID-17145768_T61", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 1277, 1281 ] ], "normalized": [] }, { "id": "PMID-17145768_T62", "type": "Gene_or_gene_product", "text": [ "Men1" ], "offsets": [ [ 1299, 1303 ] ], "normalized": [] }, { "id": "PMID-17145768_T63", "type": "Gene_or_gene_product", "text": [ "p18" ], "offsets": [ [ 1357, 1360 ] ], "normalized": [] }, { "id": "PMID-17145768_T64", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 1365, 1368 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-20549676__text", "type": "abstract", "text": [ "Telomere/telomerase interplay in virus-driven and virus-independent lymphomagenesis: pathogenic and clinical implications. \nTelomerase is a ribonucleoprotein complex critically involved in extending and maintaining telomeres. Unlike the majority of somatic cells, in which hTERT and telomerase activity are generally silent, normal lymphocytes show transient physiological hTERT expression and telomerase activity according to their differentiation/activation status. During lymphomagenesis, induction of persistent telomerase expression and activity may occur before or after telomere shortening, as a consequence of the different mechanisms through which transforming factors/agents may activate telomerase. Available data indicate that the timing of telomerase activation may allow the distinction of two different lymphomagenetic models: (i) an early activation of telomerase via exogenous regulators of hTERT, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies; (ii) a progressive shortening of telomeres, leading to genetic instability which favors a subsequent activation of telomerase via endogenous regulators may occur in most virus-unrelated lymphoid tumors. These models may have clinically relevant implications, particularly for the tailoring of therapeutic strategies targeting telomerase.\n" ], "offsets": [ [ 0, 1431 ] ] } ]

[ { "id": "PMID-20549676_T1", "type": "Cellular_component", "text": [ "Telomere" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-20549676_T2", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 9, 19 ] ], "normalized": [] }, { "id": "PMID-20549676_T3", "type": "Gene_or_gene_product", "text": [ "Telomerase" ], "offsets": [ [ 124, 134 ] ], "normalized": [] }, { "id": "PMID-20549676_T4", "type": "Cellular_component", "text": [ "telomeres" ], "offsets": [ [ 215, 224 ] ], "normalized": [] }, { "id": "PMID-20549676_T5", "type": "Cell", "text": [ "somatic cells" ], "offsets": [ [ 249, 262 ] ], "normalized": [] }, { "id": "PMID-20549676_T6", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 273, 278 ] ], "normalized": [] }, { "id": "PMID-20549676_T7", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 283, 293 ] ], "normalized": [] }, { "id": "PMID-20549676_T8", "type": "Cell", "text": [ "lymphocytes" ], "offsets": [ [ 332, 343 ] ], "normalized": [] }, { "id": "PMID-20549676_T9", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 373, 378 ] ], "normalized": [] }, { "id": "PMID-20549676_T10", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 394, 404 ] ], "normalized": [] }, { "id": "PMID-20549676_T11", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 516, 526 ] ], "normalized": [] }, { "id": "PMID-20549676_T12", "type": "Cellular_component", "text": [ "telomere" ], "offsets": [ [ 577, 585 ] ], "normalized": [] }, { "id": "PMID-20549676_T13", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 698, 708 ] ], "normalized": [] }, { "id": "PMID-20549676_T14", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 753, 763 ] ], "normalized": [] }, { "id": "PMID-20549676_T15", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 869, 879 ] ], "normalized": [] }, { "id": "PMID-20549676_T16", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 908, 913 ] ], "normalized": [] }, { "id": "PMID-20549676_T17", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 939, 949 ] ], "normalized": [] }, { "id": "PMID-20549676_T18", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 987, 992 ] ], "normalized": [] }, { "id": "PMID-20549676_T19", "type": "Pathological_formation", "text": [ "lymphoid malignancies" ], "offsets": [ [ 1070, 1091 ] ], "normalized": [] }, { "id": "PMID-20549676_T20", "type": "Cellular_component", "text": [ "telomeres" ], "offsets": [ [ 1126, 1135 ] ], "normalized": [] }, { "id": "PMID-20549676_T21", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 1208, 1218 ] ], "normalized": [] }, { "id": "PMID-20549676_T22", "type": "Cancer", "text": [ "lymphoid tumors" ], "offsets": [ [ 1279, 1294 ] ], "normalized": [] }, { "id": "PMID-20549676_T23", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 1419, 1429 ] ], "normalized": [] } ]

[ { "id": "PMID-20549676_E1", "type": "Regulation", "trigger": { "text": [ "maintaining" ], "offsets": [ [ 203, 214 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T4" }, { "role": "Cause", "ref_id": "PMID-20549676_T3" } ] }, { "id": "PMID-20549676_E2", "type": "Negative_regulation", "trigger": { "text": [ "silent" ], "offsets": [ [ 317, 323 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T7" } ] }, { "id": "PMID-20549676_E3", "type": "Negative_regulation", "trigger": { "text": [ "silent" ], "offsets": [ [ 317, 323 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T6" } ] }, { "id": "PMID-20549676_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 379, 389 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T9" } ] }, { "id": "PMID-20549676_E5", "type": "Cell_differentiation", "trigger": { "text": [ "differentiation" ], "offsets": [ [ 433, 448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T8" } ] }, { "id": "PMID-20549676_E6", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 449, 459 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T8" } ] }, { "id": "PMID-20549676_E7", "type": "Carcinogenesis", "trigger": { "text": [ "lymphomagenesis" ], "offsets": [ [ 475, 490 ] ] }, "arguments": [] }, { "id": "PMID-20549676_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 492, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_E9" } ] }, { "id": "PMID-20549676_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 527, 537 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T11" } ] }, { "id": "PMID-20549676_E10", "type": "Breakdown", "trigger": { "text": [ "shortening" ], "offsets": [ [ 586, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T12" } ] }, { "id": "PMID-20549676_E11", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 689, 697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T13" } ] }, { "id": "PMID-20549676_E12", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 764, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T14" } ] }, { "id": "PMID-20549676_E13", "type": "Carcinogenesis", "trigger": { "text": [ "lymphomagenetic" ], "offsets": [ [ 818, 833 ] ] }, "arguments": [] }, { "id": "PMID-20549676_E14", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 855, 865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T15" }, { "role": "Cause", "ref_id": "PMID-20549676_T16" } ] }, { "id": "PMID-20549676_E15", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 929, 938 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_E16" } ] }, { "id": "PMID-20549676_E16", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 950, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T17" } ] }, { "id": "PMID-20549676_E17", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 998, 1007 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_E18" } ] }, { "id": "PMID-20549676_E18", "type": "Cell_transformation", "trigger": { "text": [ "transforming" ], "offsets": [ [ 1008, 1020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T18" } ] }, { "id": "PMID-20549676_E19", "type": "Positive_regulation", "trigger": { "text": [ "progressive" ], "offsets": [ [ 1100, 1111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_E20" } ] }, { "id": "PMID-20549676_E20", "type": "Breakdown", "trigger": { "text": [ "shortening" ], "offsets": [ [ 1112, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T20" } ] }, { "id": "PMID-20549676_E21", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1137, 1144 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20549676_E20" }, { "role": "Theme", "ref_id": "PMID-20549676_E22" } ] }, { "id": "PMID-20549676_E22", "type": "Mutation", "trigger": { "text": [ "genetic instability" ], "offsets": [ [ 1148, 1167 ] ] }, "arguments": [] }, { "id": "PMID-20549676_E23", "type": "Positive_regulation", "trigger": { "text": [ "favors" ], "offsets": [ [ 1174, 1180 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20549676_E24" }, { "role": "Theme", "ref_id": "PMID-20549676_E22" } ] }, { "id": "PMID-20549676_E24", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1194, 1204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T21" } ] }, { "id": "PMID-20549676_E25", "type": "Planned_process", "trigger": { "text": [ "targeting" ], "offsets": [ [ 1409, 1418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20549676_T23" } ] } ]

[]

[]

[ { "id": "PMID-17483295__text", "type": "abstract", "text": [ "In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma. \nVery low-dose irradiation (2 x 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immunohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.\n" ], "offsets": [ [ 0, 1431 ] ] } ]

[ { "id": "PMID-17483295_T1", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 8, 11 ] ], "normalized": [] }, { "id": "PMID-17483295_T2", "type": "Cancer", "text": [ "follicular lymphoma" ], "offsets": [ [ 92, 111 ] ], "normalized": [] }, { "id": "PMID-17483295_T3", "type": "Cancer", "text": [ "follicular lymphoma" ], "offsets": [ [ 201, 220 ] ], "normalized": [] }, { "id": "PMID-17483295_T4", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 355, 363 ] ], "normalized": [] }, { "id": "PMID-17483295_T5", "type": "Cancer", "text": [ "biopsies" ], "offsets": [ [ 365, 373 ] ], "normalized": [] }, { "id": "PMID-17483295_T6", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 415, 423 ] ], "normalized": [] }, { "id": "PMID-17483295_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 461, 464 ] ], "normalized": [] }, { "id": "PMID-17483295_T8", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 488, 491 ] ], "normalized": [] }, { "id": "PMID-17483295_T9", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 512, 516 ] ], "normalized": [] }, { "id": "PMID-17483295_T10", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 641, 644 ] ], "normalized": [] }, { "id": "PMID-17483295_T11", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 663, 666 ] ], "normalized": [] }, { "id": "PMID-17483295_T12", "type": "Cell", "text": [ "macrophage" ], "offsets": [ [ 923, 933 ] ], "normalized": [] }, { "id": "PMID-17483295_T13", "type": "Gene_or_gene_product", "text": [ "TH1" ], "offsets": [ [ 949, 952 ] ], "normalized": [] }, { "id": "PMID-17483295_T14", "type": "Cell", "text": [ "macrophages" ], "offsets": [ [ 1062, 1073 ] ], "normalized": [] }, { "id": "PMID-17483295_T15", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1087, 1092 ] ], "normalized": [] }, { "id": "PMID-17483295_T16", "type": "Cancer", "text": [ "follicular lymphoma" ], "offsets": [ [ 1228, 1247 ] ], "normalized": [] }, { "id": "PMID-17483295_T17", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1323, 1326 ] ], "normalized": [] }, { "id": "PMID-17483295_T18", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1349, 1357 ] ], "normalized": [] } ]

[ { "id": "PMID-17483295_E1", "type": "Planned_process", "trigger": { "text": [ "radiotherapy" ], "offsets": [ [ 76, 88 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T2" } ] }, { "id": "PMID-17483295_E2", "type": "Planned_process", "trigger": { "text": [ "irradiation" ], "offsets": [ [ 128, 139 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T3" } ] }, { "id": "PMID-17483295_E3", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 187, 196 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T3" } ] }, { "id": "PMID-17483295_E4", "type": "Planned_process", "trigger": { "text": [ "radiation" ], "offsets": [ [ 397, 406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T5" } ] }, { "id": "PMID-17483295_E5", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 448, 457 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T7" } ] }, { "id": "PMID-17483295_E6", "type": "Pathway", "trigger": { "text": [ "cycle" ], "offsets": [ [ 517, 522 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T9" } ] }, { "id": "PMID-17483295_E7", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 523, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_E6" } ] }, { "id": "PMID-17483295_E8", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 534, 543 ] ] }, "arguments": [] }, { "id": "PMID-17483295_E9", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 645, 658 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T10" } ] }, { "id": "PMID-17483295_E10", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 667, 675 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17483295_T11" }, { "role": "Theme", "ref_id": "PMID-17483295_E11" } ] }, { "id": "PMID-17483295_E11", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 701, 710 ] ] }, "arguments": [] }, { "id": "PMID-17483295_E12", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 763, 773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_E13" } ] }, { "id": "PMID-17483295_E13", "type": "Pathway", "trigger": { "text": [ "apoptotic pathways" ], "offsets": [ [ 814, 832 ] ] }, "arguments": [] }, { "id": "PMID-17483295_E14", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 934, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T12" } ] }, { "id": "PMID-17483295_E15", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1020, 1030 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T14" }, { "role": "Cause", "ref_id": "PMID-17483295_T15" } ] }, { "id": "PMID-17483295_E16", "type": "Cell_differentiation", "trigger": { "text": [ "differentiation" ], "offsets": [ [ 1034, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T14" } ] }, { "id": "PMID-17483295_E17", "type": "Cell_death", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 1077, 1086 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T15" } ] }, { "id": "PMID-17483295_E18", "type": "Planned_process", "trigger": { "text": [ "radiotherapy" ], "offsets": [ [ 1174, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T16" } ] }, { "id": "PMID-17483295_E19", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1214, 1223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17483295_T16" } ] }, { "id": "PMID-17483295_E20", "type": "Cell_death", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 1327, 1336 ] ] }, "arguments": [] }, { "id": "PMID-17483295_E21", "type": "Cell_death", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 1381, 1390 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-19622586__text", "type": "abstract", "text": [ "EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation.\nPURPOSE: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. EXPERIMENTAL DESIGN: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. RESULTS: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T(163.) Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. CONCLUSIONS: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies.\n" ], "offsets": [ [ 0, 2047 ] ] } ]

[ { "id": "PMID-19622586_T1", "type": "Simple_chemical", "text": [ "EPOX" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19622586_T2", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 45, 50 ] ], "normalized": [] }, { "id": "PMID-19622586_T3", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 59, 62 ] ], "normalized": [] }, { "id": "PMID-19622586_T4", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 193, 199 ] ], "normalized": [] }, { "id": "PMID-19622586_T5", "type": "Simple_chemical", "text": [ "xanthone derivatives" ], "offsets": [ [ 255, 275 ] ], "normalized": [] }, { "id": "PMID-19622586_T6", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 285, 291 ] ], "normalized": [] }, { "id": "PMID-19622586_T7", "type": "Simple_chemical", "text": [ "3,6-di(2,3-epoxypropoxy)xanthone" ], "offsets": [ [ 445, 477 ] ], "normalized": [] }, { "id": "PMID-19622586_T8", "type": "Simple_chemical", "text": [ "EPOX" ], "offsets": [ [ 479, 483 ] ], "normalized": [] }, { "id": "PMID-19622586_T9", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 494, 499 ] ], "normalized": [] }, { "id": "PMID-19622586_T10", "type": "Simple_chemical", "text": [ "EPOX" ], "offsets": [ [ 580, 584 ] ], "normalized": [] }, { "id": "PMID-19622586_T11", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 593, 597 ] ], "normalized": [] }, { "id": "PMID-19622586_T12", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 609, 613 ] ], "normalized": [] }, { "id": "PMID-19622586_T13", "type": "Tissue", "text": [ "tube" ], "offsets": [ [ 621, 625 ] ], "normalized": [] }, { "id": "PMID-19622586_T14", "type": "Simple_chemical", "text": [ "EPOX" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-19622586_T15", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 723, 734 ] ], "normalized": [] }, { "id": "PMID-19622586_T16", "type": "Immaterial_anatomical_entity", "text": [ "Intracellular" ], "offsets": [ [ 831, 844 ] ], "normalized": [] }, { "id": "PMID-19622586_T17", "type": "Simple_chemical", "text": [ "glutathione" ], "offsets": [ [ 845, 856 ] ], "normalized": [] }, { "id": "PMID-19622586_T18", "type": "Simple_chemical", "text": [ "monochlorobimane" ], "offsets": [ [ 896, 912 ] ], "normalized": [] }, { "id": "PMID-19622586_T19", "type": "Simple_chemical", "text": [ "glutathione" ], "offsets": [ [ 916, 927 ] ], "normalized": [] }, { "id": "PMID-19622586_T20", "type": "Simple_chemical", "text": [ "EPOX" ], "offsets": [ [ 953, 957 ] ], "normalized": [] }, { "id": "PMID-19622586_T21", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 966, 982 ] ], "normalized": [] }, { "id": "PMID-19622586_T22", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "PMID-19622586_T23", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1072, 1077 ] ], "normalized": [] }, { "id": "PMID-19622586_T24", "type": "Gene_or_gene_product", 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[ { "id": "PMID-19622586_1", "entity_ids": [ "PMID-19622586_T7", "PMID-19622586_T8" ] }, { "id": "PMID-19622586_2", "entity_ids": [ "PMID-19622586_T29", "PMID-19622586_T30" ] }, { "id": "PMID-19622586_3", "entity_ids": [ "PMID-19622586_T37", "PMID-19622586_T38" ] } ]

[]

[ { "id": "PMID-15623598__text", "type": "abstract", "text": [ "Matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers. \nPURPOSE: The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in tumor invasion; several individual members of which have been implicated in tumor prognosis. These enzymes and their physiologic inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), act in a coordinated manner to form an integrated system. Therefore, to understand their role in tumor invasion, it is necessary to evaluate them collectively. EXPERIMENTAL DESIGN: In this study all of the major members of the matrix metalloproteinase (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MT1-MMP and MT2-MMP)/tissue inhibitor of matrix metalloproteinase (TIMP-1, TIMP-2, and TIMP-3) system have been investigated by immunohistochemistry in a series (n = 90) of stage III (Dukes' C) colorectal cancers. An immunohistochemical score based on the intensity of immunoreactivity and proportion of immunoreactive cells was established for each MMP and TIMP. RESULTS: The MMP/TIMP profile defined by hierarchical cluster analysis of the immunohistochemical score identifies a distinct group of colorectal cancers with poor prognosis (log-rank test, 12.22, P = 0.0005). The median survival time of patients in this survival group was 18 months compared with a median survival of 49 months in the \"good\" survival group. Multivariate analysis showed that this profile was independently the most significant prognostic factor (P = 0.001). CONCLUSIONS: This study has identified that the MMP/TIMP profile is an independent indicator of poor prognosis in colorectal cancer.\n" ], "offsets": [ [ 0, 1692 ] ] } ]

[ { "id": "PMID-15623598_T1", "type": "Cancer", "text": [ "colorectal cancers" ], "offsets": [ [ 107, 125 ] ], "normalized": [] }, { "id": "PMID-15623598_T2", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 222, 227 ] ], "normalized": [] }, { "id": "PMID-15623598_T3", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 298, 303 ] ], "normalized": [] }, { "id": "PMID-15623598_T4", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 520, 525 ] ], "normalized": [] }, { "id": "PMID-15623598_T5", "type": "Gene_or_gene_product", "text": [ "MMP-1" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "PMID-15623598_T6", "type": "Gene_or_gene_product", "text": [ "MMP-2" ], "offsets": [ [ 683, 688 ] ], "normalized": [] }, { "id": "PMID-15623598_T7", "type": "Gene_or_gene_product", "text": [ "MMP-3" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "PMID-15623598_T8", "type": "Gene_or_gene_product", "text": [ "MMP-7" ], "offsets": [ [ 697, 702 ] ], "normalized": [] }, { "id": "PMID-15623598_T9", "type": "Gene_or_gene_product", "text": [ "MMP-9" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "PMID-15623598_T10", "type": "Gene_or_gene_product", "text": [ "MMP-13" ], "offsets": [ [ 711, 717 ] ], "normalized": [] }, { "id": "PMID-15623598_T11", "type": "Gene_or_gene_product", "text": [ "MT1-MMP" ], "offsets": [ [ 719, 726 ] ], "normalized": [] }, { "id": "PMID-15623598_T12", "type": "Gene_or_gene_product", "text": [ "MT2-MMP" ], "offsets": [ [ 731, 738 ] ], "normalized": [] }, { "id": "PMID-15623598_T13", "type": "Gene_or_gene_product", "text": [ "TIMP-1" ], "offsets": [ [ 786, 792 ] ], "normalized": [] }, { "id": "PMID-15623598_T14", "type": "Gene_or_gene_product", "text": [ "TIMP-2" ], "offsets": [ [ 794, 800 ] ], "normalized": [] }, { "id": "PMID-15623598_T15", "type": "Gene_or_gene_product", "text": [ "TIMP-3" ], "offsets": [ [ 806, 812 ] ], "normalized": [] }, { "id": "PMID-15623598_T16", "type": "Cancer", "text": [ "stage III (Dukes' C) colorectal cancers" ], "offsets": [ [ 892, 931 ] ], "normalized": [] }, { "id": "PMID-15623598_T17", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1038, 1043 ] ], "normalized": [] }, { "id": "PMID-15623598_T18", "type": "Cancer", "text": [ "colorectal cancers" ], "offsets": [ [ 1218, 1236 ] ], "normalized": [] }, { "id": "PMID-15623598_T19", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1321, 1329 ] ], "normalized": [] }, { "id": "PMID-15623598_T20", "type": "Cancer", "text": [ "colorectal cancer" ], "offsets": [ [ 1673, 1690 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-11835401__text", "type": "abstract", "text": [ "Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors.\nInteractions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.\n" ], "offsets": [ [ 0, 1578 ] ] } ]

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"normalized": [] }, { "id": "PMID-11835401_T9", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 236, 256 ] ], "normalized": [] }, { "id": "PMID-11835401_T10", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 350, 355 ] ], "normalized": [] }, { "id": "PMID-11835401_T11", "type": "Gene_or_gene_product", "text": [ "secreted protein, acidic, and rich in cysteine" ], "offsets": [ [ 357, 403 ] ], "normalized": [] }, { "id": "PMID-11835401_T12", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 410, 416 ] ], "normalized": [] }, { "id": "PMID-11835401_T13", "type": "Cell", "text": [ "vascular cells" ], "offsets": [ [ 490, 504 ] ], "normalized": [] }, { "id": "PMID-11835401_T14", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 541, 546 ] ], "normalized": [] }, { "id": "PMID-11835401_T15", "type": "Organism", "text": [ "human" ], "offsets": [ [ 556, 561 ] ], "normalized": [] }, { "id": "PMID-11835401_T16", "type": "Cell", "text": [ "arterial smooth muscle cell" ], "offsets": [ [ 562, 589 ] ], "normalized": [] }, { "id": "PMID-11835401_T17", "type": "Gene_or_gene_product", "text": [ "platelet-derived growth factor" ], "offsets": [ [ 618, 648 ] ], "normalized": [] }, { "id": "PMID-11835401_T18", "type": "Gene_or_gene_product", "text": [ "monomeric type I collagen" ], "offsets": [ [ 667, 692 ] ], "normalized": [] }, { "id": "PMID-11835401_T19", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 715, 720 ] ], "normalized": [] }, { "id": "PMID-11835401_T20", "type": "Gene_or_gene_product", "text": [ "SPARC peptides" ], "offsets": [ [ 725, 739 ] ], "normalized": [] }, { "id": "PMID-11835401_T21", "type": "Cell", "text": [ "smooth muscle cells" ], "offsets": [ [ 789, 808 ] ], "normalized": [] }, { "id": "PMID-11835401_T22", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 894, 899 ] ], "normalized": [] }, { "id": "PMID-11835401_T23", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 918, 926 ] ], "normalized": [] }, { "id": "PMID-11835401_T24", "type": "Cell", "text": [ "smooth muscle cell" ], "offsets": [ [ 937, 955 ] ], "normalized": [] }, { "id": "PMID-11835401_T25", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 998, 1002 ] ], "normalized": [] }, { "id": "PMID-11835401_T26", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1040, 1044 ] ], "normalized": [] }, { "id": "PMID-11835401_T27", "type": "Simple_chemical", "text": [ "cyclin-dependent kinase inhibitors" ], "offsets": [ [ 1067, 1101 ] ], "normalized": [] }, { "id": "PMID-11835401_T28", "type": "Gene_or_gene_product", "text": [ "Cyclin-dependent kinase-2" ], "offsets": [ [ 1103, 1128 ] ], "normalized": [] }, { "id": "PMID-11835401_T29", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 1139, 1143 ] ], "normalized": [] }, { "id": "PMID-11835401_T30", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 1148, 1156 ] ], "normalized": [] }, { "id": "PMID-11835401_T31", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 1169, 1191 ] ], "normalized": [] }, { "id": "PMID-11835401_T32", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1270, 1275 ] ], "normalized": [] }, { "id": "PMID-11835401_T33", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1325, 1330 ] ], "normalized": [] }, { "id": "PMID-11835401_T34", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "PMID-11835401_T35", "type": "Gene_or_gene_product", "text": [ "platelet-derived growth factor" ], "offsets": [ [ 1389, 1419 ] ], "normalized": [] }, { "id": "PMID-11835401_T36", "type": "Cell", "text": [ "smooth muscle cell" ], "offsets": [ [ 1462, 1480 ] ], "normalized": [] }, { "id": "PMID-11835401_T37", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 1517, 1525 ] ], "normalized": [] }, { "id": "PMID-11835401_T38", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase-2" ], "offsets": [ [ 1542, 1567 ] ], "normalized": [] }, { "id": "PMID-11835401_T58", "type": "Protein_domain_or_region", "text": [ "C-terminal Ca2+-binding region" ], "offsets": [ [ 827, 857 ] ], "normalized": [] } ]

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[ { "id": "PMID-8398065__text", "type": "abstract", "text": [ "Vitamins regulate gene expression and induce differentiation and growth inhibition in cancer cells. Their relevance in cancer prevention. \nAlthough several hypotheses for human carcinogenesis have been proposed, the specific genetic changes that cause normal cells to become cancer cells have not been identified. In spite of uncertainties regarding the mechanisms of carcinogenesis, several vitamins such as beta-carotene and vitamins A, C, and E, which can reduce the risk of cancer, have been identified, using animal and in vitro models of carcinogenesis. These studies have led to a hypothesis that the supplemental intake of these vitamins may reduce the risk of cancer. This hypothesis in humans can be tested only by intervention trials that are in progress. Prospective and retrospective case-controlled experimental designs are not suitable for testing the above hypothesis. The fact that some vitamins induce cell differentiation and/or growth inhibition in tumor cells in culture suggests that the use of these vitamins in cancer prevention has a cellular basis. In addition to having a direct effect on tumor cells, vitamins such as alpha-tocopheryl succinate and beta-carotene enhance the effect of other agents that induce differentiation in tumor cells. Some vitamins like beta-carotene, retinoic acid, alpha-tocopheryl succinate, and vitamin D also regulate the expressions of certain oncogenes and cellular genes. These are exciting new functions of vitamins that nobody could have predicted only a few years ago.\n" ], "offsets": [ [ 0, 1532 ] ] } ]

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[ { "id": "PMID-15331370__text", "type": "abstract", "text": [ "Enhanced IGF-1 expression improves smooth muscle cell engraftment after cell transplantation.\nThe functional benefit of cell transplantation after a myocardial infarction is diminished by early cell losses. IGF-1 enhances cell proliferation and survival. We hypothesized that IGF-1-transfected smooth muscle cells (SMCs) would enhance cell survival and improve engraftment after cell transplantation. The IGF-1 gene was transfected into male SMCs and compared with SMCs transfected with a plasmid vector (vector control) and nontransfected SMCs (cell control). IGF-1 mRNA (n=10/group) and protein levels (n=6/group) were higher (P less than 0.05 for all groups) at 3, 7, and 14 days compared with controls. VEGF was also increased in parallel to enhanced IGF-1 expression. IGF-1-transfected cells demonstrated greater cell proliferation, stimulated angiogenesis, and decreased caspase-3 activity after simulated ischemia and reperfusion (P less than 0.05 for all groups compared with vector or cell controls). A uniform left ventricular injury was produced in female rats using a cryoprobe. Three weeks later, 2 x 10(6) cells from three groups were implanted into the scar. One week later, IGF-1-transfected SMCs had increased myocardial IGF-1 and VEGF levels, increased Bcl2 expression, limited cell apoptosis, and enhanced vessel formation in the myocardial scar compared with the two control groups (P less than 0.05 for all groups). The proportion of SMCs surviving in the implanted region was greater (P less than 0.05) in the IGF-1-transfected group than in the vector or cell controls. Gene enhancement with IGF-1 improved donor cell proliferation, survival, and engraftment after cell transplantation, perhaps mediated by enhanced angiogenesis and reduced apoptosis.\n" ], "offsets": [ [ 0, 1779 ] ] } ]

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[ { "id": "PMID-15331370_1", "entity_ids": [ "PMID-15331370_T10", "PMID-15331370_T11" ] } ]

[]

[ { "id": "PMID-16374459__text", "type": "abstract", "text": [ "Regulation of skin microvasculature angiogenesis, cell migration, and permeability by a specific inhibitor of PKCalpha.\nActivation of protein kinase C (PKC) induces phenotypic changes in the morphology of microvascular endothelial cells that affect major functions of the microvasculature. These functions include the first stages of sprouting in angiogenesis, cell migration following wounding, and vascular permeability. The specific isoform(s) of PKC responsible for each of these changes has not been previously identified. In this study, we used two inflammatory agents, IL-1beta and phorbol myristic acetate, to activate PKC isozymes and specific inhibitors of PKCalpha (Go6976) and PKCbeta (hispidin) to distinguish how each of these isoform(s) controls angiogenesis, wound healing, and permeability. In all cases, only inhibition of PKCalpha inhibited each of these functions when compared to the inhibition of PKCbeta. Additional analysis of the mechanism of action of Go6976 (RT-PCR, Western blots, and immunohistochemistry) of the changes in the phosphorylated and nonphosphorylated forms of PKCalpha in the cell membrane and cytoplasm confirmed the specificity of PKCalpha inhibition by Go6976. These studies therefore indicate a specific and a regulatory role of the PKCalpha isoform in three major endothelial cell functions that are important in the maintenance of microvascular homeostasis.\n" ], "offsets": [ [ 0, 1407 ] ] } ]

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[]

[ { "id": "PMID-14555793__text", "type": "abstract", "text": [ "Therapeutic angiogenesis: a complex problem requiring a sophisticated approach.\nBlood and vascular disorders underlie a plethora of pathologic conditions and are the single most frequent cause of human disease. Ischemia, involving restricted blood flow to tissues is the most common consequence of vessel dysfunction resulting in the disruption of oxygen and nutrient delivery and the accumulation of waste metabolites. Cells cannot survive extended severe ischemia but may be able to adapt to a moderate condition where diffusion to and from bordering nonischemic regions sustains vital functions. Under this condition, the secondary functions of effected cells are likely to be impaired, and a new metabolic equilibrium is established, determined by the level of cross-diffusion and degree of hypoxia. In tissues with a normally high metabolic turnover such as skeletal and cardiac muscle, even mild ischemia causes hypoxia, acidosis, and depressed function (contractility) and eventually threatens myocyte viability and organ function. Ischemic cardiac muscle is additionally vulnerable because reperfusion is essential for survival but reperfusion itself poses additional stress principally from increased production of free radicals during reoxygenation. The latter effect is called reperfusion injury and can cause as much damage as the ischemia. The treatment possibilities for ischemia-related vascular disease are limited. Lipid/cholesterol-lowering agents, diet and antiplatelet adherence (aspirin) therapy may help slow the progression of vessel disease in some instances; but surgical reconstruction may be the only option in advanced stages, and even this is not always an option. An alternative and rather obvious strategy to treat ischemia is to activate endogenous angiogenic or arteriogenic pathways to stimulate revascularization of the tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade, and a new discipline called therapeutic angiogenesis has emerged. This review focuses on the application of therapeutic angiogenesis for treating ischemic muscle disease and includes a critical evaluation of the parameters and limitations of current procedures. The development of this technology has benefited from its application to both peripheral and coronary artery disease and results from both are reviewed here.\n" ], "offsets": [ [ 0, 2396 ] ] } ]

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[]

[]

[ { "id": "PMID-16907772__text", "type": "abstract", "text": [ "Formation of new bone during vertical distraction osteogenesis of the human mandible is related to the presence of blood vessels.\nWe examined the effect of distraction rate on blood vessel growth in intramembraneous ossification after vertical distraction osteogenesis in the human mandible. Six edentulous patients (aged 60+/-9 years) with a severely atrophic mandible underwent bone augmentation with distraction osteogenesis. Two distraction rates (0.5 and 1 mm/day) were compared and for each group three patients were analyzed. Vascular histomorphometry was carried out in two different areas in the distraction gap: (1) in the first and (2) in the second 1 mm area from the osteotomy line, representing the oldest and younger new-bone area, respectively. Correlation analysis was performed between blood vessel parameters and the amount of new bone formed during distraction. Histological analysis demonstrated the presence of blood vessels throughout the soft connective tissue in the distraction gap. The volume density of blood vessels between the two investigated areas was significantly lower in the 1 mm/day groups, suggesting a delay in angiogenesis in this group of patients. A positive correlation between blood vessel volume and bone volume density was found in the younger new-bone area but not in the oldest new-bone area. This correlation was due to a higher number of blood vessels rather than to a larger size of the blood vessels. Our data suggest that the lower blood vessel density found in the patients with 1 mm/day distraction rate may be related to disruption of angiogenesis in the soft connective tissue of the gap or to a less optimal mechanical stimulation of cells involved in angiogenesis. This probably results in the slower rate of osteogenesis seen at the 1 mm/day distraction rate compared with the 0.5 mm/day distraction rate. The data support the concept that a positive relationship exists between the density of blood vessels and the formation of bone. For distraction of the human mandible in elderly patients, a distraction rate of 0.5 mm/day seems beneficial.\n" ], "offsets": [ [ 0, 2105 ] ] } ]

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[]

[]

[ { "id": "PMID-21878661__text", "type": "abstract", "text": [ "Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD. \nSunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.\n" ], "offsets": [ [ 0, 2078 ] ] } ]

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139 ] ], "normalized": [] }, { "id": "PMID-21878661_T9", "type": "Simple_chemical", "text": [ "Sunitinib" ], "offsets": [ [ 142, 151 ] ], "normalized": [] }, { "id": "PMID-21878661_T10", "type": "Organism_subdivision", "text": [ "oral" ], "offsets": [ [ 158, 162 ] ], "normalized": [] }, { "id": "PMID-21878661_T11", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 240, 245 ] ], "normalized": [] }, { "id": "PMID-21878661_T12", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptors" ], "offsets": [ [ 275, 319 ] ], "normalized": [] }, { "id": "PMID-21878661_T13", "type": "Gene_or_gene_product", "text": [ "VEGFRs" ], "offsets": [ [ 321, 327 ] ], "normalized": [] }, { "id": "PMID-21878661_T14", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 345, 354 ] ], "normalized": [] }, { "id": "PMID-21878661_T15", "type": "Cancer", "text": [ "malignant pheochromocytomas" ], "offsets": [ [ 413, 440 ] ], "normalized": [] }, { "id": "PMID-21878661_T16", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 473, 482 ] ], "normalized": [] }, { "id": "PMID-21878661_T17", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 568, 579 ] ], "normalized": [] }, { "id": "PMID-21878661_T18", "type": "Simple_chemical", "text": [ "Sunitinib" ], "offsets": [ [ 581, 590 ] ], "normalized": [] }, { "id": "PMID-21878661_T19", "type": "Cell", "text": [ "PC12 cells" ], "offsets": [ [ 621, 631 ] ], "normalized": [] }, { "id": "PMID-21878661_T20", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 736, 745 ] ], "normalized": [] }, { "id": "PMID-21878661_T21", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 814, 819 ] ], "normalized": [] }, { "id": "PMID-21878661_T22", "type": "Gene_or_gene_product", "text": [ "BAD" ], "offsets": [ [ 878, 881 ] ], "normalized": [] }, { "id": "PMID-21878661_T23", "type": "Gene_or_gene_product", "text": [ "BAD" ], "offsets": [ [ 918, 921 ] ], "normalized": [] }, { "id": "PMID-21878661_T24", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 931, 936 ] ], "normalized": [] }, { "id": "PMID-21878661_T25", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 1003, 1012 ] ], "normalized": [] }, { "id": "PMID-21878661_T26", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1042, 1045 ] ], "normalized": [] }, { "id": "PMID-21878661_T27", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1050, 1054 ] ], "normalized": [] }, { "id": "PMID-21878661_T28", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 1090, 1094 ] ], "normalized": [] }, { "id": "PMID-21878661_T29", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1128, 1132 ] ], "normalized": [] }, { "id": "PMID-21878661_T30", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 1147, 1154 ] ], "normalized": [] }, { "id": "PMID-21878661_T31", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 1170, 1179 ] ], "normalized": [] }, { "id": "PMID-21878661_T32", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1285, 1288 ] ], "normalized": [] }, { "id": "PMID-21878661_T33", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1300, 1304 ] ], "normalized": [] }, { "id": "PMID-21878661_T34", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1310, 1315 ] ], "normalized": [] }, { "id": "PMID-21878661_T35", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 1373, 1380 ] ], "normalized": [] }, { "id": "PMID-21878661_T36", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 1408, 1412 ] ], "normalized": [] }, { "id": "PMID-21878661_T37", "type": "Gene_or_gene_product", "text": [ "BAD" ], "offsets": [ [ 1483, 1486 ] ], "normalized": [] }, { "id": "PMID-21878661_T38", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1491, 1496 ] ], "normalized": [] }, { "id": "PMID-21878661_T39", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 1528, 1537 ] ], "normalized": [] }, { "id": "PMID-21878661_T40", "type": "Simple_chemical", "text": [ "sunitinib" ], "offsets": [ [ 1591, 1600 ] ], "normalized": [] }, { "id": "PMID-21878661_T41", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 1665, 1672 ] ], "normalized": [] }, { "id": "PMID-21878661_T42", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1747, 1750 ] ], "normalized": [] }, { "id": "PMID-21878661_T43", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1751, 1755 ] ], "normalized": [] }, { "id": "PMID-21878661_T44", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 1756, 1760 ] ], "normalized": [] }, { "id": "PMID-21878661_T45", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1815, 1820 ] ], "normalized": [] }, { "id": "PMID-21878661_T46", "type": "Gene_or_gene_product", "text": [ "BAD" ], "offsets": [ [ 1865, 1868 ] ], "normalized": [] }, { "id": "PMID-21878661_T47", "type": "Cell", "text": [ "PC12 cells" ], "offsets": [ [ 1872, 1882 ] ], "normalized": [] }, { "id": "PMID-21878661_T48", "type": "Cell", "text": [ "PC12 cells" ], "offsets": [ [ 1893, 1903 ] ], "normalized": [] }, { "id": "PMID-21878661_T49", "type": "Cell", "text": [ "malignant cells" ], "offsets": [ [ 1949, 1964 ] ], "normalized": [] }, { "id": "PMID-21878661_T50", "type": "Organism", "text": [ "human" ], "offsets": [ [ 2043, 2048 ] ], "normalized": [] }, { "id": "PMID-21878661_T51", "type": "Cell", "text": [ "neuroblastoma SK-N-SH cells" ], "offsets": [ [ 2049, 2076 ] ], "normalized": [] } ]

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"text": [ "inhibiting" ], "offsets": [ [ 63, 73 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21878661_E6" }, { "role": "Cause", "ref_id": "PMID-21878661_E8" } ] }, { "id": "PMID-21878661_E6", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 95, 103 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21878661_T3" }, { "role": "Participant", "ref_id": "PMID-21878661_T4" }, { "role": "Participant", "ref_id": "PMID-21878661_T5" }, { "role": "Participant", "ref_id": "PMID-21878661_T6" } ] }, { "id": "PMID-21878661_E7", "type": "Regulation", "trigger": { "text": [ "modulation" ], "offsets": [ [ 112, 122 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21878661_T1" }, { "role": "Theme", "ref_id": "PMID-21878661_T7" } ] }, { "id": "PMID-21878661_E8", "type": "Regulation", "trigger": { "text": [ "modulation" ], "offsets": [ [ 112, 122 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21878661_T1" }, { "role": "Theme", "ref_id": 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[ { "id": "PMID-21878661_1", "entity_ids": [ "PMID-21878661_T12", "PMID-21878661_T13" ] } ]

[]

[ { "id": "PMID-16204028__text", "type": "abstract", "text": [ "The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis. \nThe adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/beta-catenin pathway. To investigate the dose-dependent effects of APC protein in suppressing intestinal tumorigenesis, we constructed mutant mice carrying hypomorphic Apc alleles Apc(neoR) and Apc(neoF) whose expression levels were reduced to 20% and 10% of the wild type, respectively. Although both hypomorphic heterozygotes developed intestinal polyps, tumor multiplicities were much lower than that in Apc(Delta716) mice, heterozygotes of an Apc null allele. Like in Apc(Delta716) mice, loss of the wild-type Apc allele was confirmed for all polyps examined in the Apc(neoR) and Apc(neoF) mice. In the embryonic stem cells homozygous for these hypomorphic Apc alleles, the level of the APC protein was inversely correlated with both the beta-catenin accumulation and beta-catenin/T-cell factor transcriptional activity. These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the beta-catenin/T-cell factor transcription. We further estimated the threshold of APC protein level that forms one polyp per mouse as approximately 15% of the wild type. These results also suggest therapeutic implications concerning Wnt signaling inhibitors.\n" ], "offsets": [ [ 0, 1467 ] ] } ]

[ { "id": "PMID-16204028_T1", "type": "Gene_or_gene_product", "text": [ "adenomatous polyposis coli" ], "offsets": [ [ 23, 49 ] ], "normalized": [] }, { "id": "PMID-16204028_T2", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 62, 67 ] ], "normalized": [] }, { "id": "PMID-16204028_T3", "type": "Organ", "text": [ "intestinal" ], "offsets": [ [ 68, 78 ] ], "normalized": [] }, { "id": "PMID-16204028_T4", "type": "Gene_or_gene_product", "text": [ "adenomatous polyposis coli" ], "offsets": [ [ 99, 125 ] ], "normalized": [] }, { "id": "PMID-16204028_T5", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 127, 130 ] ], "normalized": [] }, { "id": "PMID-16204028_T6", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 244, 247 ] ], "normalized": [] }, { "id": "PMID-16204028_T7", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 248, 260 ] ], "normalized": [] }, { "id": "PMID-16204028_T8", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 315, 318 ] ], "normalized": [] }, { "id": "PMID-16204028_T9", "type": "Organ", "text": [ "intestinal" ], "offsets": [ [ 342, 352 ] ], "normalized": [] }, { "id": "PMID-16204028_T10", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "PMID-16204028_T11", "type": "Gene_or_gene_product", "text": [ "Apc" ], "offsets": [ [ 416, 419 ] ], "normalized": [] }, { "id": "PMID-16204028_T12", "type": "Gene_or_gene_product", "text": [ "Apc(neoR)" ], "offsets": [ [ 428, 437 ] ], "normalized": [] }, { "id": "PMID-16204028_T13", "type": "Gene_or_gene_product", "text": [ "Apc(neoF)" ], "offsets": [ [ 442, 451 ] ], "normalized": [] }, { "id": "PMID-16204028_T14", "type": "Pathological_formation", "text": [ "intestinal polyps" ], "offsets": [ [ 586, 603 ] ], "normalized": [] }, { "id": "PMID-16204028_T15", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 605, 610 ] ], "normalized": [] }, { "id": "PMID-16204028_T16", "type": "Gene_or_gene_product", "text": [ "Apc(Delta716)" ], "offsets": [ [ 655, 668 ] ], "normalized": [] }, { "id": "PMID-16204028_T17", "type": "Organism", "text": [ "Apc(Delta716) mice" ], "offsets": [ [ 655, 673 ] ], "normalized": [] }, { "id": "PMID-16204028_T18", "type": "Gene_or_gene_product", "text": [ "Apc" ], "offsets": [ [ 695, 698 ] ], "normalized": [] }, { "id": "PMID-16204028_T19", "type": "Gene_or_gene_product", "text": [ "Apc(Delta716)" ], "offsets": [ [ 720, 733 ] ], "normalized": [] }, { "id": "PMID-16204028_T20", "type": "Organism", "text": [ "Apc(Delta716) mice" ], "offsets": [ [ 720, 738 ] ], "normalized": [] }, { "id": "PMID-16204028_T21", "type": "Gene_or_gene_product", "text": [ "Apc" ], "offsets": [ [ 762, 765 ] ], "normalized": [] }, { "id": "PMID-16204028_T22", "type": "Pathological_formation", "text": [ "polyps" ], "offsets": [ [ 795, 801 ] ], "normalized": [] }, { "id": "PMID-16204028_T23", "type": "Gene_or_gene_product", "text": [ "Apc(neoR)" ], "offsets": [ [ 818, 827 ] ], "normalized": [] }, { "id": "PMID-16204028_T24", "type": "Gene_or_gene_product", "text": [ "Apc(neoF)" ], "offsets": [ [ 832, 841 ] ], "normalized": [] }, { "id": "PMID-16204028_T25", "type": "Organism", "text": [ "Apc(neoF) mice" ], "offsets": [ [ 832, 846 ] ], "normalized": [] }, { "id": "PMID-16204028_T26", "type": "Cell", "text": [ "embryonic stem cells" ], "offsets": [ [ 855, 875 ] ], "normalized": [] }, { "id": "PMID-16204028_T27", "type": "Gene_or_gene_product", "text": [ "Apc" ], "offsets": [ [ 909, 912 ] ], "normalized": [] }, { "id": "PMID-16204028_T28", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 939, 942 ] ], "normalized": [] }, { "id": "PMID-16204028_T29", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 990, 1002 ] ], "normalized": [] }, { "id": "PMID-16204028_T30", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1020, 1032 ] ], "normalized": [] }, { "id": "PMID-16204028_T31", "type": "Gene_or_gene_product", "text": [ "T-cell factor" ], "offsets": [ [ 1033, 1046 ] ], "normalized": [] }, { "id": "PMID-16204028_T32", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 1112, 1115 ] ], "normalized": [] }, { "id": "PMID-16204028_T33", "type": "Pathological_formation", "text": [ "intestinal polyp" ], "offsets": [ [ 1140, 1156 ] ], "normalized": [] }, { "id": "PMID-16204028_T34", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1210, 1222 ] ], "normalized": [] }, { "id": "PMID-16204028_T35", "type": "Gene_or_gene_product", "text": [ "T-cell factor" ], "offsets": [ [ 1223, 1236 ] ], "normalized": [] }, { "id": "PMID-16204028_T36", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 1290, 1293 ] ], "normalized": [] }, { "id": "PMID-16204028_T37", "type": "Pathological_formation", "text": [ "polyp" ], "offsets": [ [ 1323, 1328 ] ], "normalized": [] }, { "id": "PMID-16204028_T38", "type": "Organism", "text": [ "mouse" ], 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[]

[ { "id": "PMID-21196400__text", "type": "abstract", "text": [ "MTSS1: a multifunctional protein and its role in cancer invasion and metastasis. \nMTSS1 (metastasis suppressor-1) was first identified as a metastasis suppressor missing in metastatic bladder carcinoma cell lines. The down-regulation of MTSS1 that may be caused by DNA methylation was also observed in many other types of cancer. While accumlating evidence for the function of MTSS1 support the concept that it is unlikely to be a metastasis suppressor, but actually acts as a scaffold protein that interacts with multiple partners to regulate actin dynamics. It has also been demonstrated that MTSS1 is involved in the Shh signaling pathway in the developing hair follicle and in basal cell carcinomas of the skin. Such evidence indicates that MTSS1 as a multiple functional molecular player and has an important role in development, carcinogenesis and metastasis. However, the biochemical mechanisms by which MTSS1 functions in cells and the physiological role of this protein in animals remain largely unknown. In this review, we will discuss the current knowledge of MTSS1's role in cancer metastasis, carcinogenesis, and development. The clinical significance of MTSS1 will also be discussed.\n" ], "offsets": [ [ 0, 1198 ] ] } ]

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[ { "id": "PMID-21196400_E1", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 41, 45 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T1" }, { "role": "Theme", "ref_id": "PMID-21196400_E3" } ] }, { "id": "PMID-21196400_E2", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 41, 45 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T1" }, { "role": "Theme", "ref_id": "PMID-21196400_E4" } ] }, { "id": "PMID-21196400_E3", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 56, 64 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T2" } ] }, { "id": "PMID-21196400_E4", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 69, 79 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T2" } ] }, { "id": "PMID-21196400_E5", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 140, 150 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E6", "type": "Negative_regulation", "trigger": { "text": [ "suppressor" ], "offsets": [ [ 151, 161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_E5" }, { "role": "Cause", "ref_id": "PMID-21196400_T3" } ] }, { "id": "PMID-21196400_E7", "type": "Metastasis", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 173, 183 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E8", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 218, 233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T6" } ] }, { "id": "PMID-21196400_E9", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 255, 261 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_E10" }, { "role": "Theme", "ref_id": "PMID-21196400_E8" } ] }, { "id": "PMID-21196400_E10", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 269, 280 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T7" } ] }, { "id": "PMID-21196400_E11", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 431, 441 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppressor" ], "offsets": [ [ 442, 452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_E11" }, { "role": "Cause", "ref_id": "PMID-21196400_T9" } ] }, { "id": "PMID-21196400_E13", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 499, 508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T9" } ] }, { "id": "PMID-21196400_E14", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 535, 543 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T10" }, { "role": "Cause", "ref_id": "PMID-21196400_E13" } ] }, { "id": "PMID-21196400_E15", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 604, 612 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T11" }, { "role": "Theme", "ref_id": "PMID-21196400_E16" } ] }, { "id": "PMID-21196400_E16", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 624, 641 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21196400_T12" } ] }, { "id": "PMID-21196400_E17", "type": "Development", "trigger": { "text": [ "developing" ], "offsets": [ [ 649, 659 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T13" } ] }, { "id": "PMID-21196400_E18", "type": "Regulation", "trigger": { "text": [ "important role" ], "offsets": [ [ 804, 818 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T16" }, { "role": "Theme", "ref_id": "PMID-21196400_E20" } ] }, { "id": "PMID-21196400_E19", "type": "Regulation", "trigger": { "text": [ "important role" ], "offsets": [ [ 804, 818 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T16" }, { "role": "Theme", "ref_id": "PMID-21196400_E21" } ] }, { "id": "PMID-21196400_E20", "type": "Carcinogenesis", "trigger": { "text": [ "carcinogenesis" ], "offsets": [ [ 835, 849 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E21", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 854, 864 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E22", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1079, 1083 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T19" }, { "role": "Theme", "ref_id": "PMID-21196400_E25" } ] }, { "id": "PMID-21196400_E23", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1079, 1083 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T19" }, { "role": "Theme", "ref_id": "PMID-21196400_E26" } ] }, { "id": "PMID-21196400_E24", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1079, 1083 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21196400_T19" }, { "role": "Theme", "ref_id": "PMID-21196400_E27" } ] }, { "id": "PMID-21196400_E25", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1094, 1104 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T20" } ] }, { "id": "PMID-21196400_E26", "type": "Carcinogenesis", "trigger": { "text": [ "carcinogenesis" ], "offsets": [ [ 1106, 1120 ] ] }, "arguments": [] }, { "id": "PMID-21196400_E27", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 1126, 1137 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21196400_T20" } ] } ]

[ { "id": "PMID-21196400_1", "entity_ids": [ "PMID-21196400_T3", "PMID-21196400_T4" ] } ]

[]

[ { "id": "PMID-19695243__text", "type": "abstract", "text": [ "Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer.\nMetronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.\n" ], "offsets": [ [ 0, 1997 ] ] } ]

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"normalized": [] }, { "id": "PMID-19695243_T9", "type": "Simple_chemical", "text": [ "oxaliplatin" ], "offsets": [ [ 519, 530 ] ], "normalized": [] }, { "id": "PMID-19695243_T10", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 532, 537 ] ], "normalized": [] }, { "id": "PMID-19695243_T11", "type": "Simple_chemical", "text": [ "5-fluorouracil" ], "offsets": [ [ 543, 557 ] ], "normalized": [] }, { "id": "PMID-19695243_T12", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-19695243_T13", "type": "Cancer", "text": [ "colorectal cancer" ], "offsets": [ [ 568, 585 ] ], "normalized": [] }, { "id": "PMID-19695243_T14", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 657, 661 ] ], "normalized": [] }, { "id": "PMID-19695243_T15", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 701, 735 ] ], "normalized": [] }, { "id": "PMID-19695243_T16", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 737, 741 ] ], "normalized": [] }, { "id": "PMID-19695243_T17", "type": "Cell", "text": [ "endothelial (HMVEC-d)" ], "offsets": [ [ 780, 801 ] ], "normalized": [] }, { "id": "PMID-19695243_T18", "type": "Cell", "text": [ "colorectal cancer (HT-29) cells" ], "offsets": [ [ 806, 837 ] ], "normalized": [] }, { "id": "PMID-19695243_T19", "type": "Simple_chemical", "text": [ "SN-38" ], "offsets": [ [ 888, 893 ] ], "normalized": [] }, { "id": "PMID-19695243_T20", "type": "Simple_chemical", "text": [ "CPT-11" ], "offsets": [ [ 920, 926 ] ], "normalized": [] }, { "id": "PMID-19695243_T21", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 928, 933 ] ], "normalized": [] }, { "id": "PMID-19695243_T22", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 938, 942 ] ], "normalized": [] }, { "id": "PMID-19695243_T23", "type": "Cell", "text": [ "HT-29" ], "offsets": [ [ 944, 949 ] ], "normalized": [] }, { "id": "PMID-19695243_T24", "type": "Organism", "text": [ "human" ], "offsets": [ [ 950, 955 ] ], "normalized": [] }, { "id": "PMID-19695243_T25", "type": "Cancer", "text": [ "colorectal cancer xenograft" ], "offsets": [ [ 956, 983 ] ], "normalized": [] }, { "id": "PMID-19695243_T26", "type": "Cancer", "text": [ "tumour" ], "offsets": [ [ 1003, 1009 ] ], "normalized": [] }, { "id": "PMID-19695243_T27", "type": "Tissue", "text": [ "microvessel" ], "offsets": [ [ 1018, 1029 ] ], "normalized": [] }, { "id": "PMID-19695243_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1042, 1046 ] ], "normalized": [] }, { "id": "PMID-19695243_T29", "type": "Cancer", "text": [ "tumours" ], "offsets": [ [ 1080, 1087 ] ], "normalized": [] }, { "id": "PMID-19695243_T30", "type": "Simple_chemical", "text": [ "CPT-11" ], "offsets": [ [ 1127, 1133 ] ], "normalized": [] }, { "id": "PMID-19695243_T31", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 1135, 1140 ] ], "normalized": [] }, { "id": "PMID-19695243_T32", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 1142, 1146 ] ], "normalized": [] }, { "id": "PMID-19695243_T33", "type": "Simple_chemical", "text": [ "SN-38" ], "offsets": [ [ 1205, 1210 ] ], "normalized": [] }, { "id": "PMID-19695243_T34", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 1220, 1224 ] ], "normalized": [] }, { "id": "PMID-19695243_T35", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 1229, 1234 ] ], "normalized": [] }, { "id": "PMID-19695243_T36", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1261, 1277 ] ], "normalized": [] }, { "id": "PMID-19695243_T37", "type": "Cell", "text": [ "HT-29" ], "offsets": [ [ 1333, 1338 ] ], "normalized": [] }, { "id": "PMID-19695243_T38", "type": "Cell", "text": [ "HMVEC-d cells" ], "offsets": [ [ 1343, 1356 ] ], "normalized": [] }, { "id": "PMID-19695243_T39", "type": "Simple_chemical", "text": [ "SN-38" ], "offsets": [ [ 1379, 1384 ] ], "normalized": [] }, { "id": "PMID-19695243_T40", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 1385, 1390 ] ], "normalized": [] }, { "id": "PMID-19695243_T41", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 1391, 1395 ] ], "normalized": [] }, { "id": "PMID-19695243_T42", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1546, 1550 ] ], "normalized": [] }, { "id": "PMID-19695243_T43", "type": "Cell", "text": [ "HT-29 cancer cells" ], "offsets": [ [ 1564, 1582 ] ], "normalized": [] }, { "id": "PMID-19695243_T44", "type": "Cancer", "text": [ "xenograft" ], "offsets": [ [ 1589, 1598 ] ], "normalized": [] }, { "id": "PMID-19695243_T45", "type": "Simple_chemical", "text": [ "CPT-11" ], "offsets": [ [ 1616, 1622 ] ], "normalized": [] }, { "id": "PMID-19695243_T46", "type": "Simple_chemical", "text": [ "5-FU" ], "offsets": [ [ 1632, 1636 ] ], "normalized": [] }, { "id": "PMID-19695243_T47", "type": "Simple_chemical", "text": [ "L-OHP" ], "offsets": [ [ 1641, 1646 ] 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{ "role": "Theme", "ref_id": "PMID-19695243_T6" } ] }, { "id": "PMID-19695243_E10", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 662, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19695243_T14" } ] }, { "id": "PMID-19695243_E11", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 743, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19695243_T15" } ] }, { "id": "PMID-19695243_E12", "type": "Planned_process", "trigger": { "text": [ "exposed" ], "offsets": [ [ 838, 845 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19695243_T19" }, { "role": "Theme", "ref_id": "PMID-19695243_T18" } ] }, { "id": "PMID-19695243_E13", "type": "Planned_process", "trigger": { "text": [ "exposed" ], "offsets": [ [ 838, 845 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19695243_T17" }, { "role": "Instrument", "ref_id": "PMID-19695243_T19" } ] }, { "id": "PMID-19695243_E14", "type": 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"Cause", "ref_id": "PMID-19695243_T46" } ] }, { "id": "PMID-19695243_E34", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1662, 1670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19695243_E35" }, { "role": "Cause", "ref_id": "PMID-19695243_T45" } ] }, { "id": "PMID-19695243_E35", "type": "Growth", "trigger": { "text": [ "tumor growth" ], "offsets": [ [ 1677, 1689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19695243_T48" } ] }, { "id": "PMID-19695243_E36", "type": "Planned_process", "trigger": { "text": [ "therapy" ], "offsets": [ [ 1788, 1795 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19695243_T52" }, { "role": "Instrument", "ref_id": "PMID-19695243_T51" }, { "role": "Instrument", "ref_id": "PMID-19695243_T50" } ] }, { "id": "PMID-19695243_E37", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1804, 1810 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19695243_E36" }, { "role": "Theme", "ref_id": "PMID-19695243_T53" } ] } ]

[ { "id": "PMID-19695243_1", "entity_ids": [ "PMID-19695243_T7", "PMID-19695243_T8" ] }, { "id": "PMID-19695243_2", "entity_ids": [ "PMID-19695243_T9", "PMID-19695243_T10" ] }, { "id": "PMID-19695243_3", "entity_ids": [ "PMID-19695243_T11", "PMID-19695243_T12" ] }, { "id": "PMID-19695243_4", "entity_ids": [ "PMID-19695243_T15", "PMID-19695243_T16" ] } ]

[]

[ { "id": "PMID-21743150__text", "type": "abstract", "text": [ "[Expression of Merlin protein in non-small cell lung carcinoma and the clinical significance]. \nOBJECTIVE: To determine the expression and clinical significance of Merlin protein in non-small cell lung cancer (NSCLC). METHODS: The expression of Merlin protein in 45 cases of NSCLC and adjacent tissue of NSCLC and normal lung tissue was checked by immunohistochemistry. The relation between the expression of Merlin protein and the multiple factors of pathological type, gender, P-TNM stage, differentiation and lymph node metastasis was analyzed. RESULTS: The expression rates of Merlin protein in NSCLC and normal lung tissue sections were 73.33% and 15.56%, respectively (P<0.05). The expression of Merlin protein was not associated with the pathological type, gender, P-TNM stage, differentiation and lymph node metastasis (P>0.05). CONCLUSION: Merlin protein might contribute to the initiation of metastasis of NSCLC.\n" ], "offsets": [ [ 0, 923 ] ] } ]

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[ { "id": "PMID-21743150_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 1, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T1" } ] }, { "id": "PMID-21743150_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 124, 134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T3" } ] }, { "id": "PMID-21743150_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 231, 241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T6" } ] }, { "id": "PMID-21743150_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 395, 405 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T11" } ] }, { "id": "PMID-21743150_E5", "type": "Cell_differentiation", "trigger": { "text": [ "differentiation" ], "offsets": [ [ 492, 507 ] ] }, "arguments": [] }, { "id": "PMID-21743150_E6", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 523, 533 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-21743150_T12" } ] }, { "id": "PMID-21743150_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 561, 571 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T13" } ] }, { "id": "PMID-21743150_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 688, 698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T16" } ] }, { "id": "PMID-21743150_E9", "type": "Cell_differentiation", "trigger": { "text": [ "differentiation" ], "offsets": [ [ 785, 800 ] ] }, "arguments": [] }, { "id": "PMID-21743150_E10", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 816, 826 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-21743150_T17" } ] }, { "id": "PMID-21743150_E11", "type": "Regulation", "trigger": { "text": [ "contribute" ], "offsets": [ [ 870, 880 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21743150_T18" }, { "role": "Theme", "ref_id": "PMID-21743150_E13" } ] }, { "id": "PMID-21743150_E12", "type": "Regulation", "trigger": { "text": [ "contribute" ], "offsets": [ [ 870, 880 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21743150_T18" }, { "role": "Theme", "ref_id": "PMID-21743150_E14" } ] }, { "id": "PMID-21743150_E13", "type": "Development", "trigger": { "text": [ "initiation" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T19" } ] }, { "id": "PMID-21743150_E14", "type": "Metastasis", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 902, 912 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21743150_T19" } ] } ]

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[]

[ { "id": "PMID-15015551__text", "type": "abstract", "text": [ "Morphogenesis of embryonic CNS vessels.\nThis chapter focuses on the morphology of blood vessel formation in and around the early central nervous system (CNS, i.e., brain and spinal cord) of avian embryos. We discuss cell lineages, proliferation and interactions of endothelial cells, pericytes and smooth muscle cells, and macrophages. Due to space limitations, we can not review the molecular control of CNS angiogenesis, but refer the reader to other chapters in this book and to recent publications on the assembly of the vasculature (1,2).\n" ], "offsets": [ [ 0, 544 ] ] } ]

[ { "id": "PMID-15015551_T1", "type": "Multi-tissue_structure", "text": [ "embryonic CNS vessels" ], "offsets": [ [ 17, 38 ] ], "normalized": [] }, { "id": "PMID-15015551_T2", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 82, 94 ] ], "normalized": [] }, { "id": "PMID-15015551_T3", "type": "Anatomical_system", "text": [ "central nervous system" ], "offsets": [ [ 129, 151 ] ], "normalized": [] }, { "id": "PMID-15015551_T4", "type": "Anatomical_system", "text": [ "CNS" ], "offsets": [ [ 153, 156 ] ], "normalized": [] }, { "id": "PMID-15015551_T5", "type": "Organ", "text": [ "brain" ], "offsets": [ [ 164, 169 ] ], "normalized": [] }, { "id": "PMID-15015551_T6", "type": "Organ", "text": [ "spinal cord" ], "offsets": [ [ 174, 185 ] ], "normalized": [] }, { "id": "PMID-15015551_T7", "type": "Organism", "text": [ "avian" ], "offsets": [ [ 190, 195 ] ], "normalized": [] }, { "id": "PMID-15015551_T8", "type": "Developing_anatomical_structure", "text": [ "embryos" ], "offsets": [ [ 196, 203 ] ], "normalized": [] }, { "id": "PMID-15015551_T9", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 216, 220 ] ], "normalized": [] }, { "id": "PMID-15015551_T10", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 265, 282 ] ], "normalized": [] }, { "id": "PMID-15015551_T11", "type": "Cell", "text": [ "pericytes" ], "offsets": [ [ 284, 293 ] ], "normalized": [] }, { "id": "PMID-15015551_T12", "type": "Cell", "text": [ "smooth muscle cells" ], "offsets": [ [ 298, 317 ] ], "normalized": [] }, { "id": "PMID-15015551_T13", "type": "Cell", "text": [ "macrophages" ], "offsets": [ [ 323, 334 ] ], "normalized": [] }, { "id": "PMID-15015551_T14", "type": "Anatomical_system", "text": [ "CNS" ], "offsets": [ [ 405, 408 ] ], "normalized": [] }, { "id": "PMID-15015551_T15", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 525, 536 ] ], "normalized": [] } ]

[ { "id": "PMID-15015551_E1", "type": "Development", "trigger": { "text": [ "Morphogenesis" ], "offsets": [ [ 0, 13 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T1" } ] }, { "id": "PMID-15015551_E2", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 95, 104 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T2" } ] }, { "id": "PMID-15015551_E3", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 231, 244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T10" } ] }, { "id": "PMID-15015551_E4", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 231, 244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T11" } ] }, { "id": "PMID-15015551_E5", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 231, 244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T12" } ] }, { "id": "PMID-15015551_E6", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 231, 244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T13" } ] }, { "id": "PMID-15015551_E7", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 249, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T10" } ] }, { "id": "PMID-15015551_E8", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 249, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T11" } ] }, { "id": "PMID-15015551_E9", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 249, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T12" } ] }, { "id": "PMID-15015551_E10", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 249, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T13" } ] }, { "id": "PMID-15015551_E11", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 394, 401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_E12" } ] }, { "id": "PMID-15015551_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 409, 421 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15015551_T14" } ] }, { "id": "PMID-15015551_E13", "type": "Development", "trigger": { "text": [ "assembly" ], "offsets": [ [ 509, 517 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15015551_T15" } ] } ]

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[]

[ { "id": "PMID-12855648__text", "type": "abstract", "text": [ "Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis.\nPURPOSE: Molecular antagonists of the inhibitor of apoptosis protein survivin have shown promise as novel anticancer strategies for triggering tumor cell apoptosis, dysregulating mitotic progression, and inhibiting tumor growth in preclinical models. However, how survivin couples to the cell death machinery has remained elusive, and the relevant cellular targets of survivin antagonists have not been completely elucidated. Experimental Design: Human umbilical vein and dermal microvascular endothelial cells were infected with replication-deficient adenoviruses encoding survivin (pAd-Survivin), green fluorescent protein (pAd-GFP), or a phosphorylation-defective survivin Thr(34)-->Ala (pAd-T34A) dominant negative mutant. The effect of wild-type or mutant survivin was investigated on capillary network stability, endothelial cell viability, and caspase activation in vitro and on kinetics of tumor growth and development of angiogenesis in a breast cancer xenograft model in vivo. The cell death pathway initiated by survivin targeting was mapped with respect to cytochrome c release, changes in mitochondrial transmembrane potential, and apoptosome requirements using mouse embryonic fibroblasts deficient in Apaf-1 or caspase-9. RESULTS: Adenoviral transduction of endothelial cells with pAd-Survivin inhibited growth factor deprivation- or ceramide-induced apoptosis, reduced caspase-3 and -7 generation, and stabilized three-dimensional capillary networks in vitro. Conversely, expression of pAd-T34A caused apoptosis in umbilical vein and dermal microvascular endothelial cells and resulted in caspase-3 activity. Cell death induced by survivin targeting exhibited the hallmarks of mitochondrial-dependent apoptosis with release of cytochrome c and loss of mitochondrial transmembrane potential and was suppressed in Apaf-1 or caspase-9 knockout mouse embryonic fibroblasts. When injected in human breast cancer xenografts, pAd-T34A inhibited growth of established tumors and triggered tumor cell apoptosis in vivo. This was associated with a approximately 60% reduction in tumor-derived blood vessels by quantitative morphometry of CD31-stained tumor areas, and appearance of endothelial cell apoptosis by internucleosomal DNA fragmentation in vivo. CONCLUSIONS: Survivin functions as a novel upstream regulator of mitochondrial-dependent apoptosis, and molecular targeting of this pathway results in anticancer activity via a dual mechanism of induction of tumor cell apoptosis and suppression of angiogenesis.\n" ], "offsets": [ [ 0, 2669 ] ] } ]

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"PMID-12855648_T9", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 409, 417 ] ], "normalized": [] }, { "id": "PMID-12855648_T10", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 433, 437 ] ], "normalized": [] }, { "id": "PMID-12855648_T11", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 493, 501 ] ], "normalized": [] }, { "id": "PMID-12855648_T12", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 513, 521 ] ], "normalized": [] }, { "id": "PMID-12855648_T13", "type": "Organism", "text": [ "Human" ], "offsets": [ [ 592, 597 ] ], "normalized": [] }, { "id": "PMID-12855648_T14", "type": "Cell", "text": [ "umbilical vein" ], "offsets": [ [ 598, 612 ] ], "normalized": [] }, { "id": "PMID-12855648_T15", "type": "Cell", "text": [ "dermal microvascular endothelial cells" ], "offsets": [ [ 617, 655 ] ], "normalized": [] }, { "id": "PMID-12855648_T16", "type": "Organism", "text": [ "adenoviruses" ], "offsets": [ [ 697, 709 ] ], "normalized": [] }, { "id": "PMID-12855648_T17", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 719, 727 ] ], "normalized": [] }, { "id": "PMID-12855648_T18", "type": "Gene_or_gene_product", "text": [ "pAd-Survivin" ], "offsets": [ [ 729, 741 ] ], "normalized": [] }, { "id": "PMID-12855648_T19", "type": "Gene_or_gene_product", "text": [ "green fluorescent protein" ], "offsets": [ [ 744, 769 ] ], "normalized": [] }, { "id": "PMID-12855648_T20", "type": "Gene_or_gene_product", "text": [ "pAd-GFP" ], "offsets": [ [ 771, 778 ] ], "normalized": [] }, { "id": "PMID-12855648_T21", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 812, 820 ] ], "normalized": [] }, { "id": "PMID-12855648_T22", "type": "Gene_or_gene_product", "text": [ "pAd-T34A" ], "offsets": [ [ 836, 844 ] ], "normalized": [] }, { "id": "PMID-12855648_T23", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 906, 914 ] ], "normalized": [] }, { "id": "PMID-12855648_T24", "type": "Multi-tissue_structure", "text": [ "capillary network" ], "offsets": [ [ 935, 952 ] ], "normalized": [] }, { "id": "PMID-12855648_T25", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 964, 980 ] ], "normalized": [] }, { "id": "PMID-12855648_T26", "type": "Gene_or_gene_product", "text": [ "caspase" ], "offsets": [ [ 996, 1003 ] ], "normalized": [] }, { "id": "PMID-12855648_T27", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1043, 1048 ] ], "normalized": [] }, { "id": "PMID-12855648_T28", "type": "Cancer", "text": [ "breast cancer xenograft" ], "offsets": [ [ 1093, 1116 ] ], "normalized": [] }, { "id": "PMID-12855648_T29", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1136, 1140 ] ], "normalized": [] }, { "id": "PMID-12855648_T30", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 1168, 1176 ] ], "normalized": [] }, { "id": "PMID-12855648_T31", "type": "Gene_or_gene_product", "text": [ "cytochrome c" ], "offsets": [ [ 1214, 1226 ] ], "normalized": [] }, { "id": "PMID-12855648_T32", "type": "Cellular_component", "text": [ "mitochondrial" ], "offsets": [ [ 1247, 1260 ] ], "normalized": [] }, { "id": "PMID-12855648_T33", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 1320, 1325 ] ], "normalized": [] }, { "id": "PMID-12855648_T34", "type": "Cell", "text": [ "embryonic fibroblasts" ], "offsets": [ [ 1326, 1347 ] ], "normalized": [] }, { "id": "PMID-12855648_T35", "type": "Gene_or_gene_product", "text": [ "Apaf-1" ], "offsets": [ [ 1361, 1367 ] ], "normalized": [] }, { "id": "PMID-12855648_T36", "type": "Gene_or_gene_product", "text": [ "caspase-9" ], "offsets": [ [ 1371, 1380 ] ], "normalized": [] }, { "id": "PMID-12855648_T37", "type": "Organism", "text": [ "Adenoviral" ], "offsets": [ [ 1391, 1401 ] ], "normalized": [] }, { "id": "PMID-12855648_T38", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1418, 1435 ] ], "normalized": [] }, { "id": "PMID-12855648_T39", "type": "Gene_or_gene_product", "text": [ "pAd-Survivin" ], "offsets": [ [ 1441, 1453 ] ], "normalized": [] }, { "id": "PMID-12855648_T40", "type": "Simple_chemical", "text": [ "ceramide" ], "offsets": [ [ 1494, 1502 ] ], "normalized": [] }, { "id": "PMID-12855648_T41", "type": "Gene_or_gene_product", "text": [ "caspase-3" ], "offsets": [ [ 1530, 1539 ] ], "normalized": [] }, { "id": "PMID-12855648_T42", "type": "Gene_or_gene_product", "text": [ "-7" ], "offsets": [ [ 1544, 1546 ] ], "normalized": [] }, { "id": "PMID-12855648_T43", "type": "Multi-tissue_structure", "text": [ "capillary networks" ], "offsets": [ [ 1592, 1610 ] ], "normalized": [] }, { "id": "PMID-12855648_T44", "type": "Gene_or_gene_product", "text": [ "pAd-T34A" ], "offsets": [ [ 1647, 1655 ] ], "normalized": [] }, { "id": "PMID-12855648_T45", "type": "Cell", "text": [ "umbilical vein" ], "offsets": [ [ 1676, 1690 ] ], "normalized": [] }, { "id": "PMID-12855648_T46", "type": "Cell", "text": [ "dermal microvascular 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[]

[]

[ { "id": "PMID-11957196__text", "type": "abstract", "text": [ "Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias. \nGranulocyte colony-stimulating factor (G-CSF) has had a major impact on the management of \"severe chronic neutropenia\" (SCN), a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia and Shwachman-Diamond syndrome (SDS) have developed myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. To address this, the Severe Chronic Neutropenia International Registry (SCNIR) used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. In murine models, the latter produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. Since congenital neutropenia and SDS are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an \"innocent bystander\" that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. In patients who transform to overt MDS or AML, hematopoietic stem cell transplantation is the only chance for cure. In those with \"soft\" signs of MDS, such as an isolated clonal cytogenetic change but without other evidence of MDS, or with an isolated G-CSF receptor mutation, there is room for conservative management. One option is to reduce the G-CSF dosage as much as possible, and observe the tempo of progression, if any, to more overt signs of malignancy.\n" ], "offsets": [ [ 0, 2554 ] ] } ]

[ { "id": "PMID-11957196_T1", "type": "Cancer", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 37, 59 ] ], "normalized": [] }, { "id": "PMID-11957196_T2", "type": "Gene_or_gene_product", "text": [ "Granulocyte colony-stimulating factor" ], "offsets": [ [ 89, 126 ] ], "normalized": [] }, { "id": "PMID-11957196_T3", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 128, 133 ] ], "normalized": [] }, { "id": "PMID-11957196_T4", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 304, 312 ] ], "normalized": [] }, { "id": "PMID-11957196_T5", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 324, 329 ] ], "normalized": [] }, { "id": "PMID-11957196_T6", "type": "Cell", "text": [ "neutrophils" ], "offsets": [ [ 345, 356 ] ], "normalized": [] }, { "id": "PMID-11957196_T7", "type": "Cancer", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 526, 548 ] ], "normalized": [] }, { "id": "PMID-11957196_T8", "type": "Cancer", "text": [ "AML" ], "offsets": [ [ 554, 557 ] ], "normalized": [] }, { "id": "PMID-11957196_T9", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 601, 606 ] ], "normalized": [] }, { "id": "PMID-11957196_T10", "type": "Cancer", "text": [ "AML" ], "offsets": [ [ 701, 704 ] ], "normalized": [] }, { "id": "PMID-11957196_T11", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 865, 873 ] ], "normalized": [] }, { "id": "PMID-11957196_T12", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 887, 892 ] ], "normalized": [] }, { "id": "PMID-11957196_T13", "type": "Cell", "text": [ "malignant myeloid" ], "offsets": [ [ 923, 940 ] ], "normalized": [] }, { "id": "PMID-11957196_T14", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1025, 1032 ] ], "normalized": [] }, { "id": "PMID-11957196_T15", "type": "Cancer", "text": [ "AML" ], "offsets": [ [ 1135, 1138 ] ], "normalized": [] }, { "id": "PMID-11957196_T16", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1143, 1150 ] ], "normalized": [] }, { "id": "PMID-11957196_T17", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "PMID-11957196_T18", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 1186, 1191 ] ], "normalized": [] }, { "id": "PMID-11957196_T19", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 1271, 1279 ] ], "normalized": [] }, { "id": "PMID-11957196_T20", "type": "Cell", "text": [ "marrow cells" ], "offsets": [ [ 1299, 1311 ] ], "normalized": [] }, { "id": "PMID-11957196_T21", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1317, 1325 ] ], "normalized": [] }, { "id": "PMID-11957196_T22", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 1364, 1367 ] ], "normalized": [] }, { "id": "PMID-11957196_T23", "type": "Gene_or_gene_product", "text": [ "G-CSF receptor" ], "offsets": [ [ 1426, 1440 ] ], "normalized": [] }, { "id": "PMID-11957196_T24", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 1455, 1461 ] ], "normalized": [] }, { "id": "PMID-11957196_T25", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 1523, 1528 ] ], "normalized": [] }, { "id": "PMID-11957196_T26", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1576, 1580 ] ], "normalized": [] }, { "id": "PMID-11957196_T27", "type": "Multi-tissue_structure", "text": [ "bone marrow" ], "offsets": [ [ 1651, 1662 ] ], "normalized": [] }, { "id": "PMID-11957196_T28", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 1672, 1677 ] ], "normalized": [] }, { "id": "PMID-11957196_T29", "type": "Cancer", "text": [ "AML" ], "offsets": [ [ 1716, 1719 ] ], "normalized": [] }, { "id": "PMID-11957196_T30", "type": "Cell", "text": [ "stem" ], "offsets": [ [ 1747, 1751 ] ], "normalized": [] }, { "id": "PMID-11957196_T31", "type": "Cell", "text": [ "progenitor cells" ], "offsets": [ [ 1756, 1772 ] ], "normalized": [] }, { "id": "PMID-11957196_T32", "type": "Gene_or_gene_product", "text": [ "G-CSF receptor" ], "offsets": [ [ 1799, 1813 ] ], "normalized": [] }, { "id": "PMID-11957196_T33", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 1818, 1821 ] ], "normalized": [] }, { "id": "PMID-11957196_T34", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1848, 1856 ] ], "normalized": [] }, { "id": "PMID-11957196_T35", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 1925, 1930 ] ], "normalized": [] }, { "id": "PMID-11957196_T36", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 2005, 2012 ] ], "normalized": [] }, { "id": "PMID-11957196_T37", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 2094, 2102 ] ], "normalized": [] }, { "id": "PMID-11957196_T38", "type": "Cancer", "text": [ "AML" ], "offsets": [ [ 2133, 2136 ] ], "normalized": [] }, { "id": "PMID-11957196_T39", "type": "Cell", "text": [ "hematopoietic stem cell" ], "offsets": [ [ 2138, 2161 ] ], "normalized": [] }, { "id": "PMID-11957196_T40", "type": "Gene_or_gene_product", "text": [ "G-CSF receptor" ], "offsets": [ [ 2343, 2357 ] ], "normalized": [] }, { "id": "PMID-11957196_T41", "type": "Gene_or_gene_product", "text": [ "G-CSF" ], "offsets": [ [ 2439, 2444 ] ], "normalized": [] }, { "id": "PMID-11957196_T42", "type": "Cancer", "text": [ "malignancy" ], "offsets": [ [ 2542, 2552 ] ], "normalized": [] } ]

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"ref_id": "PMID-11957196_T9" }, { "role": "Theme", "ref_id": "PMID-11957196_E11" } ] }, { "id": "PMID-11957196_E11", "type": "Development", "trigger": { "text": [ "pathogenesis" ], "offsets": [ [ 610, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T7" } ] }, { "id": "PMID-11957196_E12", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 874, 881 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11957196_T12" }, { "role": "Theme", "ref_id": "PMID-11957196_T11" } ] }, { "id": "PMID-11957196_E13", "type": "Cell_transformation", "trigger": { "text": [ "transformation" ], "offsets": [ [ 941, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T13" } ] }, { "id": "PMID-11957196_E14", "type": "Planned_process", "trigger": { "text": [ "therapy" ], "offsets": [ [ 1192, 1199 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11957196_T18" } ] }, { "id": "PMID-11957196_E15", "type": "Mutation", "trigger": { "text": [ "genetic changes" ], "offsets": [ [ 1280, 1295 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-11957196_T20" } ] }, { "id": "PMID-11957196_E16", "type": "Positive_regulation", "trigger": { "text": [ "activating" ], "offsets": [ [ 1353, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T22" } ] }, { "id": "PMID-11957196_E17", "type": "Mutation", "trigger": { "text": [ "mutations" ], "offsets": [ [ 1377, 1386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T22" } ] }, { "id": "PMID-11957196_E18", "type": "Mutation", "trigger": { "text": [ "clonal cytogenetic abnormalities" ], "offsets": [ [ 1388, 1420 ] ] }, "arguments": [] }, { "id": "PMID-11957196_E19", "type": "Mutation", "trigger": { "text": [ "mutations" ], "offsets": [ [ 1441, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T23" } ] }, { "id": "PMID-11957196_E20", "type": "Cell_proliferation", "trigger": { "text": [ "hyperproliferative" ], "offsets": [ [ 1492, 1510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T20" } ] }, { "id": "PMID-11957196_E21", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 1511, 1519 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11957196_T25" }, { "role": "Theme", "ref_id": "PMID-11957196_E20" } ] }, { "id": "PMID-11957196_E22", "type": "Negative_regulation", "trigger": { "text": [ "resistance" ], "offsets": [ [ 1538, 1548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_E23" } ] }, { "id": "PMID-11957196_E23", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1552, 1561 ] ] }, "arguments": [] }, { "id": "PMID-11957196_E24", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 1567, 1575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_E25" } ] }, { "id": "PMID-11957196_E25", "type": "Death", "trigger": { "text": [ "survival" ], "offsets": [ [ 1581, 1589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T26" } ] }, { "id": "PMID-11957196_E26", "type": "Positive_regulation", "trigger": { "text": [ "accelerate" ], "offsets": [ [ 1682, 1692 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11957196_T28" }, { "role": "Theme", "ref_id": "PMID-11957196_T29" } ] }, { "id": "PMID-11957196_E27", "type": "Mutation", "trigger": { "text": [ "genetically altered" ], "offsets": [ [ 1727, 1746 ] ] }, "arguments": [] }, { "id": "PMID-11957196_E28", "type": "Mutation", "trigger": { "text": [ "mutations" ], "offsets": [ [ 1822, 1831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T33" } ] }, { "id": "PMID-11957196_E29", "type": "Mutation", "trigger": { "text": [ "mutations" ], "offsets": [ [ 1822, 1831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11957196_T32" } ] }, { "id": "PMID-11957196_E30", "type": "Positive_regulation", "trigger": { "text": [ "prolongs" ], "offsets": [ [ 1996, 2004 ] ] }, 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[ { "id": "PMID-11957196_1", "entity_ids": [ "PMID-11957196_T2", "PMID-11957196_T3" ] }, { "id": "PMID-11957196_2", "entity_ids": [ "PMID-11957196_T7", "PMID-11957196_T8" ] } ]

[]

[ { "id": "PMID-18565374__text", "type": "abstract", "text": [ "Contemporary perspectives on vital pulp therapy: views from the endodontists and pediatric dentists.\nThe purpose of this study was to determine the level of agreement between pediatric dentists and endodontists at a pulp therapy symposium conjointly sponsored by the American Association of Endodontists (AAE) and the American Academy of Pediatric Dentistry (AAPD) on November 2-3, 2007. Presymposium and postsymposium tests were administered, and respondent answers were compared between pediatric dentists and endodontists. Opinions on 3 areas were sought: pulp therapy for cariously involved primary teeth; indirect pulp treatment (IPT) for cariously involved immature permanent teeth; and innovative treatment options including pulpal revascularization and regeneration. Results were analyzed with chi2 tests. Comparisons of presymposium and postsymposium responses and between the 2 groups of attendees indicated that the pediatric dentistry and endodontic communities agree that formocresol will be replaced as a primary tooth pulpotomy agent, that mineral trioxide is the first choice to take its place, that IPT in primary teeth holds hope as a replacement for pulpotomy, and that IPT is an acceptable pulp therapy technique for cariously involved young permanent teeth. Both groups believe that pulp revascularization and regeneration will be viable treatment modalities in the future. The AAE and the AAPD are positioned to begin preparation of best practice guidelines that share common language and treatment recommendations for pulp therapies performed by both specialties.\n" ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "PMID-18565374_T1", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 35, 39 ] ], "normalized": [] }, { "id": "PMID-18565374_T2", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 216, 220 ] ], "normalized": [] }, { "id": "PMID-18565374_T3", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-18565374_T4", "type": "Organ", "text": [ "teeth" ], "offsets": [ [ 603, 608 ] ], "normalized": [] }, { "id": "PMID-18565374_T5", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 619, 623 ] ], "normalized": [] }, { "id": "PMID-18565374_T6", "type": "Organ", "text": [ "teeth" ], "offsets": [ [ 682, 687 ] ], "normalized": [] }, { "id": "PMID-18565374_T7", "type": "Tissue", "text": [ "pulpal" ], "offsets": [ [ 732, 738 ] ], "normalized": [] }, { "id": "PMID-18565374_T8", "type": "Simple_chemical", "text": [ "formocresol" ], "offsets": [ [ 985, 996 ] ], "normalized": [] }, { "id": "PMID-18565374_T9", "type": "Organ", "text": [ "tooth" ], "offsets": [ [ 1027, 1032 ] ], "normalized": [] }, { "id": "PMID-18565374_T10", "type": "Simple_chemical", "text": [ "mineral trioxide" ], "offsets": [ [ 1055, 1071 ] ], "normalized": [] }, { "id": "PMID-18565374_T11", "type": "Organ", "text": [ "teeth" ], "offsets": [ [ 1131, 1136 ] ], "normalized": [] }, { "id": "PMID-18565374_T12", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 1210, 1214 ] ], "normalized": [] }, { "id": "PMID-18565374_T13", "type": "Organ", "text": [ "teeth" ], "offsets": [ [ 1272, 1277 ] ], "normalized": [] }, { "id": "PMID-18565374_T14", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 1304, 1308 ] ], "normalized": [] }, { "id": "PMID-18565374_T15", "type": "Tissue", "text": [ "pulp" ], "offsets": [ [ 1541, 1545 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-18469146__text", "type": "abstract", "text": [ "Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells.\nPhysiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1alpha protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.\n" ], "offsets": [ [ 0, 1972 ] ] } ]

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"normalized": [] }, { "id": "PMID-18469146_T24", "type": "Simple_chemical", "text": [ "ethanol" ], "offsets": [ [ 918, 925 ] ], "normalized": [] }, { "id": "PMID-18469146_T25", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 959, 970 ] ], "normalized": [] }, { "id": "PMID-18469146_T26", "type": "Gene_or_gene_product", "text": [ "VEGF receptor-2" ], "offsets": [ [ 971, 986 ] ], "normalized": [] }, { "id": "PMID-18469146_T27", "type": "Gene_or_gene_product", "text": [ "VEGF receptor-2" ], "offsets": [ [ 999, 1014 ] ], "normalized": [] }, { "id": "PMID-18469146_T28", "type": "Simple_chemical", "text": [ "ethanol" ], "offsets": [ [ 1055, 1062 ] ], "normalized": [] }, { "id": "PMID-18469146_T29", "type": "Simple_chemical", "text": [ "4-methylpyrazole" ], "offsets": [ [ 1077, 1093 ] ], "normalized": [] }, { "id": "PMID-18469146_T30", "type": "Simple_chemical", "text": [ "ethanol" ], "offsets": [ [ 1128, 1135 ] ], "normalized": [] }, { "id": "PMID-18469146_T31", "type": "Tissue", "text": [ "endothelial cell cord" ], "offsets": [ [ 1139, 1160 ] ], "normalized": [] }, { "id": "PMID-18469146_T32", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1181, 1185 ] ], "normalized": [] }, { "id": "PMID-18469146_T33", "type": "Simple_chemical", "text": [ "t-butanol" ], "offsets": [ [ 1199, 1208 ] ], "normalized": [] }, { "id": "PMID-18469146_T34", "type": "Simple_chemical", "text": [ "alcohol" ], "offsets": [ [ 1213, 1220 ] ], "normalized": [] }, { "id": "PMID-18469146_T35", "type": "Gene_or_gene_product", "text": [ "alcohol dehydrogenase" ], "offsets": [ [ 1240, 1261 ] ], "normalized": [] }, { "id": "PMID-18469146_T36", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1286, 1291 ] ], "normalized": [] }, { "id": "PMID-18469146_T37", "type": "Simple_chemical", "text": [ "ethanol" ], "offsets": [ [ 1344, 1351 ] ], "normalized": [] }, { "id": "PMID-18469146_T38", "type": "Simple_chemical", "text": [ "ethanol" ], "offsets": [ [ 1407, 1414 ] ], 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[]

[]

[ { "id": "PMID-8874381__text", "type": "abstract", "text": [ "Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo.\nVascular endothelial growth factor (VEGF) is a naturally secreted endothelial cell-specific mitogen. We investigated the hypothesis that naked DNA encoding for VEGF could be used in a strategy of arterial gene therapy to stimulate collateral artery development. Plasmid DNA encoding each of the three principal human VEGF isoforms (phVEGF121, phVEGF165, or phVEGF189) was applied to the hydrogel polymer coating of an angioplasty balloon and delivered percutaneously to one iliac artery of rabbits with operatively induced hindlimb ischemia. Compared with control animals transfected with LacZ, site-specific transfection of phVEGF resulted in augmented collateral vessel development documented by serial angiography, and improvement in calf blood pressure ratio (ischemic to normal limb), resting and maximum blood flow, and capillary to myocyte ratio. Similar results were obtained with phVEGF121, phVEGF165, and phVEGF189, which suggests that these isoforms are biologically equivalent with respect to in vivo angiogenesis. The fact that viral or other adjunctive vectors were not required further suggests that secreted gene products may have potential therapeutic utility even when the number of successfully transfected cells remains low. Arterial gene transfer of naked DNA encoding for a secreted angiogenic cytokine, thus, represents a potential alternative to recombinant protein administration for stimulating collateral vessel development.\n" ], "offsets": [ [ 0, 1588 ] ] } ]

[ { "id": "PMID-8874381_T1", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 23, 26 ] ], "normalized": [] }, { "id": "PMID-8874381_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 58, 92 ] ], "normalized": [] }, { "id": "PMID-8874381_T3", "type": "Multi-tissue_structure", "text": [ "collateral" ], "offsets": [ [ 104, 114 ] ], "normalized": [] }, { "id": "PMID-8874381_T4", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 136, 170 ] ], "normalized": [] }, { "id": "PMID-8874381_T5", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 172, 176 ] ], "normalized": [] }, { "id": "PMID-8874381_T6", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 202, 218 ] ], "normalized": [] }, { "id": "PMID-8874381_T7", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 279, 282 ] ], "normalized": [] }, { "id": "PMID-8874381_T8", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "PMID-8874381_T9", "type": "Multi-tissue_structure", "text": [ "arterial" ], "offsets": [ [ 332, 340 ] ], "normalized": [] }, { "id": "PMID-8874381_T10", "type": "Multi-tissue_structure", "text": [ "collateral artery" ], "offsets": [ [ 367, 384 ] ], "normalized": [] }, { "id": "PMID-8874381_T11", "type": "Cellular_component", "text": [ "Plasmid DNA" ], "offsets": [ [ 398, 409 ] ], "normalized": [] }, { "id": "PMID-8874381_T12", "type": "Organism", "text": [ "human" ], "offsets": [ [ 447, 452 ] ], "normalized": [] }, { "id": "PMID-8874381_T13", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 453, 457 ] ], "normalized": [] }, { "id": "PMID-8874381_T14", "type": "Gene_or_gene_product", "text": [ "phVEGF121" ], "offsets": [ [ 468, 477 ] ], "normalized": [] }, { "id": "PMID-8874381_T15", "type": "Gene_or_gene_product", "text": [ "phVEGF165" ], "offsets": [ [ 479, 488 ] ], "normalized": [] }, { "id": "PMID-8874381_T16", "type": "Gene_or_gene_product", "text": [ "phVEGF189" ], "offsets": [ [ 493, 502 ] ], "normalized": [] }, { "id": "PMID-8874381_T17", "type": "Multi-tissue_structure", "text": [ "iliac artery" ], "offsets": [ [ 610, 622 ] ], "normalized": [] }, { "id": "PMID-8874381_T18", "type": "Organism", "text": [ "rabbits" ], "offsets": [ [ 626, 633 ] ], "normalized": [] }, { "id": "PMID-8874381_T19", "type": "Organism_subdivision", "text": [ "hindlimb" ], "offsets": [ [ 659, 667 ] ], "normalized": [] }, { "id": "PMID-8874381_T20", "type": "Gene_or_gene_product", "text": [ "LacZ" ], "offsets": [ [ 725, 729 ] ], "normalized": [] }, { "id": "PMID-8874381_T21", "type": "Gene_or_gene_product", "text": [ "phVEGF" ], "offsets": [ [ 761, 767 ] ], "normalized": [] }, { "id": "PMID-8874381_T22", "type": "Multi-tissue_structure", "text": [ "collateral vessel" ], "offsets": [ [ 790, 807 ] ], "normalized": [] }, { "id": "PMID-8874381_T23", "type": "Organism_subdivision", "text": [ "calf" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "PMID-8874381_T24", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 878, 883 ] ], "normalized": [] }, { "id": "PMID-8874381_T25", "type": "Organism_subdivision", "text": [ "ischemic" ], "offsets": [ [ 900, 908 ] ], "normalized": [] }, { "id": "PMID-8874381_T26", "type": "Organism_subdivision", "text": [ "normal limb" ], "offsets": [ [ 912, 923 ] ], "normalized": [] }, { "id": "PMID-8874381_T27", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 946, 951 ] ], "normalized": [] }, { "id": "PMID-8874381_T28", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 962, 971 ] ], "normalized": [] }, { "id": "PMID-8874381_T29", "type": "Cell", "text": [ "myocyte" ], "offsets": [ [ 975, 982 ] ], "normalized": [] }, { "id": "PMID-8874381_T30", "type": "Gene_or_gene_product", "text": [ "phVEGF121" ], "offsets": [ [ 1025, 1034 ] ], "normalized": [] }, { "id": "PMID-8874381_T31", "type": "Gene_or_gene_product", "text": [ "phVEGF165" ], "offsets": [ [ 1036, 1045 ] ], "normalized": [] }, { "id": "PMID-8874381_T32", "type": "Gene_or_gene_product", "text": [ "phVEGF189" ], "offsets": [ [ 1051, 1060 ] ], "normalized": [] }, { "id": "PMID-8874381_T33", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1362, 1367 ] ], "normalized": [] }, { "id": "PMID-8874381_T34", "type": "Multi-tissue_structure", "text": [ "Arterial" ], "offsets": [ [ 1381, 1389 ] ], "normalized": [] }, { "id": "PMID-8874381_T35", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 1413, 1416 ] ], "normalized": [] }, { "id": "PMID-8874381_T36", "type": "Multi-tissue_structure", "text": [ "collateral vessel" ], "offsets": [ [ 1557, 1574 ] ], "normalized": [] } ]

[ { "id": "PMID-8874381_E1", "type": "Positive_regulation", "trigger": { "text": [ "stimulates" ], "offsets": [ [ 93, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_E2" }, { "role": "Cause", "ref_id": "PMID-8874381_T2" } ] }, { "id": "PMID-8874381_E2", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 115, 126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_T3" } ] }, { "id": "PMID-8874381_E3", "type": "Localization", "trigger": { "text": [ "secreted" ], "offsets": [ [ 193, 201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_T4" }, { "role": "FromLoc", "ref_id": "PMID-8874381_T6" } ] }, { "id": "PMID-8874381_E4", "type": "Planned_process", "trigger": { "text": [ "gene therapy" ], "offsets": [ [ 341, 353 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-8874381_T8" } ] }, { "id": "PMID-8874381_E5", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 357, 366 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8874381_T8" }, { "role": "Theme", "ref_id": "PMID-8874381_E6" } ] }, { "id": "PMID-8874381_E6", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 385, 396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_T10" } ] }, { "id": "PMID-8874381_E7", "type": "Planned_process", "trigger": { "text": [ "transfected" ], "offsets": [ [ 708, 719 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-8874381_T20" } ] }, { "id": "PMID-8874381_E8", "type": "Planned_process", "trigger": { "text": [ "site-specific transfection" ], "offsets": [ [ 731, 757 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-8874381_T21" } ] }, { "id": "PMID-8874381_E9", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 768, 776 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8874381_E8" }, { "role": "Theme", "ref_id": "PMID-8874381_E10" } ] }, { "id": "PMID-8874381_E10", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 808, 819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_T22" } ] }, { "id": "PMID-8874381_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1149, 1161 ] ] }, "arguments": [] }, { "id": "PMID-8874381_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1441, 1451 ] ] }, "arguments": [] }, { "id": "PMID-8874381_E13", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 1545, 1556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_E14" } ] }, { "id": "PMID-8874381_E14", "type": "Development", "trigger": { "text": [ "development" ], "offsets": [ [ 1575, 1586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8874381_T36" } ] } ]

[ { "id": "PMID-8874381_1", "entity_ids": [ "PMID-8874381_T4", "PMID-8874381_T5" ] } ]

[]

[ { "id": "PMID-12727857__text", "type": "abstract", "text": [ "Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression.\nThe expression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions is suppressed in malignancies. In the present study, we investigated in vivo the regulation of leukocyte-vessel wall interactions by the presence of a tumor. By means of intravital microscopy, tumor necrosis factor alpha-stimulated leukocyte-vessel wall interactions were studied in ear skin microvessels of nude mice bearing small human LS174T colon carcinomas and in C57Bl/6 mice bearing murine B16F10 melanomas. Leukocyte-vessel wall interactions were studied both within and outside small tumors growing in the ear, and in ear microvessels of mice with a large tumor growing on their flank. Tumor-free mice were used as controls. Compared with values measured at the edge of the ear and in the contralateral ear, leukocyte adhesion was found to be diminished significantly in vessels inside the ear tumor in both mouse models. This reduction disappeared with increasing distance from the tumor. Surprisingly, the level of leukocyte adhesion in ear venules of mice with a large flank tumor was also reduced significantly. Leukocyte rolling, i.e., the step preceding adhesion, was not influenced by the presence of a tumor in nude mice, but was down-regulated in immune-competent C57Bl/6 mice. Treatment of mice bearing a small ear tumor with a humanized antivascular endothelial growth factor antibody prevented the down-regulation of leukocyte-vessel wall interactions inside the tumor vessels compared with the nontreated group. Fluorescence-activated cell sorter analysis showed that isolated tumor ECs have suppressed levels of intercellular adhesion molecule 1 as compared with ECs from normal mouse tissues. In cultured b.END5 cells the tumor necrosis factor alpha-induced up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was reduced in ECs that were preincubated with basic fibroblast growth factor or vascular endothelial growth factor. The current results may have an impact on the effectiveness of clinical immunotherapeutic treatment protocols, because immune effector cells may not be able to enter tumor tissue.\n" ], "offsets": [ [ 0, 2300 ] ] } ]

[ { "id": "PMID-12727857_T1", "type": "Cancer", "text": [ "Tumor" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-12727857_T2", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 29, 38 ] ], "normalized": [] }, { "id": "PMID-12727857_T3", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 39, 50 ] ], "normalized": [] }, { "id": "PMID-12727857_T4", "type": "Gene_or_gene_product", "text": [ "endothelial adhesion molecule" ], "offsets": [ [ 84, 113 ] ], "normalized": [] }, { "id": "PMID-12727857_T5", "type": "Gene_or_gene_product", "text": [ "endothelial cell (EC) adhesion molecules" ], "offsets": [ [ 144, 184 ] ], "normalized": [] }, { "id": "PMID-12727857_T6", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 197, 206 ] ], "normalized": [] }, { "id": "PMID-12727857_T7", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 207, 218 ] ], "normalized": [] }, { "id": "PMID-12727857_T8", "type": "Cancer", "text": [ "malignancies" ], "offsets": [ [ 249, 261 ] ], "normalized": [] }, { "id": "PMID-12727857_T9", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 327, 336 ] ], "normalized": [] }, { "id": "PMID-12727857_T10", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 337, 348 ] ], "normalized": [] }, { "id": "PMID-12727857_T11", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 383, 388 ] ], "normalized": [] }, { "id": "PMID-12727857_T12", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 425, 452 ] ], "normalized": [] }, { "id": "PMID-12727857_T13", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 464, 473 ] ], "normalized": [] }, { "id": "PMID-12727857_T14", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 474, 485 ] ], "normalized": [] }, { "id": "PMID-12727857_T15", "type": "Tissue", "text": [ "ear skin microvessels" ], "offsets": [ [ 515, 536 ] ], "normalized": [] }, { "id": "PMID-12727857_T16", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 540, 549 ] ], "normalized": [] }, { "id": "PMID-12727857_T17", "type": "Organism", "text": [ "human" ], "offsets": [ [ 564, 569 ] ], "normalized": [] }, { "id": "PMID-12727857_T18", "type": "Cancer", "text": [ "LS174T colon carcinomas" ], "offsets": [ [ 570, 593 ] ], "normalized": [] }, { "id": "PMID-12727857_T19", "type": "Organism", "text": [ "C57Bl/6 mice" ], "offsets": [ [ 601, 613 ] ], "normalized": [] }, { "id": "PMID-12727857_T20", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 622, 628 ] ], "normalized": [] }, { "id": "PMID-12727857_T21", "type": "Cancer", "text": [ "B16F10 melanomas" ], "offsets": [ [ 629, 645 ] ], "normalized": [] }, { "id": "PMID-12727857_T22", "type": "Cell", "text": [ "Leukocyte" ], "offsets": [ [ 647, 656 ] ], "normalized": [] }, { "id": "PMID-12727857_T23", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 657, 668 ] ], "normalized": [] }, { "id": "PMID-12727857_T24", "type": "Cancer", "text": [ "tumors" ], "offsets": [ [ 725, 731 ] ], "normalized": [] }, { "id": "PMID-12727857_T25", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 747, 750 ] ], "normalized": [] }, { "id": "PMID-12727857_T26", "type": "Tissue", "text": [ "ear microvessels" ], "offsets": [ [ 759, 775 ] ], "normalized": [] }, { "id": "PMID-12727857_T27", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 779, 783 ] ], "normalized": [] }, { "id": "PMID-12727857_T28", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 797, 802 ] ], "normalized": [] }, { "id": "PMID-12727857_T29", "type": "Organism_subdivision", "text": [ "flank" ], "offsets": [ [ 820, 825 ] ], "normalized": [] }, { "id": "PMID-12727857_T30", "type": "Cancer", "text": [ "Tumor" ], "offsets": [ [ 827, 832 ] ], "normalized": [] }, { "id": "PMID-12727857_T31", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "PMID-12727857_T32", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 915, 918 ] ], "normalized": [] }, { "id": "PMID-12727857_T33", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "PMID-12727857_T34", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 949, 958 ] ], "normalized": [] }, { "id": "PMID-12727857_T35", "type": "Tissue", "text": [ "vessels" ], "offsets": [ [ 1012, 1019 ] ], "normalized": [] }, { "id": "PMID-12727857_T36", "type": "Cancer", "text": [ "ear tumor" ], "offsets": [ [ 1031, 1040 ] ], "normalized": [] }, { "id": "PMID-12727857_T37", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 1049, 1054 ] ], "normalized": [] }, { "id": "PMID-12727857_T38", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1124, 1129 ] ], "normalized": [] }, { "id": "PMID-12727857_T39", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 1158, 1167 ] ], "normalized": [] }, { "id": "PMID-12727857_T40", "type": "Multi-tissue_structure", "text": [ "ear venules" ], "offsets": [ [ 1180, 1191 ] ], "normalized": [] }, { "id": "PMID-12727857_T41", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1195, 1199 ] ], "normalized": [] }, { "id": "PMID-12727857_T42", "type": "Cancer", "text": [ "flank tumor" ], "offsets": [ [ 1213, 1224 ] ], "normalized": [] }, { "id": "PMID-12727857_T43", "type": "Cell", "text": [ "Leukocyte" ], "offsets": [ [ 1257, 1266 ] ], "normalized": [] }, { "id": "PMID-12727857_T44", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1351, 1356 ] ], "normalized": [] }, { "id": "PMID-12727857_T45", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 1360, 1369 ] ], "normalized": [] }, { "id": "PMID-12727857_T46", "type": "Organism", "text": [ "C57Bl/6 mice" ], "offsets": [ [ 1414, 1426 ] ], "normalized": [] }, { "id": "PMID-12727857_T47", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1441, 1445 ] ], "normalized": [] }, { "id": "PMID-12727857_T48", "type": "Cancer", "text": [ "ear tumor" ], "offsets": [ [ 1462, 1471 ] ], "normalized": [] }, { "id": "PMID-12727857_T49", "type": "Gene_or_gene_product", "text": [ "antivascular endothelial growth factor antibody" ], "offsets": [ [ 1489, 1536 ] ], "normalized": [] }, { "id": "PMID-12727857_T50", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 1570, 1579 ] ], "normalized": [] }, { "id": "PMID-12727857_T51", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 1580, 1591 ] ], "normalized": [] }, { "id": "PMID-12727857_T52", "type": "Multi-tissue_structure", "text": [ "tumor vessels" ], "offsets": [ [ 1616, 1629 ] ], "normalized": [] }, { "id": "PMID-12727857_T53", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1689, 1693 ] ], "normalized": [] }, { "id": "PMID-12727857_T54", "type": "Cell", "text": [ "tumor ECs" ], "offsets": [ [ 1731, 1740 ] ], "normalized": [] }, { "id": "PMID-12727857_T55", "type": "Gene_or_gene_product", "text": [ "intercellular adhesion molecule 1" ], "offsets": [ [ 1767, 1800 ] ], "normalized": [] }, { "id": "PMID-12727857_T56", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1818, 1821 ] ], "normalized": [] }, { "id": "PMID-12727857_T57", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 1834, 1839 ] ], "normalized": [] }, { "id": "PMID-12727857_T58", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 1840, 1847 ] ], "normalized": [] }, { "id": "PMID-12727857_T59", "type": "Cell", "text": [ "b.END5 cells" ], "offsets": [ [ 1861, 1873 ] ], "normalized": [] }, { "id": "PMID-12727857_T60", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 1878, 1905 ] ], "normalized": [] }, { "id": "PMID-12727857_T61", "type": "Gene_or_gene_product", "text": [ "intercellular adhesion molecule 1" ], "offsets": [ [ 1931, 1964 ] ], "normalized": [] }, { "id": "PMID-12727857_T62", "type": "Gene_or_gene_product", "text": [ "vascular cell adhesion molecule 1" ], "offsets": [ [ 1969, 2002 ] ], "normalized": [] }, { "id": "PMID-12727857_T63", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 2018, 2021 ] ], "normalized": [] }, { "id": "PMID-12727857_T64", "type": "Gene_or_gene_product", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 2050, 2080 ] ], "normalized": [] }, { "id": "PMID-12727857_T65", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 2084, 2118 ] ], "normalized": [] }, { "id": "PMID-12727857_T66", "type": "Cell", "text": [ "immune effector cells" ], "offsets": [ [ 2239, 2260 ] ], "normalized": [] }, { "id": "PMID-12727857_T67", "type": "Tissue", "text": [ "tumor tissue" ], "offsets": [ [ 2286, 2298 ] ], "normalized": [] } ]

[ { "id": "PMID-12727857_E1", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 6, 18 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12727857_T1" } ] }, { "id": "PMID-12727857_E2", "type": "Regulation", "trigger": { "text": [ "modulates" ], "offsets": [ [ 19, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_E3" }, { "role": "Cause", "ref_id": "PMID-12727857_E4" } ] }, { "id": "PMID-12727857_E3", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 51, 63 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T3" }, { "role": "Theme", "ref_id": "PMID-12727857_T2" } ] }, { "id": "PMID-12727857_E4", "type": "Negative_regulation", "trigger": { "text": [ "reducing" ], "offsets": [ [ 75, 83 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_E5" }, { "role": "Cause", "ref_id": "PMID-12727857_E1" } ] }, { "id": "PMID-12727857_E5", "type": "Gene_expression", "trigger": { 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] }, { "id": "PMID-12727857_E28", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1906, 1913 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12727857_T60" }, { "role": "Theme", "ref_id": "PMID-12727857_E30" } ] }, { "id": "PMID-12727857_E29", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1906, 1913 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12727857_T60" }, { "role": "Theme", "ref_id": "PMID-12727857_E31" } ] }, { "id": "PMID-12727857_E30", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1914, 1927 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T61" } ] }, { "id": "PMID-12727857_E31", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1914, 1927 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T62" } ] }, { "id": "PMID-12727857_E32", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 2007, 2014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_E30" } ] }, { "id": "PMID-12727857_E33", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 2007, 2014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_E31" } ] }, { "id": "PMID-12727857_E34", "type": "Planned_process", "trigger": { "text": [ "preincubated" ], "offsets": [ [ 2032, 2044 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T63" }, { "role": "Instrument", "ref_id": "PMID-12727857_T64" } ] }, { "id": "PMID-12727857_E35", "type": "Planned_process", "trigger": { "text": [ "preincubated" ], "offsets": [ [ 2032, 2044 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T63" }, { "role": "Instrument", "ref_id": "PMID-12727857_T65" } ] }, { "id": "PMID-12727857_E36", "type": "Localization", "trigger": { "text": [ "enter" ], "offsets": [ [ 2280, 2285 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12727857_T66" }, { "role": "ToLoc", "ref_id": "PMID-12727857_T67" } ] } ]

[]

[]

[ { "id": "PMID-6325250__text", "type": "abstract", "text": [ "Molecular events leading to enhanced glucose transport in Rous sarcoma virus-transformed cells. \nTransformation by Rous sarcoma virus results in a dramatic increase in the rate at which the transformed cells transport glucose across the cell membrane. The increased transport rate is a consequence of an increased number of transporters in the transformed cells. Utilizing antibody raised against the purified human erythrocyte glucose transporter, we have identified the glucose transporter as a membrane glycoprotein with a monomer Mr of approximately 41,000. The increased rate of glucose transport is dependent on the activity of pp60src, the transforming protein of Rous sarcoma virus. This protein has been shown to be a protein kinase that phosphorylates on tyrosine residues. We have examined the tyrosine phosphorylation of a major cellular protein of Mr 36,000 in cells infected with a panel of partially transforming mutants of Rous sarcoma virus. One of these mutants (CU2) increases the rate of glucose transport only slightly and does not render the infected cells fully anchorage independent or tumorigenic (although other transformation parameters are fully induced). Cells infected with this mutant display a 36,000-dalton protein that is phosphorylated to a considerably lesser extent than cells infected with wild-type virus. Analyses of this sort may help to identify the cellular targets of pp60src whose phosphorylation is necessary for the increased glucose transport rate.\n" ], "offsets": [ [ 0, 1497 ] ] } ]

[ { "id": "PMID-6325250_T1", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 37, 44 ] ], "normalized": [] }, { "id": "PMID-6325250_T2", "type": "Organism", "text": [ "Rous sarcoma virus" ], "offsets": [ [ 58, 76 ] ], "normalized": [] }, { "id": "PMID-6325250_T3", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 89, 94 ] ], "normalized": [] }, { "id": "PMID-6325250_T4", "type": "Organism", "text": [ "Rous sarcoma virus" ], "offsets": [ [ 115, 133 ] ], "normalized": [] }, { "id": "PMID-6325250_T5", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 202, 207 ] ], "normalized": [] }, { "id": "PMID-6325250_T6", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 218, 225 ] ], "normalized": [] }, { "id": "PMID-6325250_T7", "type": "Cellular_component", "text": [ "cell membrane" ], "offsets": [ [ 237, 250 ] ], "normalized": [] }, { "id": "PMID-6325250_T8", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "PMID-6325250_T9", "type": "Organism", "text": [ "human" ], "offsets": [ [ 410, 415 ] ], "normalized": [] }, { "id": "PMID-6325250_T10", "type": "Cell", "text": [ "erythrocyte" ], "offsets": [ [ 416, 427 ] ], "normalized": [] }, { "id": "PMID-6325250_T11", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 428, 435 ] ], "normalized": [] }, { "id": "PMID-6325250_T12", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 472, 479 ] ], "normalized": [] }, { "id": "PMID-6325250_T13", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 497, 505 ] ], "normalized": [] }, { "id": "PMID-6325250_T14", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 584, 591 ] ], "normalized": [] }, { "id": "PMID-6325250_T15", "type": "Gene_or_gene_product", "text": [ "pp60src" ], "offsets": [ [ 634, 641 ] ], "normalized": [] }, { "id": "PMID-6325250_T16", "type": "Organism", "text": [ "Rous sarcoma virus" ], "offsets": [ [ 671, 689 ] ], "normalized": [] }, { "id": "PMID-6325250_T17", "type": "Amino_acid", "text": [ "tyrosine" ], "offsets": [ [ 805, 813 ] ], "normalized": [] }, { "id": "PMID-6325250_T18", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 841, 849 ] ], "normalized": [] }, { "id": "PMID-6325250_T19", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 874, 879 ] ], "normalized": [] }, { "id": "PMID-6325250_T20", "type": "Organism", "text": [ "Rous sarcoma virus" ], "offsets": [ [ 939, 957 ] ], "normalized": [] }, { "id": "PMID-6325250_T21", "type": "Organism", "text": [ "CU2" ], "offsets": [ [ 981, 984 ] ], "normalized": [] }, { "id": "PMID-6325250_T22", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 1008, 1015 ] ], "normalized": [] }, { "id": "PMID-6325250_T23", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1073, 1078 ] ], "normalized": [] }, { "id": "PMID-6325250_T24", "type": "Cell", "text": [ "Cells" ], "offsets": [ [ 1184, 1189 ] ], "normalized": [] }, { "id": "PMID-6325250_T25", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1308, 1313 ] ], "normalized": [] }, { "id": "PMID-6325250_T26", "type": "Organism", "text": [ "wild-type virus" ], "offsets": [ [ 1328, 1343 ] ], "normalized": [] }, { "id": "PMID-6325250_T27", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 1392, 1400 ] ], "normalized": [] }, { "id": "PMID-6325250_T28", "type": "Gene_or_gene_product", "text": [ "pp60src" ], "offsets": [ [ 1412, 1419 ] ], "normalized": [] }, { "id": "PMID-6325250_T29", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 1473, 1480 ] ], "normalized": [] } ]

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"type": "Positive_regulation", "trigger": { "text": [ "Transformation" ], "offsets": [ [ 97, 111 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-6325250_T4" }, { "role": "Theme", "ref_id": "PMID-6325250_E5" } ] }, { "id": "PMID-6325250_E7", "type": "Cell_transformation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 190, 201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T5" } ] }, { "id": "PMID-6325250_E8", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 208, 217 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T6" }, { "role": "ToLoc", "ref_id": "PMID-6325250_T5" } ] }, { "id": "PMID-6325250_E9", "type": "Cell_transformation", "trigger": { "text": [ "transformed" ], "offsets": [ [ 344, 355 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T8" } ] }, { "id": "PMID-6325250_E10", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 566, 575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_E11" } ] }, { "id": "PMID-6325250_E11", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 592, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T14" } ] }, { "id": "PMID-6325250_E12", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 605, 614 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-6325250_T15" }, { "role": "Theme", "ref_id": "PMID-6325250_E10" } ] }, { "id": "PMID-6325250_E13", "type": "Infection", "trigger": { "text": [ "infected" ], "offsets": [ [ 880, 888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T19" }, { "role": "Participant", "ref_id": "PMID-6325250_T20" } ] }, { "id": "PMID-6325250_E14", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 986, 995 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_E15" }, { "role": "Cause", "ref_id": "PMID-6325250_T21" } ] }, { "id": "PMID-6325250_E15", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 1016, 1025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T22" } ] }, { "id": "PMID-6325250_E16", "type": "Infection", "trigger": { "text": [ "infected" ], "offsets": [ [ 1064, 1072 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-6325250_T21" }, { "role": "Theme", "ref_id": "PMID-6325250_T23" } ] }, { "id": "PMID-6325250_E17", "type": "Carcinogenesis", "trigger": { "text": [ "tumorigenic" ], "offsets": [ [ 1110, 1121 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-6325250_T23" } ] }, { "id": "PMID-6325250_E18", "type": "Cell_transformation", "trigger": { "text": [ "transformation" ], "offsets": [ [ 1138, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T23" } ] }, { "id": "PMID-6325250_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1174, 1181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_E18" } ] }, { "id": "PMID-6325250_E20", "type": "Infection", "trigger": { "text": [ "infected" ], "offsets": [ [ 1190, 1198 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-6325250_T21" }, { "role": "Theme", "ref_id": "PMID-6325250_T24" } ] }, { "id": "PMID-6325250_E21", "type": "Infection", "trigger": { "text": [ "infected" ], "offsets": [ [ 1314, 1322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T25" }, { "role": "Participant", "ref_id": "PMID-6325250_T26" } ] }, { "id": "PMID-6325250_E22", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1445, 1454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_E24" } ] }, { "id": "PMID-6325250_E23", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1463, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_E24" } ] }, { "id": "PMID-6325250_E24", "type": "Localization", "trigger": { "text": [ "transport" ], "offsets": [ [ 1481, 1490 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-6325250_T29" } ] } ]

[]

[]

[ { "id": "PMID-19806573__text", "type": "abstract", "text": [ "[Effect of osteopontin silencing by lentivirus-mediated delivery of siRNA on glioma cell invasion and apoptosis]. \nOBJECTIVE: To investigate the effect of osteopontin silencing on the invasion and apoptosis of U251 cells. METHODS: The invasion, apoptosis and levels of uPA, MMP-2 and MMP-9 were determined by invasion assay, flow cytometry, Western blot and real-time fluorescence quantitative PCR respectively. RESULTS: Osteopontin small interference RNA (siRNA) inhibited osteopontin expression and cell invasion, promoted apoptosis in U251 cells. In addition, the expression of Bcl-2, uPA, MMP-2 and MMP-9 was decreased, while Bax level was elevated. CONCLUSION: Osteopontin siRNA can inhibit U251 cells invasion via the down-regulation of uPA, MMP-2 and MMP-9 levels, and promote apoptosis through induction of Bax expression and inhibition of Bcl 2 level. It suggests that osteopontin plays an important role in human glioma progression.\n" ], "offsets": [ [ 0, 943 ] ] } ]

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[]

[]

[ { "id": "PMID-22172720__text", "type": "abstract", "text": [ "beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. \nMalignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating beta-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and Braf(V600E) mutation, we demonstrate that beta-catenin is a central mediator of melanoma metastasis to the lymph nodes and lungs. In addition to altering metastasis, beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with beta-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma.\n" ], "offsets": [ [ 0, 955 ] ] } ]

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[]

[ { "id": "PMID-21506108__text", "type": "abstract", "text": [ "Induction of Id-1 by FGF-2 involves activity of EGR-1 and sensitizes neuroblastoma cells to cell death. \nInhibitor of differentiation-1 (Id-1) is a member of helix-loop-helix (HLH) family of proteins that regulate gene transcription through their inhibitory binding to basic-HLH transcription factors. Similarly to other members of this family, Id-1 is involved in the repression of cell differentiation and activation of cell growth. The dual function of Id-1, inhibition of differentiation, and stimulation of cell proliferation, might be interdependent, as cell differentiation is generally coupled with the exit from the cell cycle. Fibroblast growth factor-2 (FGF-2) has been reported to play multiple roles in different biological processes during development of the central nervous system (CNS). In addition, FGF-2 has been described to induce \"neuronal-like\" differentiation and trigger apoptosis in neuroblastoma SK-N-MC cells. Although regulation of Id-1 protein by several mitogenic factors is well-established, little is known about the role of FGF-2 in the regulation of Id-1. Using human neuroblastoma cell line, SK-N-MC, we found that treatment of these cells with FGF-2 resulted in early induction of both Id-1 mRNA and protein. The induction occurs within 1 h from FGF-2 treatment and is mediated by ERK1/2 pathway, which in turn stimulates expression of the early growth response-1 (Egr-1) transcription factor. We also demonstrate direct interaction of Egr-1 with Id-1 promoter in vitro and in cell culture. Finally, inhibition of Id-1 expression results in G(2) /M accumulation of FGF-2-treated cells and delayed cell death.\n" ], "offsets": [ [ 0, 1645 ] ] } ]

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345, 349 ] ], "normalized": [] }, { "id": "PMID-21506108_T9", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 383, 387 ] ], "normalized": [] }, { "id": "PMID-21506108_T10", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-21506108_T11", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 456, 460 ] ], "normalized": [] }, { "id": "PMID-21506108_T12", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 512, 516 ] ], "normalized": [] }, { "id": "PMID-21506108_T13", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-21506108_T14", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMID-21506108_T15", "type": "Gene_or_gene_product", "text": [ "Fibroblast growth factor-2" ], "offsets": [ [ 637, 663 ] ], "normalized": [] }, { "id": "PMID-21506108_T16", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 665, 670 ] ], "normalized": [] }, { "id": "PMID-21506108_T17", "type": "Anatomical_system", "text": [ "central nervous system" ], "offsets": [ [ 773, 795 ] ], "normalized": [] }, { "id": "PMID-21506108_T18", "type": "Anatomical_system", "text": [ "CNS" ], "offsets": [ [ 797, 800 ] ], "normalized": [] }, { "id": "PMID-21506108_T19", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 816, 821 ] ], "normalized": [] }, { "id": "PMID-21506108_T20", "type": "Cell", "text": [ "neuronal" ], "offsets": [ [ 852, 860 ] ], "normalized": [] }, { "id": "PMID-21506108_T21", "type": "Cell", "text": [ "neuroblastoma SK-N-MC cells" ], "offsets": [ [ 908, 935 ] ], "normalized": [] }, { "id": "PMID-21506108_T22", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 960, 964 ] ], "normalized": [] }, { "id": "PMID-21506108_T23", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 1057, 1062 ] ], "normalized": [] }, { "id": "PMID-21506108_T24", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 1084, 1088 ] ], "normalized": [] }, { "id": "PMID-21506108_T25", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1096, 1101 ] ], "normalized": [] }, { "id": "PMID-21506108_T26", "type": "Cell", "text": [ "neuroblastoma cell line" ], "offsets": [ [ 1102, 1125 ] ], "normalized": [] }, { "id": "PMID-21506108_T27", "type": "Cell", "text": [ "SK-N-MC" ], "offsets": [ [ 1127, 1134 ] ], "normalized": [] }, { "id": "PMID-21506108_T28", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1169, 1174 ] ], "normalized": [] }, { "id": "PMID-21506108_T29", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 1180, 1185 ] ], "normalized": [] }, { "id": "PMID-21506108_T30", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 1222, 1226 ] ], "normalized": [] }, { "id": "PMID-21506108_T31", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 1282, 1287 ] ], "normalized": [] }, { "id": "PMID-21506108_T32", "type": "Gene_or_gene_product", "text": [ "ERK1/2" ], "offsets": [ [ 1317, 1323 ] ], "normalized": [] }, { "id": "PMID-21506108_T33", "type": "Gene_or_gene_product", "text": [ "early growth response-1" ], "offsets": [ [ 1376, 1399 ] ], "normalized": [] }, { "id": "PMID-21506108_T34", "type": "Gene_or_gene_product", "text": [ "Egr-1" ], "offsets": [ [ 1401, 1406 ] ], "normalized": [] }, { "id": "PMID-21506108_T35", "type": "Gene_or_gene_product", "text": [ "Egr-1" ], "offsets": [ [ 1472, 1477 ] ], "normalized": [] }, { "id": "PMID-21506108_T36", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 1483, 1487 ] ], "normalized": [] }, { "id": "PMID-21506108_T37", "type": "Cell", "text": [ "cell culture" ], "offsets": [ [ 1513, 1525 ] ], "normalized": [] }, { "id": "PMID-21506108_T38", "type": "Gene_or_gene_product", "text": [ "Id-1" ], "offsets": [ [ 1550, 1554 ] ], "normalized": [] }, { "id": "PMID-21506108_T39", "type": "Gene_or_gene_product", "text": [ "FGF-2" ], "offsets": [ [ 1601, 1606 ] ], "normalized": [] }, { "id": "PMID-21506108_T40", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1615, 1620 ] ], "normalized": [] }, { "id": "PMID-21506108_T41", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1633, 1637 ] ], "normalized": [] }, { "id": "PMID-21506108_T78", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1488, 1496 ] ], "normalized": [] } ]

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"offsets": [ [ 97, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21506108_T5" } ] }, { "id": "PMID-21506108_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 258, 265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21506108_T6" } ] }, { "id": "PMID-21506108_E7", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 353, 361 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21506108_T8" }, { "role": "Theme", "ref_id": "PMID-21506108_E9" } ] }, { "id": "PMID-21506108_E8", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 353, 361 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21506108_T8" }, { "role": "Theme", "ref_id": "PMID-21506108_E11" } ] }, { "id": "PMID-21506108_E9", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 369, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21506108_E10" } ] }, { "id": "PMID-21506108_E10", "type": 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[ { "id": "PMID-21506108_1", "entity_ids": [ "PMID-21506108_T6", "PMID-21506108_T7" ] }, { "id": "PMID-21506108_2", "entity_ids": [ "PMID-21506108_T15", "PMID-21506108_T16" ] }, { "id": "PMID-21506108_3", "entity_ids": [ "PMID-21506108_T17", "PMID-21506108_T18" ] }, { "id": "PMID-21506108_4", "entity_ids": [ "PMID-21506108_T33", "PMID-21506108_T34" ] } ]

[]

[ { "id": "PMID-10978248__text", "type": "abstract", "text": [ "Vasodilator-stimulated phosphoprotein is involved in stress-fiber and membrane ruffle formation in endothelial cells.\nVasodilator-stimulated phosphoprotein (VASP) is highly expressed in vascular endothelial cells, where it has been implicated in cellular reorganization during angiogenesis, as well as in endothelial retraction and changes in vessel permeability. However, the cellular functions of VASP are not known. In this study, we have expressed wild-type and mutant forms of VASP in endothelial cells to determine in what aspects of cytoskeletal behavior this protein participates. Expression of wild-type VASP induces marked membrane ruffling and formation of prominent stress fibers in bovine aortic endothelial cells. Deletion of the proline-rich domain of VASP abolishes its ability to bind profilin but does not affect ruffling or stress fiber formation. Further deletions reveal a sequence within the carboxy-terminal domain that is responsible for in vivo bundle formation. Ruffling occurs only on the expression of forms of VASP that possess bundling activity and the capacity to bind zyxin/vinculin-derived peptide. The ability of distinct subdomains within VASP to bind adhesion proteins and induce F-actin bundling in vivo suggests that this protein could function in the aggregation and tethering of actin filaments during the formation of endothelial cell-substrate and cell-cell contacts. These data provide a mechanism whereby VASP can influence endothelial migration and organization during capillary formation and modulate vascular permeability via effects on endothelial cell contractility.\n" ], "offsets": [ [ 0, 1616 ] ] } ]

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"PMID-10978248_T8", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 246, 254 ] ], "normalized": [] }, { "id": "PMID-10978248_T9", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 305, 316 ] ], "normalized": [] }, { "id": "PMID-10978248_T10", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 343, 349 ] ], "normalized": [] }, { "id": "PMID-10978248_T11", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 377, 385 ] ], "normalized": [] }, { "id": "PMID-10978248_T12", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 399, 403 ] ], "normalized": [] }, { "id": "PMID-10978248_T13", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-10978248_T14", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 490, 507 ] ], "normalized": [] }, { "id": "PMID-10978248_T15", "type": "Cellular_component", "text": [ "cytoskeletal" ], "offsets": [ [ 540, 552 ] ], "normalized": [] }, { "id": "PMID-10978248_T16", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "PMID-10978248_T17", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 633, 641 ] ], "normalized": [] }, { "id": "PMID-10978248_T18", "type": "Cellular_component", "text": [ "stress fibers" ], "offsets": [ [ 678, 691 ] ], "normalized": [] }, { "id": "PMID-10978248_T19", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 695, 701 ] ], "normalized": [] }, { "id": "PMID-10978248_T20", "type": "Cell", "text": [ "aortic endothelial cells" ], "offsets": [ [ 702, 726 ] ], "normalized": [] }, { "id": "PMID-10978248_T21", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 767, 771 ] ], "normalized": [] }, { "id": "PMID-10978248_T22", "type": "Gene_or_gene_product", "text": [ "profilin" ], "offsets": [ [ 802, 810 ] ], "normalized": [] }, { "id": "PMID-10978248_T23", "type": "Cellular_component", "text": [ "stress fiber" ], "offsets": [ [ 843, 855 ] ], "normalized": [] }, { "id": "PMID-10978248_T24", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "PMID-10978248_T25", "type": "Gene_or_gene_product", "text": [ "zyxin" ], "offsets": [ [ 1100, 1105 ] ], "normalized": [] }, { "id": "PMID-10978248_T26", "type": "Gene_or_gene_product", "text": [ "vinculin" ], "offsets": [ [ 1106, 1114 ] ], "normalized": [] }, { "id": "PMID-10978248_T27", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 1174, 1178 ] ], "normalized": [] }, { "id": "PMID-10978248_T28", "type": "Gene_or_gene_product", "text": [ "F-actin" ], "offsets": [ [ 1216, 1223 ] ], "normalized": [] }, { "id": "PMID-10978248_T29", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 1319, 1324 ] ], "normalized": [] }, { "id": "PMID-10978248_T30", "type": "Cellular_component", "text": [ "endothelial cell-substrate" ], "offsets": [ [ 1359, 1385 ] ], "normalized": [] }, { "id": "PMID-10978248_T31", "type": "Cellular_component", "text": [ "cell-cell contacts" ], "offsets": [ [ 1390, 1408 ] ], "normalized": [] }, { "id": "PMID-10978248_T32", "type": "Gene_or_gene_product", "text": [ "VASP" ], "offsets": [ [ 1449, 1453 ] ], "normalized": [] }, { "id": "PMID-10978248_T33", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 1468, 1479 ] ], "normalized": [] }, { "id": "PMID-10978248_T34", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 1514, 1523 ] ], "normalized": [] }, { "id": "PMID-10978248_T35", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1547, 1555 ] ], "normalized": [] }, { "id": "PMID-10978248_T36", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1584, 1600 ] ], "normalized": [] }, { "id": "PMID-10978248_T51", "type": "Protein_domain_or_region", "text": [ "proline-rich domain" ], "offsets": [ [ 744, 763 ] ], "normalized": [] }, { "id": "PMID-10978248_T58", "type": "Protein_domain_or_region", "text": [ "subdomains" ], "offsets": [ [ 1156, 1166 ] ], "normalized": [] } ]

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[ { "id": "PMID-15623651__text", "type": "abstract", "text": [ "2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma.\nPURPOSE: Head and neck squamous cell carcinomas have been reported to overexpress hypoxia-inducible factor (HIF)-1alpha, a transcription factor that promotes expression of angiogenesis factors and resistance to programmed and therapy-induced cell death. 2-Methoxyestradiol (2ME2) is a natural compound with HIF-1alpha inhibitory activity that is currently being evaluated in phase 1 and 2 clinical trials for advanced solid tumors and multiple myeloma. To our knowledge, this is the first study to evaluate the effects of 2ME2 in head and neck squamous cell carcinoma. EXPERIMENTAL DESIGN: In the present study, we investigated the effects of 2ME2 alone and in combination with paclitaxel, an active agent in recurrent or advanced head and neck squamous cell carcinoma. RESULTS: 2ME2 exhibited antiproliferative and cytotoxic effects in a panel of five head and neck squamous cell carcinoma cell lines in the 0.5 to 10 micromol/L range, including induction of G2-M blockade, caspase-3/7 activation, and apoptosis at 48 hours. 2ME2 resulted in decreased nuclear HIF-1alpha-binding activity and affected the expression of downstream genes, such as bid, a proapoptotic bcl-2 family member, and vascular endothelial growth factor, a proangiogenic cytokine. The up-regulation of Bid (57.5% at 12 hours, P less than 0.0006) and inhibition of vascular endothelial growth factor secretion (57.7% at 24 hours, P less than 0.015; and 50.3% at 48 hours, P less than 0.0006) could be partially attributed to the effects on HIF-1alpha, because HIF-1alpha small interfering RNAs produced similar effects. Finally, in vivo, in a xenograft model of head and neck squamous cell carcinoma using UM-SCC-11A cells, 2ME2 exhibited antitumor and antiangiogenic activity, as measured by CD31 immunostaining. CONCLUSIONS: These results provide support for the use of 2ME2 in combination with paclitaxel for the treatment of recurrent or advanced head and neck squamous cell carcinoma.\n" ], "offsets": [ [ 0, 2134 ] ] } ]

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"id": "PMID-15623651_T8", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 409, 413 ] ], "normalized": [] }, { "id": "PMID-15623651_T9", "type": "Simple_chemical", "text": [ "2-Methoxyestradiol" ], "offsets": [ [ 421, 439 ] ], "normalized": [] }, { "id": "PMID-15623651_T10", "type": "Simple_chemical", "text": [ "2ME2" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "PMID-15623651_T11", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 474, 484 ] ], "normalized": [] }, { "id": "PMID-15623651_T12", "type": "Cancer", "text": [ "solid tumors" ], "offsets": [ [ 585, 597 ] ], "normalized": [] }, { "id": "PMID-15623651_T13", "type": "Cancer", "text": [ "myeloma" ], "offsets": [ [ 611, 618 ] ], "normalized": [] }, { "id": "PMID-15623651_T14", "type": "Simple_chemical", "text": [ "2ME2" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-15623651_T15", "type": "Cancer", "text": [ "head and neck squamous cell carcinoma" ], "offsets": [ [ 697, 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"PMID-15623651_T23", "type": "Simple_chemical", "text": [ "2ME2" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "PMID-15623651_T24", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 1228, 1238 ] ], "normalized": [] }, { "id": "PMID-15623651_T25", "type": "Gene_or_gene_product", "text": [ "bid" ], "offsets": [ [ 1313, 1316 ] ], "normalized": [] }, { "id": "PMID-15623651_T26", "type": "Gene_or_gene_product", "text": [ "bcl-2" ], "offsets": [ [ 1333, 1338 ] ], "normalized": [] }, { "id": "PMID-15623651_T27", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1358, 1392 ] ], "normalized": [] }, { "id": "PMID-15623651_T28", "type": "Gene_or_gene_product", "text": [ "Bid" ], "offsets": [ [ 1441, 1444 ] ], "normalized": [] }, { "id": "PMID-15623651_T29", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1505, 1539 ] ], "normalized": [] }, { "id": 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"Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 2060, 2069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15623651_T40" }, { "role": "Instrument", "ref_id": "PMID-15623651_T39" }, { "role": "Instrument", "ref_id": "PMID-15623651_T38" } ] } ]

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[]

[ { "id": "PMID-19292679__text", "type": "abstract", "text": [ "The effect of perfluorocarbon-based artificial oxygen carriers on tissue-engineered trachea.\nThe biological effect of the perfluorocarbon-based artificial oxygen carrier (Oxygent) was investigated in tissue-engineered trachea (TET) construction. Media supplemented with and without 10% Oxygent were compared in all assessments. Partial tissue oxygen tension (PtO(2)) was measured with polarographic microprobes; epithelial metabolism was monitored by microdialysis inside the TET epithelium perfused with the medium underneath. Chondrocyte-DegraPol constructs were cultured for 1 month with the medium before glycosaminoglycan assessment and histology. Tissue reaction of TET epithelial scaffolds immersed with the medium was evaluated on the chick embryo chorioallantoic membrane. Oxygent perfusion medium increased the TET epithelial PtO(2) (51.2 +/- 0.3 mm Hg vs. 33.4 +/- 0.3 mm Hg at 200 microm thickness; 12.5 +/- 0.1 mm Hg vs. 3.1 +/- 0.1 mm Hg at 400 microm thickness, p less than 0.01) and decreased the lactate concentration (0.63 +/- 0.08 vs. 0.80 +/- 0.06 mmol/L, p less than 0.05), lactate/pyruvate (1.87 +/- 0.26 vs. 3.36 +/- 10.13, p less than 0.05), and lactate/glucose ratios (0.10 +/- 0.00 vs. 0.29 +/- 0.14, p less than 0.05). Chondrocyte-DegraPol in Oxygent group presented lower glycosaminoglycan value (0.03 +/- 0.00 vs. 0.13 +/- 0.00, p less than 0.05); histology slides showed poor acid mucopolysaccharides formation. Orthogonal polarization spectral imaging showed no difference in functional capillary density between the scaffolds cultured on chorioallantoic membranes. The foreign body reaction was similar in both groups. We conclude that Oxygent increases TET epithelial PtO(2), improves epithelial metabolism, does not impair angiogenesis, and tends to slow cartilage tissue formation.\n" ], "offsets": [ [ 0, 1827 ] ] } ]

[ { "id": "PMID-19292679_T1", "type": "Simple_chemical", "text": [ "perfluorocarbon" ], "offsets": [ [ 14, 29 ] ], "normalized": [] }, { "id": "PMID-19292679_T2", "type": "Simple_chemical", "text": [ "oxygen" ], "offsets": [ [ 47, 53 ] ], "normalized": [] }, { "id": "PMID-19292679_T3", "type": "Multi-tissue_structure", "text": [ "tissue-engineered trachea" ], "offsets": [ [ 66, 91 ] ], "normalized": [] }, { "id": "PMID-19292679_T4", "type": "Simple_chemical", "text": [ "perfluorocarbon" ], "offsets": [ [ 122, 137 ] ], "normalized": [] }, { "id": "PMID-19292679_T5", "type": "Simple_chemical", "text": [ "oxygen" ], "offsets": [ [ 155, 161 ] ], "normalized": [] }, { "id": "PMID-19292679_T6", "type": "Simple_chemical", "text": [ "Oxygent" ], "offsets": [ [ 171, 178 ] ], "normalized": [] }, { "id": "PMID-19292679_T7", "type": "Multi-tissue_structure", "text": [ "tissue-engineered trachea" ], "offsets": [ [ 200, 225 ] ], "normalized": [] }, { "id": "PMID-19292679_T8", "type": "Multi-tissue_structure", "text": [ "TET" ], "offsets": [ [ 227, 230 ] ], "normalized": [] }, { "id": "PMID-19292679_T9", "type": "Simple_chemical", "text": [ "Oxygent" ], "offsets": [ [ 286, 293 ] ], "normalized": [] }, { "id": "PMID-19292679_T10", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 336, 342 ] ], "normalized": [] }, { "id": "PMID-19292679_T11", "type": "Simple_chemical", "text": [ "oxygen" ], "offsets": [ [ 343, 349 ] ], "normalized": [] }, { "id": "PMID-19292679_T12", "type": "Cell", "text": [ "epithelial" ], "offsets": [ [ 412, 422 ] ], "normalized": [] }, { "id": "PMID-19292679_T13", "type": "Tissue", "text": [ "TET epithelium" ], "offsets": [ [ 476, 490 ] ], "normalized": [] }, { "id": "PMID-19292679_T14", "type": "Cell", "text": [ "Chondrocyte" ], "offsets": [ [ 528, 539 ] ], "normalized": [] }, { "id": "PMID-19292679_T15", "type": "Simple_chemical", "text": [ "glycosaminoglycan" ], "offsets": [ [ 609, 626 ] ], "normalized": [] }, { "id": "PMID-19292679_T16", "type": "Tissue", "text": [ "Tissue" ], "offsets": [ [ 653, 659 ] ], "normalized": [] }, { "id": "PMID-19292679_T17", "type": "Tissue", "text": [ "TET epithelial scaffolds" ], "offsets": [ [ 672, 696 ] ], "normalized": [] }, { "id": "PMID-19292679_T18", "type": "Organism", "text": [ "chick" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMID-19292679_T19", "type": "Multi-tissue_structure", "text": [ "embryo chorioallantoic membrane" ], "offsets": [ [ 749, 780 ] ], "normalized": [] }, { "id": "PMID-19292679_T20", "type": "Simple_chemical", "text": [ "Oxygent" ], "offsets": [ [ 782, 789 ] ], "normalized": [] }, { "id": "PMID-19292679_T21", "type": "Tissue", "text": [ "TET epithelial" ], "offsets": [ [ 821, 835 ] ], "normalized": [] }, { "id": "PMID-19292679_T22", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 1015, 1022 ] ], "normalized": [] }, { "id": "PMID-19292679_T23", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 1099, 1106 ] ], "normalized": [] }, { "id": "PMID-19292679_T24", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 1107, 1115 ] ], "normalized": [] }, { "id": "PMID-19292679_T25", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 1176, 1183 ] ], "normalized": [] }, { "id": "PMID-19292679_T26", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 1184, 1191 ] ], "normalized": [] }, { "id": "PMID-19292679_T27", "type": "Cell", "text": [ "Chondrocyte" ], "offsets": [ [ 1254, 1265 ] ], "normalized": [] }, { "id": "PMID-19292679_T28", "type": "Simple_chemical", "text": [ "Oxygent" ], "offsets": [ [ 1278, 1285 ] ], "normalized": [] }, { "id": "PMID-19292679_T29", "type": "Simple_chemical", "text": [ "glycosaminoglycan" ], "offsets": [ [ 1308, 1325 ] ], "normalized": [] }, { "id": "PMID-19292679_T30", "type": "Simple_chemical", "text": [ "mucopolysaccharides" ], "offsets": [ [ 1421, 1440 ] ], "normalized": [] }, { "id": "PMID-19292679_T31", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 1528, 1537 ] ], "normalized": [] }, { "id": "PMID-19292679_T32", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membranes" ], "offsets": [ [ 1580, 1605 ] ], "normalized": [] }, { "id": "PMID-19292679_T33", "type": "Simple_chemical", "text": [ "Oxygent" ], "offsets": [ [ 1678, 1685 ] ], "normalized": [] }, { "id": "PMID-19292679_T34", "type": "Tissue", "text": [ "TET epithelial" ], "offsets": [ [ 1696, 1710 ] ], "normalized": [] }, { "id": "PMID-19292679_T35", "type": "Tissue", "text": [ "epithelial" ], "offsets": [ [ 1728, 1738 ] ], "normalized": [] }, { "id": "PMID-19292679_T36", "type": "Tissue", "text": [ "cartilage tissue" ], "offsets": [ [ 1799, 1815 ] ], "normalized": [] } ]

[ { "id": "PMID-19292679_E1", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 4, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_T3" } ] }, { "id": "PMID-19292679_E2", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 108, 114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_T7" }, { "role": "Cause", "ref_id": "PMID-19292679_T6" } ] }, { "id": "PMID-19292679_E3", "type": "Synthesis", "trigger": { "text": [ "formation" ], "offsets": [ [ 1441, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_T30" } ] }, { "id": "PMID-19292679_E4", "type": "Planned_process", "trigger": { "text": [ "cultured" ], "offsets": [ [ 1568, 1576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_T31" } ] }, { "id": "PMID-19292679_E5", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1686, 1695 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19292679_T33" }, { "role": "Theme", "ref_id": "PMID-19292679_T34" } ] }, { "id": "PMID-19292679_E6", "type": "Negative_regulation", "trigger": { "text": [ "impair" ], "offsets": [ [ 1760, 1766 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_E7" }, { "role": "Cause", "ref_id": "PMID-19292679_T33" } ] }, { "id": "PMID-19292679_E7", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1767, 1779 ] ] }, "arguments": [] }, { "id": "PMID-19292679_E8", "type": "Negative_regulation", "trigger": { "text": [ "slow" ], "offsets": [ [ 1794, 1798 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19292679_T33" }, { "role": "Theme", "ref_id": "PMID-19292679_E9" } ] }, { "id": "PMID-19292679_E9", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1816, 1825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19292679_T36" } ] } ]

[ { "id": "PMID-19292679_1", "entity_ids": [ "PMID-19292679_T7", "PMID-19292679_T8" ] } ]

[]

[ { "id": "PMID-1553573__text", "type": "abstract", "text": [ "Granulocyte-macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia. \nIn the present study the effects of the 48-hour administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) (100 U/mL) or interleukin-3 (IL-3) (100 U/mL) on the proliferative activity of leukemic cells and on the intracellular metabolism and cytotoxic efficacy of a subsequent 12-hour application of cytosine arabinoside (ara-C) at doses of 0.1, 1.0, 10.0, and 100.0 mumol/L were evaluated on bone marrow cells from 17 patients with acute myeloid leukemia. After GM-CSF or IL-3, a 1.2- to 2.4-fold increase in S-phase cells was observed in nine of 14 GM-CSF and seven of 11 IL-3 cases. 3H-Cytosine arabinoside incorporation into the DNA was enhanced 1.33- to 18.3-fold over respective controls in 14 of 17 patients. While in control specimens are ara-C dose-dependent increase in 3H-ara-C uptake was accompanied by a corresponding rise in intracellular ara-C-5' triphosphate (ara-CTP) levels, ara-CTP concentrations were not increased after GM-CSF or IL-3 exposure, resulting in a higher ara-C to ara-CTP ratio over controls. This finding may be explained by a stimulatory effect of GM-CSF and IL-3 on ara-C phosphorylating enzymes and a more rapid incorporation of ara-CTP into the DNA of leukemic blasts. These effects translated into a 2.2- to 229.0-fold increase in the cytotoxic activity of ara-C against clonogenic leukemic cells after GM-CSF or IL-3 pretreatment. Hence, GM-CSF and IL-3 enhance the intracellular metabolism of ara-C and its incorporation into the DNA of leukemic cells leading to a higher antileukemic activity of ara-C on clonogenic leukemic cells (CFU-L).\n" ], "offsets": [ [ 0, 1836 ] ] } ]

[ { "id": "PMID-1553573_T1", "type": "Gene_or_gene_product", "text": [ "Granulocyte-macrophage colony-stimulating factor" ], "offsets": [ [ 0, 48 ] ], "normalized": [] }, { "id": "PMID-1553573_T2", "type": "Gene_or_gene_product", "text": [ "interleukin-3" ], "offsets": [ [ 53, 66 ] ], "normalized": [] }, { "id": "PMID-1553573_T3", "type": "Simple_chemical", "text": [ "cytosine arabinoside" ], "offsets": [ [ 96, 116 ] ], "normalized": [] }, { "id": "PMID-1553573_T4", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 126, 129 ] ], "normalized": [] }, { "id": "PMID-1553573_T5", "type": "Cell", "text": [ "leukemic blasts" ], "offsets": [ [ 133, 148 ] ], "normalized": [] }, { "id": "PMID-1553573_T6", "type": "Cell", "text": [ "clonogenic cells" ], "offsets": [ [ 177, 193 ] ], "normalized": [] }, { "id": "PMID-1553573_T7", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 199, 207 ] ], "normalized": [] }, { "id": "PMID-1553573_T8", "type": "Cancer", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 213, 235 ] ], "normalized": [] }, { "id": "PMID-1553573_T9", "type": "Gene_or_gene_product", "text": [ "granulocyte-macrophage colony-stimulating factor" ], "offsets": [ [ 304, 352 ] ], "normalized": [] }, { "id": "PMID-1553573_T10", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 354, 360 ] ], "normalized": [] }, { "id": "PMID-1553573_T11", "type": "Gene_or_gene_product", "text": [ "interleukin-3" ], "offsets": [ [ 376, 389 ] ], "normalized": [] }, { "id": "PMID-1553573_T12", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 391, 395 ] ], "normalized": [] }, { "id": "PMID-1553573_T13", "type": "Cell", "text": [ "leukemic cells" ], "offsets": [ [ 441, 455 ] ], "normalized": [] }, { "id": "PMID-1553573_T14", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 467, 480 ] ], "normalized": [] }, { "id": "PMID-1553573_T15", "type": "Simple_chemical", "text": [ "cytosine arabinoside" ], "offsets": [ [ 554, 574 ] ], "normalized": [] }, { "id": "PMID-1553573_T16", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 576, 581 ] ], "normalized": [] }, { "id": "PMID-1553573_T17", "type": "Cell", "text": [ "bone marrow cells" ], "offsets": [ [ 647, 664 ] ], "normalized": [] }, { "id": "PMID-1553573_T18", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 673, 681 ] ], "normalized": [] }, { "id": "PMID-1553573_T19", "type": "Cancer", "text": [ "acute myeloid leukemia" ], "offsets": [ [ 687, 709 ] ], "normalized": [] }, { "id": "PMID-1553573_T20", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 717, 723 ] ], "normalized": [] }, { "id": "PMID-1553573_T21", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 727, 731 ] ], "normalized": [] }, { "id": "PMID-1553573_T22", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 772, 777 ] ], "normalized": [] }, { "id": "PMID-1553573_T23", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 805, 811 ] ], "normalized": [] }, { "id": "PMID-1553573_T24", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 828, 832 ] ], "normalized": [] }, { "id": "PMID-1553573_T25", "type": "Simple_chemical", "text": [ "3H-Cytosine arabinoside" ], "offsets": [ [ 840, 863 ] ], "normalized": [] }, { "id": "PMID-1553573_T26", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 887, 890 ] ], "normalized": [] }, { "id": "PMID-1553573_T27", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 960, 968 ] ], "normalized": [] }, { "id": "PMID-1553573_T28", "type": "Cell", "text": [ "specimens" ], "offsets": [ [ 987, 996 ] ], "normalized": [] }, { "id": "PMID-1553573_T29", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1001, 1006 ] ], "normalized": [] }, { "id": "PMID-1553573_T30", "type": "Simple_chemical", "text": [ "3H-ara-C" ], "offsets": [ [ 1034, 1042 ] ], "normalized": [] }, { "id": "PMID-1553573_T31", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1093, 1106 ] ], "normalized": [] }, { "id": "PMID-1553573_T32", "type": "Simple_chemical", "text": [ "ara-C-5' triphosphate" ], "offsets": [ [ 1107, 1128 ] ], "normalized": [] }, { "id": "PMID-1553573_T33", "type": "Simple_chemical", "text": [ "ara-CTP" ], "offsets": [ [ 1130, 1137 ] ], "normalized": [] }, { "id": "PMID-1553573_T34", "type": "Simple_chemical", "text": [ "ara-CTP" ], "offsets": [ [ 1147, 1154 ] ], "normalized": [] }, { "id": "PMID-1553573_T35", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 1195, 1201 ] ], "normalized": [] }, { "id": "PMID-1553573_T36", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 1205, 1209 ] ], "normalized": [] }, { "id": "PMID-1553573_T37", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1242, 1247 ] ], "normalized": [] }, { "id": "PMID-1553573_T38", "type": "Simple_chemical", "text": [ "ara-CTP" ], "offsets": [ [ 1251, 1258 ] ], "normalized": [] }, { "id": "PMID-1553573_T39", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 1337, 1343 ] ], "normalized": [] }, { "id": "PMID-1553573_T40", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 1348, 1352 ] ], "normalized": [] }, { "id": "PMID-1553573_T41", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1356, 1361 ] ], "normalized": [] }, { "id": "PMID-1553573_T42", "type": "Simple_chemical", "text": [ "ara-CTP" ], "offsets": [ [ 1420, 1427 ] ], "normalized": [] }, { "id": "PMID-1553573_T43", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 1437, 1440 ] ], "normalized": [] }, { "id": "PMID-1553573_T44", "type": "Cell", "text": [ "leukemic blasts" ], "offsets": [ [ 1444, 1459 ] ], "normalized": [] }, { "id": "PMID-1553573_T45", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1550, 1555 ] ], "normalized": [] }, { "id": "PMID-1553573_T46", "type": "Cell", "text": [ "clonogenic leukemic cells" ], "offsets": [ [ 1564, 1589 ] ], "normalized": [] }, { "id": "PMID-1553573_T47", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 1596, 1602 ] ], "normalized": [] }, { "id": "PMID-1553573_T48", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 1606, 1610 ] ], "normalized": [] }, { "id": "PMID-1553573_T49", "type": "Gene_or_gene_product", "text": [ "GM-CSF" ], "offsets": [ [ 1632, 1638 ] ], "normalized": [] }, { "id": "PMID-1553573_T50", "type": "Gene_or_gene_product", "text": [ "IL-3" ], "offsets": [ [ 1643, 1647 ] ], "normalized": [] }, { "id": "PMID-1553573_T51", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1660, 1673 ] ], "normalized": [] }, { "id": "PMID-1553573_T52", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1688, 1693 ] ], "normalized": [] }, { "id": "PMID-1553573_T53", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 1725, 1728 ] ], "normalized": [] }, { "id": "PMID-1553573_T54", "type": "Cell", "text": [ "leukemic cells" ], "offsets": [ [ 1732, 1746 ] ], "normalized": [] }, { "id": "PMID-1553573_T55", "type": "Simple_chemical", "text": [ "ara-C" ], "offsets": [ [ 1792, 1797 ] ], "normalized": [] }, { "id": "PMID-1553573_T56", "type": "Cell", "text": [ "clonogenic leukemic cells" ], "offsets": [ [ 1801, 1826 ] ], "normalized": [] }, { "id": "PMID-1553573_T57", "type": "Cell", "text": [ "CFU-L" ], "offsets": [ [ 1828, 1833 ] ], "normalized": [] } ]

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"PMID-1553573_T15" }, { "role": "Theme", "ref_id": "PMID-1553573_T17" } ] }, { "id": "PMID-1553573_E14", "type": "Planned_process", "trigger": { "text": [ "exposure" ], "offsets": [ [ 1210, 1218 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1553573_T36" } ] }, { "id": "PMID-1553573_E15", "type": "Planned_process", "trigger": { "text": [ "exposure" ], "offsets": [ [ 1210, 1218 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1553573_T35" } ] }, { "id": "PMID-1553573_E16", "type": "Positive_regulation", "trigger": { "text": [ "stimulatory effect" ], "offsets": [ [ 1315, 1333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1553573_E18" }, { "role": "Cause", "ref_id": "PMID-1553573_T39" } ] }, { "id": "PMID-1553573_E17", "type": "Positive_regulation", "trigger": { "text": [ "stimulatory effect" ], "offsets": [ [ 1315, 1333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1553573_E18" }, { "role": "Cause", "ref_id": "PMID-1553573_T40" } ] }, { 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], "offsets": [ [ 1648, 1655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1553573_E24" }, { "role": "Cause", "ref_id": "PMID-1553573_T50" } ] }, { "id": "PMID-1553573_E23", "type": "Positive_regulation", "trigger": { "text": [ "enhance" ], "offsets": [ [ 1648, 1655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1553573_E24" }, { "role": "Cause", "ref_id": "PMID-1553573_T49" } ] }, { "id": "PMID-1553573_E24", "type": "Metabolism", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 1674, 1684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1553573_T52" } ] }, { "id": "PMID-1553573_E25", "type": "Negative_regulation", "trigger": { "text": [ "antileukemic activity" ], "offsets": [ [ 1767, 1788 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1553573_T55" }, { "role": "Theme", "ref_id": "PMID-1553573_T56" } ] } ]

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[]

[ { "id": "PMID-11425277__text", "type": "abstract", "text": [ "Current prospects for controlling cancer growth with non-cytotoxic agents--nutrients, phytochemicals, herbal extracts, and available drugs.\nIn animal or cell culture studies, the growth and spread of cancer can be slowed by many nutrients, food factors, herbal extracts, and well-tolerated, available drugs that are still rarely used in the clinical management of cancer, in part because they seem unlikely to constitute definitive therapies in themselves. However, it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and, when used as adjuvants, could improve the cure rates achievable with standard therapies. The therapeutic options available in this regard include measures that: down-regulate serum free IGF-I; suppress the synthesis of mevalonic acid and/or certain derivatives thereof; modulate arachidonate metabolism by inhibiting 5-lipoxygenase, 12-lipoxygenase, or COX-2; antagonize the activation of AP-1 transcription factors; promote the activation of PPAR-gamma transcription factors; and that suppress angiogenesis by additional mechanisms. Many of these measures appear suitable for use in cancer prevention.\n" ], "offsets": [ [ 0, 1216 ] ] } ]

[ { "id": "PMID-11425277_T1", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 34, 40 ] ], "normalized": [] }, { "id": "PMID-11425277_T2", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 153, 157 ] ], "normalized": [] }, { "id": "PMID-11425277_T3", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 200, 206 ] ], "normalized": [] }, { "id": "PMID-11425277_T4", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 364, 370 ] ], "normalized": [] }, { "id": "PMID-11425277_T5", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 788, 793 ] ], "normalized": [] }, { "id": "PMID-11425277_T6", "type": "Gene_or_gene_product", "text": [ "IGF-I" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-11425277_T7", "type": "Simple_chemical", "text": [ "mevalonic acid" ], "offsets": [ [ 832, 846 ] ], "normalized": [] }, { "id": "PMID-11425277_T8", "type": "Simple_chemical", "text": [ "arachidonate" ], "offsets": [ [ 892, 904 ] ], "normalized": [] }, { "id": "PMID-11425277_T9", "type": "Gene_or_gene_product", "text": [ "5-lipoxygenase" ], "offsets": [ [ 930, 944 ] ], "normalized": [] }, { "id": "PMID-11425277_T10", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 946, 961 ] ], "normalized": [] }, { "id": "PMID-11425277_T11", "type": "Gene_or_gene_product", "text": [ "COX-2" ], "offsets": [ [ 966, 971 ] ], "normalized": [] }, { "id": "PMID-11425277_T12", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 1002, 1006 ] ], "normalized": [] }, { "id": "PMID-11425277_T13", "type": "Gene_or_gene_product", "text": [ "PPAR-gamma" ], "offsets": [ [ 1056, 1066 ] ], "normalized": [] }, { "id": "PMID-11425277_T14", "type": "Cancer", "text": [ "cancer" ], "offsets": [ [ 1197, 1203 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-11836604__text", "type": "abstract", "text": [ "Prognostic significance of heat shock protein 27 (HSP27) in patients with oral squamous cell carcinoma. \nHeat shock proteins (HSPs) have been defined as proteins induced by heat shock and other environmental and pathophysiologic stress. Heat shock protein 27 (HSP27) is one of the small heat shock proteins. HSP27 is implicated in protein-protein interactions such as folding, translocation, and prevention of inappropriate protein aggregation. Many of their functions suggest that they play important roles in cancers. Archival tissues from 40 patients with oral squamous cell carcinoma who received primary surgical resection were examined for HSP27 by immunohistochemistry and correlated with clinical stage, lymph node metastasis, histological grade and survival period. HSP27 expression was positive staining (+) in 20 (50%), weak or negative staining (-) in 20 (50%) of total 40 cases. There was no correlation between HSP27 expression and clinical stage, lymph node metastasis and histological grade. However, when compared with clinicopathological features, the expression of HSP27 correlated inversely with survival period. This study suggests that the expression of HSP27 is frequently promoted in patients with oral squamous cell carcinoma and should be considered an independent prognostic factor of oral squamous cell carcinoma patients.\n" ], "offsets": [ [ 0, 1351 ] ] } ]

[ { "id": "PMID-11836604_T1", "type": "Gene_or_gene_product", "text": [ "heat shock protein 27" ], "offsets": [ [ 27, 48 ] ], "normalized": [] }, { "id": "PMID-11836604_T2", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 50, 55 ] ], "normalized": [] }, { "id": "PMID-11836604_T3", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 60, 68 ] ], "normalized": [] }, { "id": "PMID-11836604_T4", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 74, 102 ] ], "normalized": [] }, { "id": "PMID-11836604_T5", "type": "Gene_or_gene_product", "text": [ "Heat shock proteins" ], "offsets": [ [ 105, 124 ] ], "normalized": [] }, { "id": "PMID-11836604_T6", "type": "Gene_or_gene_product", "text": [ "HSPs" ], "offsets": [ [ 126, 130 ] ], "normalized": [] }, { "id": "PMID-11836604_T7", "type": "Gene_or_gene_product", "text": [ "Heat shock protein 27" ], "offsets": [ [ 237, 258 ] ], "normalized": [] }, { "id": "PMID-11836604_T8", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 260, 265 ] ], "normalized": [] }, { "id": "PMID-11836604_T9", "type": "Gene_or_gene_product", "text": [ "small heat shock proteins" ], "offsets": [ [ 281, 306 ] ], "normalized": [] }, { "id": "PMID-11836604_T10", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 308, 313 ] ], "normalized": [] }, { "id": "PMID-11836604_T11", "type": "Cancer", "text": [ "cancers" ], "offsets": [ [ 511, 518 ] ], "normalized": [] }, { "id": "PMID-11836604_T12", "type": "Tissue", "text": [ "Archival tissues" ], "offsets": [ [ 520, 536 ] ], "normalized": [] }, { "id": "PMID-11836604_T13", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 545, 553 ] ], "normalized": [] }, { "id": "PMID-11836604_T14", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 559, 587 ] ], "normalized": [] }, { "id": "PMID-11836604_T15", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 646, 651 ] ], "normalized": [] }, { "id": "PMID-11836604_T16", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 712, 722 ] ], "normalized": [] }, { "id": "PMID-11836604_T17", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 775, 780 ] ], "normalized": [] }, { "id": "PMID-11836604_T18", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 925, 930 ] ], "normalized": [] }, { "id": "PMID-11836604_T19", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 962, 972 ] ], "normalized": [] }, { "id": "PMID-11836604_T20", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 1084, 1089 ] ], "normalized": [] }, { "id": "PMID-11836604_T21", "type": "Gene_or_gene_product", "text": [ "HSP27" ], "offsets": [ [ 1176, 1181 ] ], "normalized": [] }, { "id": "PMID-11836604_T22", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1208, 1216 ] ], "normalized": [] }, { "id": "PMID-11836604_T23", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 1222, 1250 ] ], "normalized": [] }, { "id": "PMID-11836604_T24", "type": "Cancer", "text": [ "oral squamous cell carcinoma" ], "offsets": [ [ 1312, 1340 ] ], "normalized": [] }, { "id": "PMID-11836604_T25", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1341, 1349 ] ], "normalized": [] } ]

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[ { "id": "PMID-11836604_1", "entity_ids": [ "PMID-11836604_T1", "PMID-11836604_T2" ] }, { "id": "PMID-11836604_2", "entity_ids": [ "PMID-11836604_T5", "PMID-11836604_T6" ] }, { "id": "PMID-11836604_3", "entity_ids": [ "PMID-11836604_T7", "PMID-11836604_T8" ] } ]

[]

[ { "id": "PMID-15355640__text", "type": "abstract", "text": [ "[Altered expression of PTEN gene and LOH of its epigenetic microsatellite in gastric carcinoma]. \nOBJECTIVE: To investigate the expression of PTEN and loss of heterozygosity (LOH) of its epigenetic microsatellite in gastric carcinoma and explore their roles in progression of gastric carcinoma. METHODS: LOH of epigenetic microsatellites of PTEN (D10S541, D10S583 and D10S1687) in advanced gastric cancer was detected by PCR-SSCP. Expression of PTEN mRNA and protein in normal gastric mucosa and gastric cancer was evaluated by RT-PCR and SABC immunohistochemistry, respectively. The relationship between expression of PTEN mRNA and protein and lymph node metastasis or LOH of microsatellites was discussed. RESULTS: LOH of D10S541, D10S583 and D10S1687 was found in 37.5% (21/56) of advanced gastric cancers. The positive rates of PTEN mRNA expression were 80.4% (45/56), 45.5% (5/11) and 32.1% (18/56) in normal mucosa, early and advanced gastric carcinomas, respectively, while 78.6% (44/56), 44.5% (5/11) and 28.6% (16/56) at the protein level. PTEN mRNA and protein were less frequently expressed in early and advanced gastric carcinomas than that in normal gastric mucosa (P < 0.05). There was positive correlation between PTEN mRNA expression and LOH of microsatellites in advanced gastric carcinomas. PTEN protein expression paralleled with its mRNA expression (P < 0.05). The expression of PTEN mRNA and protein was negatively correlated with lymph node metastasis of advanced gastric carcinomas (P < 0.05). CONCLUSION: Down-regulated expression of PTEN gene is found in different stages of gastric carcinoma, and is closely correlated with LOH of its epigenetic microsatellites, which probably is its underlying molecular mechanisms. It suggests that altered PTEN gene contributes to tumorigenesis and progression of gastric carcinomas.\n" ], "offsets": [ [ 0, 1847 ] ] } ]

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], "normalized": [] }, { "id": "PMID-15355640_T9", "type": "Multi-tissue_structure", "text": [ "gastric mucosa" ], "offsets": [ [ 477, 491 ] ], "normalized": [] }, { "id": "PMID-15355640_T10", "type": "Cancer", "text": [ "gastric cancer" ], "offsets": [ [ 496, 510 ] ], "normalized": [] }, { "id": "PMID-15355640_T11", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 619, 623 ] ], "normalized": [] }, { "id": "PMID-15355640_T12", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 645, 655 ] ], "normalized": [] }, { "id": "PMID-15355640_T13", "type": "Cancer", "text": [ "gastric cancers" ], "offsets": [ [ 793, 808 ] ], "normalized": [] }, { "id": "PMID-15355640_T14", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 832, 836 ] ], "normalized": [] }, { "id": "PMID-15355640_T15", "type": "Multi-tissue_structure", "text": [ "mucosa" ], "offsets": [ [ 914, 920 ] ], "normalized": [] }, { "id": "PMID-15355640_T16", "type": "Cancer", "text": [ "gastric carcinomas" ], "offsets": [ [ 941, 959 ] ], "normalized": [] }, { "id": "PMID-15355640_T17", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1049, 1053 ] ], "normalized": [] }, { "id": "PMID-15355640_T18", "type": "Cancer", "text": [ "gastric carcinomas" ], "offsets": [ [ 1124, 1142 ] ], "normalized": [] }, { "id": "PMID-15355640_T19", "type": "Multi-tissue_structure", "text": [ "gastric mucosa" ], "offsets": [ [ 1163, 1177 ] ], "normalized": [] }, { "id": "PMID-15355640_T20", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "PMID-15355640_T21", "type": "Cancer", "text": [ "gastric carcinomas" ], "offsets": [ [ 1289, 1307 ] ], "normalized": [] }, { "id": "PMID-15355640_T22", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1309, 1313 ] ], "normalized": [] }, { "id": "PMID-15355640_T23", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1399, 1403 ] ], "normalized": [] }, { "id": "PMID-15355640_T24", "type": "Multi-tissue_structure", "text": [ "lymph node" ], "offsets": [ [ 1452, 1462 ] ], "normalized": [] }, { "id": "PMID-15355640_T25", "type": "Cancer", "text": [ "gastric carcinomas" ], "offsets": [ [ 1486, 1504 ] ], "normalized": [] }, { "id": "PMID-15355640_T26", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1558, 1562 ] ], "normalized": [] }, { "id": "PMID-15355640_T27", "type": "Cancer", "text": [ "gastric carcinoma" ], "offsets": [ [ 1600, 1617 ] ], "normalized": [] }, { "id": "PMID-15355640_T28", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1769, 1773 ] ], "normalized": [] }, { "id": "PMID-15355640_T29", "type": "Cancer", "text": [ "gastric carcinomas" ], "offsets": [ [ 1827, 1845 ] ], "normalized": [] }, { "id": "PMID-15355640_T33", "type": "DNA_domain_or_region", "text": [ "epigenetic microsatellite" ], "offsets": [ [ 48, 73 ] ], "normalized": [] }, { "id": "PMID-15355640_T36", "type": "DNA_domain_or_region", "text": [ "epigenetic microsatellite" ], "offsets": [ [ 187, 212 ] ], "normalized": [] }, { "id": "PMID-15355640_T40", "type": "DNA_domain_or_region", "text": [ "epigenetic microsatellites" ], "offsets": [ [ 311, 337 ] ], "normalized": [] }, { "id": "PMID-15355640_T48", "type": "DNA_domain_or_region", "text": [ "microsatellites" ], "offsets": [ [ 677, 692 ] ], "normalized": [] }, { "id": "PMID-15355640_T50", "type": "DNA_domain_or_region", "text": [ "D10S541" ], "offsets": [ [ 724, 731 ] ], "normalized": [] }, { "id": "PMID-15355640_T51", "type": "DNA_domain_or_region", "text": [ "D10S583" ], "offsets": [ [ 733, 740 ] ], "normalized": [] }, { "id": "PMID-15355640_T52", "type": "DNA_domain_or_region", "text": [ "D10S1687" ], "offsets": [ [ 745, 753 ] ], "normalized": [] }, { "id": "PMID-15355640_T58", "type": "DNA_domain_or_region", "text": [ "microsatellites" ], "offsets": [ [ 1261, 1276 ] ], "normalized": [] }, { "id": "PMID-15355640_T67", "type": "DNA_domain_or_region", "text": [ "epigenetic microsatellites" ], "offsets": [ [ 1661, 1687 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-10816661__text", "type": "abstract", "text": [ "Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts.\nAlpha-melanocyte-stimulating hormone (alpha-MSH) has evolved as a mediator of diverse biological activities in an ever-growing number of non-melanocytic cell types. One mechanism by which alpha-MSH exerts its effects is modulation of AP-1 and NF-kappa B. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that alpha-MSH (10(-6) to 10(-14) M) activates AP-1 in human dermal fibroblasts, whereas coincubation with interleukin-1 beta (IL-1 beta) results in suppression of its activation. alpha-MSH also induces activation of NF-kappa B but does not modulate DNA binding on costimulation with IL-1 beta. Since AP-1 and NF-kappa B are key elements in controlling interleukin-8 (IL-8) transcription, human fibroblasts were treated with alpha-MSH and IL-1 beta for 24 hours, and cytokine levels in the supernatants were measured by ELISA. alpha-MSH alone had little effect, whereas coincubation with IL-1 beta led to marked downregulation of IL-8 secretion (at most 288 +/- 152 ng/mL) when compared to treatment with IL-1 beta alone (919 +/- 157 ng/mL). Our results indicate that alpha-MSH exerts modulatory effects on the activation of NF-kappa B and AP-1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of alpha-MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.\n" ], "offsets": [ [ 0, 1650 ] ] } ]

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"Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 179, 188 ] ], "normalized": [] }, { "id": "PMID-10816661_T9", "type": "Cell", "text": [ "non-melanocytic cell" ], "offsets": [ [ 278, 298 ] ], "normalized": [] }, { "id": "PMID-10816661_T10", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 329, 338 ] ], "normalized": [] }, { "id": "PMID-10816661_T11", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 375, 379 ] ], "normalized": [] }, { "id": "PMID-10816661_T12", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 384, 394 ] ], "normalized": [] }, { "id": "PMID-10816661_T13", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 459, 470 ] ], "normalized": [] }, { "id": "PMID-10816661_T14", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 475, 495 ] ], "normalized": [] }, { "id": "PMID-10816661_T15", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 599, 608 ] ], "normalized": [] }, { "id": "PMID-10816661_T16", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 641, 645 ] ], "normalized": [] }, { "id": "PMID-10816661_T17", "type": "Organism", "text": [ "human" ], "offsets": [ [ 649, 654 ] ], "normalized": [] }, { "id": "PMID-10816661_T18", "type": "Cell", "text": [ "dermal fibroblasts" ], "offsets": [ [ 655, 673 ] ], "normalized": [] }, { "id": "PMID-10816661_T19", "type": "Gene_or_gene_product", "text": [ "interleukin-1 beta" ], "offsets": [ [ 701, 719 ] ], "normalized": [] }, { "id": "PMID-10816661_T20", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 721, 730 ] ], "normalized": [] }, { "id": "PMID-10816661_T21", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 774, 783 ] ], "normalized": [] }, { "id": "PMID-10816661_T22", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 811, 821 ] ], "normalized": [] }, { "id": "PMID-10816661_T23", "type": "Cellular_component", "text": [ "DNA" ], "offsets": [ [ 844, 847 ] ], "normalized": [] }, { "id": "PMID-10816661_T24", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 878, 887 ] ], "normalized": [] }, { "id": "PMID-10816661_T25", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 895, 899 ] ], "normalized": [] }, { "id": "PMID-10816661_T26", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 904, 914 ] ], "normalized": [] }, { "id": "PMID-10816661_T27", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 947, 960 ] ], "normalized": [] }, { "id": "PMID-10816661_T28", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 962, 966 ] ], "normalized": [] }, { "id": "PMID-10816661_T29", "type": "Organism", "text": [ "human" ], "offsets": [ [ 983, 988 ] ], "normalized": [] }, { "id": "PMID-10816661_T30", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 989, 1000 ] ], "normalized": [] }, { "id": "PMID-10816661_T31", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1019, 1028 ] ], "normalized": [] }, { "id": "PMID-10816661_T32", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1033, 1042 ] ], "normalized": [] }, { "id": "PMID-10816661_T33", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1121, 1130 ] ], "normalized": [] }, { "id": "PMID-10816661_T34", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1182, 1191 ] ], "normalized": [] }, { "id": "PMID-10816661_T35", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1224, 1228 ] ], "normalized": [] }, { "id": "PMID-10816661_T36", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1299, 1308 ] ], "normalized": [] }, { "id": "PMID-10816661_T37", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1362, 1371 ] ], "normalized": [] }, { "id": "PMID-10816661_T38", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 1419, 1429 ] ], "normalized": [] }, { "id": "PMID-10816661_T39", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 1434, 1438 ] ], "normalized": [] }, { "id": "PMID-10816661_T40", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1488, 1493 ] ], "normalized": [] }, { "id": "PMID-10816661_T41", "type": "Cell", "text": [ "dermal fibroblasts" ], "offsets": [ [ 1494, 1512 ] ], "normalized": [] }, { "id": "PMID-10816661_T42", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1531, 1540 ] ], "normalized": [] }, { "id": "PMID-10816661_T43", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 1584, 1604 ] ], "normalized": [] }, { "id": "PMID-10816661_T44", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1618, 1623 ] ], "normalized": [] } ]

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"activation" ], "offsets": [ [ 47, 57 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T3" } ] }, { "id": "PMID-10816661_E6", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 85, 94 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T4" }, { "role": "FromLoc", "ref_id": "PMID-10816661_T6" } ] }, { "id": "PMID-10816661_E7", "type": "Regulation", "trigger": { "text": [ "mediator" ], "offsets": [ [ 207, 215 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_T7" }, { "role": "Theme", "ref_id": "PMID-10816661_T9" } ] }, { "id": "PMID-10816661_E8", "type": "Cell_proliferation", "trigger": { "text": [ "growing" ], "offsets": [ [ 260, 267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T9" } ] }, { "id": "PMID-10816661_E9", "type": "Regulation", "trigger": { "text": [ "modulation" ], "offsets": [ [ 361, 371 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_T10" }, { "role": "Theme", 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"role": "Instrument", "ref_id": "PMID-10816661_T34" }, { "role": "Instrument", "ref_id": "PMID-10816661_T33" } ] }, { "id": "PMID-10816661_E27", "type": "Positive_regulation", "trigger": { "text": [ "led" ], "offsets": [ [ 1192, 1195 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_E26" }, { "role": "Theme", "ref_id": "PMID-10816661_E28" } ] }, { "id": "PMID-10816661_E28", "type": "Negative_regulation", "trigger": { "text": [ "downregulation" ], "offsets": [ [ 1206, 1220 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_E29" } ] }, { "id": "PMID-10816661_E29", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 1229, 1238 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T35" } ] }, { "id": "PMID-10816661_E30", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1284, 1293 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10816661_T36" } ] }, { "id": "PMID-10816661_E31", 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1580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T43" }, { "role": "Cause", "ref_id": "PMID-10816661_T42" } ] }, { "id": "PMID-10816661_E36", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1636, 1648 ] ] }, "arguments": [] } ]

[ { "id": "PMID-10816661_1", "entity_ids": [ "PMID-10816661_T8", "PMID-10816661_T7" ] }, { "id": "PMID-10816661_2", "entity_ids": [ "PMID-10816661_T19", "PMID-10816661_T20" ] }, { "id": "PMID-10816661_3", "entity_ids": [ "PMID-10816661_T28", "PMID-10816661_T27" ] } ]

[]

[ { "id": "PMID-11381168__text", "type": "abstract", "text": [ "Effects of morphological patterning on endothelial cell migration.\nThe migration of vascular endothelial cells (ECs) plays an important role in vascular remodeling. Here we studied the effects of cell morphology on the migration of bovine aortic ECs by culturing cells on micropatterned strips of collagen matrix (60-, 30-, and 15-microm wide). The spreading areas of the cells on 15- and 30-microm wide strips were 30% lower than those on 60-microm wide strips and unpatterned collagen. The cells on 15-microm wide strips completely aligned in the direction of the strip, and had significantly lower shape index than those in all other groups. On strips of all widths, ECs tended to migrate in the direction of strips. ECs on 15-microm wide strips had highest speed, particularly in the direction of the strip. Vinculin staining showed that the leading edge of ECs on 15-microm wide strips had focal adhesions that were oriented with their lamellipodial protrusion and the direction of cell migration; this arrangement of the focal adhesions may promote EC migration. The present study provides direct evidence on the role of cell morphology in EC migration, and will help us to understand the mechanisms of EC migration during angiogenesis and wound healing.\n" ], "offsets": [ [ 0, 1261 ] ] } ]

[ { "id": "PMID-11381168_T1", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 39, 55 ] ], "normalized": [] }, { "id": "PMID-11381168_T2", "type": "Cell", "text": [ "vascular endothelial cells" ], "offsets": [ [ 84, 110 ] ], "normalized": [] }, { "id": "PMID-11381168_T3", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 112, 115 ] ], "normalized": [] }, { "id": "PMID-11381168_T4", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 144, 152 ] ], "normalized": [] }, { "id": "PMID-11381168_T5", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 196, 200 ] ], "normalized": [] }, { "id": "PMID-11381168_T6", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 232, 238 ] ], "normalized": [] }, { "id": "PMID-11381168_T7", "type": "Cell", "text": [ "aortic ECs" ], "offsets": [ [ 239, 249 ] ], "normalized": [] }, { "id": "PMID-11381168_T8", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 263, 268 ] ], "normalized": [] }, { "id": "PMID-11381168_T9", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 297, 305 ] ], "normalized": [] }, { "id": "PMID-11381168_T10", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 306, 312 ] ], "normalized": [] }, { "id": "PMID-11381168_T11", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 372, 377 ] ], "normalized": [] }, { "id": "PMID-11381168_T12", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 478, 486 ] ], "normalized": [] }, { "id": "PMID-11381168_T13", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "PMID-11381168_T14", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 670, 673 ] ], "normalized": [] }, { "id": "PMID-11381168_T15", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 720, 723 ] ], "normalized": [] }, { "id": "PMID-11381168_T16", "type": "Gene_or_gene_product", "text": [ "Vinculin" ], "offsets": [ [ 812, 820 ] ], "normalized": [] }, { "id": "PMID-11381168_T17", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 862, 865 ] ], "normalized": [] }, { "id": "PMID-11381168_T18", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 987, 991 ] ], "normalized": [] }, { "id": "PMID-11381168_T19", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1055, 1057 ] ], "normalized": [] }, { "id": "PMID-11381168_T20", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1127, 1131 ] ], "normalized": [] }, { "id": "PMID-11381168_T21", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1146, 1148 ] ], "normalized": [] }, { "id": "PMID-11381168_T22", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1209, 1211 ] ], "normalized": [] }, { "id": "PMID-11381168_T23", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1246, 1251 ] ], "normalized": [] } ]

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[ { "id": "PMID-11381168_1", "entity_ids": [ "PMID-11381168_T2", "PMID-11381168_T3" ] } ]

[]

[ { "id": "PMID-11107120__text", "type": "abstract", "text": [ "p75 mediated apoptosis in neuroblastoma cells is inhibited by expression of TrkA. \nBACKGROUND: Neurotrophins mediate their effects by binding to members of the Trk family of receptor tyrosine kinases and to the low-affinity nerve growth factor receptor p75. Nerve growth factor (NGF) has been demonstrated to support survival and differentiation of neuroblastoma (NB) cells by activation of the TrkA receptor. The p75 receptor belongs to the tumor necrosis factor (TNF) family of death receptors and has been suggested as a receptor that mediates apoptosis in neuronal and NB cells. PROCEDURE: To investigate the effect of p75 expression in NB, we transfected the p75 cDNA into SH-SY5Y cells, an NB cell line lacking expression of both p75 and TrkA. RESULTS: Cell clones expressing elevated levels of p75 showed a high degree of apoptosis even in 10% serum-supplemented medium. Apoptotic signaling by p75 was ligand-independent and only partly caspase-dependent. The level of apoptosis correlated directly with the expression level of the receptor, indicating that p75 may activate the cell death program directly. However, additional transfection of TrkA into SY5Y-p75 cells resulted in a significantly reduced rate of apoptosis even in the absence of NGF. CONCLUSIONS: Thus, expression of the TrkA receptor itself inhibits p75 mediated apoptosis in NB cells.\n" ], "offsets": [ [ 0, 1361 ] ] } ]

[ { "id": "PMID-11107120_T1", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-11107120_T2", "type": "Cell", "text": [ "neuroblastoma cells" ], "offsets": [ [ 26, 45 ] ], "normalized": [] }, { "id": "PMID-11107120_T3", "type": "Gene_or_gene_product", "text": [ "TrkA" ], "offsets": [ [ 76, 80 ] ], "normalized": [] }, { "id": "PMID-11107120_T4", "type": "Gene_or_gene_product", "text": [ "Neurotrophins" ], "offsets": [ [ 95, 108 ] ], "normalized": [] }, { "id": "PMID-11107120_T5", "type": "Gene_or_gene_product", "text": [ "Trk" ], "offsets": [ [ 160, 163 ] ], "normalized": [] }, { "id": "PMID-11107120_T6", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 253, 256 ] ], "normalized": [] }, { "id": "PMID-11107120_T7", "type": "Gene_or_gene_product", "text": [ "Nerve growth factor" ], "offsets": [ [ 258, 277 ] ], "normalized": [] }, { "id": "PMID-11107120_T8", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 279, 282 ] ], "normalized": [] }, { "id": "PMID-11107120_T9", "type": "Cell", "text": [ "neuroblastoma (NB) cells" ], "offsets": [ [ 349, 373 ] ], "normalized": [] }, { "id": "PMID-11107120_T10", "type": "Gene_or_gene_product", "text": [ "TrkA" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-11107120_T11", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 414, 417 ] ], "normalized": [] }, { "id": "PMID-11107120_T12", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor" ], "offsets": [ [ 442, 463 ] ], "normalized": [] }, { "id": "PMID-11107120_T13", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 465, 468 ] ], "normalized": [] }, { "id": "PMID-11107120_T14", "type": "Cell", "text": [ "neuronal" ], "offsets": [ [ 560, 568 ] ], "normalized": [] }, { "id": "PMID-11107120_T15", "type": "Cell", "text": [ "NB cells" ], "offsets": [ [ 573, 581 ] ], "normalized": [] }, { "id": "PMID-11107120_T16", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 623, 626 ] ], "normalized": [] }, { "id": "PMID-11107120_T17", "type": "Cancer", "text": [ "NB" ], "offsets": [ [ 641, 643 ] ], "normalized": [] }, { "id": "PMID-11107120_T18", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 664, 667 ] ], "normalized": [] }, { "id": "PMID-11107120_T19", "type": "Cell", "text": [ "SH-SY5Y cells" ], "offsets": [ [ 678, 691 ] ], "normalized": [] }, { "id": "PMID-11107120_T20", "type": "Cell", "text": [ "NB cell line" ], "offsets": [ [ 696, 708 ] ], "normalized": [] }, { "id": "PMID-11107120_T21", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 736, 739 ] ], "normalized": [] }, { "id": "PMID-11107120_T22", "type": "Gene_or_gene_product", "text": [ "TrkA" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "PMID-11107120_T23", "type": "Cell", "text": [ "Cell clones" ], "offsets": [ [ 759, 770 ] ], "normalized": [] }, { "id": "PMID-11107120_T24", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 801, 804 ] ], "normalized": [] }, { "id": "PMID-11107120_T25", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 851, 856 ] ], "normalized": [] }, { "id": "PMID-11107120_T26", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 901, 904 ] ], "normalized": [] }, { "id": "PMID-11107120_T27", "type": "Gene_or_gene_product", "text": [ "caspase" ], "offsets": [ [ 944, 951 ] ], "normalized": [] }, { "id": "PMID-11107120_T28", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 1065, 1068 ] ], "normalized": [] }, { "id": "PMID-11107120_T29", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1086, 1090 ] ], "normalized": [] }, { "id": "PMID-11107120_T30", "type": "Gene_or_gene_product", "text": [ "TrkA" ], "offsets": [ [ 1151, 1155 ] ], "normalized": [] }, { "id": "PMID-11107120_T31", "type": "Gene_or_gene_product", "text": [ "SY5Y" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "PMID-11107120_T32", "type": "Cell", "text": [ "SY5Y-p75 cells" ], "offsets": [ [ 1161, 1175 ] ], "normalized": [] }, { "id": "PMID-11107120_T33", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 1166, 1169 ] ], "normalized": [] }, { "id": "PMID-11107120_T34", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 1253, 1256 ] ], "normalized": [] }, { "id": "PMID-11107120_T35", "type": "Gene_or_gene_product", "text": [ "TrkA" ], "offsets": [ [ 1295, 1299 ] ], "normalized": [] }, { "id": "PMID-11107120_T36", "type": "Gene_or_gene_product", "text": [ "p75" ], "offsets": [ [ 1325, 1328 ] ], "normalized": [] }, { "id": "PMID-11107120_T37", "type": "Cell", "text": [ "NB cells" ], "offsets": [ [ 1351, 1359 ] ], "normalized": [] } ]

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"role": "Theme", "ref_id": "PMID-11107120_T21" } ] }, { "id": "PMID-11107120_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 717, 727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T22" } ] }, { "id": "PMID-11107120_E20", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 771, 781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T24" } ] }, { "id": "PMID-11107120_E21", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 782, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_E20" } ] }, { "id": "PMID-11107120_E22", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 829, 838 ] ] }, "arguments": [] }, { "id": "PMID-11107120_E23", "type": "Planned_process", "trigger": { "text": [ "supplemented" ], "offsets": [ [ 857, 869 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11107120_T25" } ] }, { "id": "PMID-11107120_E24", "type": "Pathway", "trigger": { "text": [ "Apoptotic signaling" ], "offsets": [ [ 878, 897 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11107120_T26" } ] }, { "id": "PMID-11107120_E25", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 952, 961 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11107120_T27" }, { "role": "Theme", "ref_id": "PMID-11107120_E24" } ] }, { "id": "PMID-11107120_E26", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 976, 985 ] ] }, "arguments": [] }, { "id": "PMID-11107120_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1015, 1025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T26" } ] }, { "id": "PMID-11107120_E28", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1073, 1081 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11107120_T28" }, { "role": "Theme", "ref_id": "PMID-11107120_E29" } ] }, { "id": "PMID-11107120_E29", "type": "Death", "trigger": { "text": [ "death" ], "offsets": [ [ 1091, 1096 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T29" } ] }, { "id": "PMID-11107120_E30", "type": "Planned_process", "trigger": { "text": [ "transfection" ], "offsets": [ [ 1135, 1147 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11107120_T30" }, { "role": "Theme", "ref_id": "PMID-11107120_T32" } ] }, { "id": "PMID-11107120_E31", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1176, 1184 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11107120_E30" }, { "role": "Theme", "ref_id": "PMID-11107120_E32" } ] }, { "id": "PMID-11107120_E32", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1204, 1211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_E33" } ] }, { "id": "PMID-11107120_E33", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1220, 1229 ] ] }, "arguments": [] }, { "id": "PMID-11107120_E34", "type": "Localization", "trigger": { "text": [ "absence" ], "offsets": [ [ 1242, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T34" } ] }, { "id": "PMID-11107120_E35", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1277, 1287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T35" } ] }, { "id": "PMID-11107120_E36", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1316, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_E38" }, { "role": "Cause", "ref_id": "PMID-11107120_E35" } ] }, { "id": "PMID-11107120_E37", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1329, 1337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_E38" }, { "role": "Cause", "ref_id": "PMID-11107120_T36" } ] }, { "id": "PMID-11107120_E38", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1338, 1347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11107120_T37" } ] } ]

[ { "id": "PMID-11107120_1", "entity_ids": [ "PMID-11107120_T7", "PMID-11107120_T8" ] }, { "id": "PMID-11107120_2", "entity_ids": [ "PMID-11107120_T12", "PMID-11107120_T13" ] } ]

[]

[ { "id": "PMID-12920663__text", "type": "abstract", "text": [ "Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.\nRetinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.\n" ], "offsets": [ [ 0, 1947 ] ] } ]

[ { "id": "PMID-12920663_T1", "type": "Organ", "text": [ "ocular" ], "offsets": [ [ 81, 87 ] ], "normalized": [] }, { "id": "PMID-12920663_T2", "type": "Gene_or_gene_product", "text": [ "pigment epithelium-derived factor" ], "offsets": [ [ 110, 143 ] ], "normalized": [] }, { "id": "PMID-12920663_T3", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 145, 149 ] ], "normalized": [] }, { "id": "PMID-12920663_T4", "type": "Organism_substance", "text": [ "aqueous humor" ], "offsets": [ [ 154, 167 ] ], "normalized": [] }, { "id": "PMID-12920663_T5", "type": "Tissue", "text": [ "microvascular" ], "offsets": [ [ 215, 228 ] ], "normalized": [] }, { "id": "PMID-12920663_T6", "type": "Organism_substance", "text": [ "aqueous humor" ], "offsets": [ [ 413, 426 ] ], "normalized": [] }, { "id": "PMID-12920663_T7", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 434, 437 ] ], "normalized": [] }, { "id": "PMID-12920663_T8", "type": "Organism_substance", "text": [ "Aqueous humor" ], "offsets": [ [ 439, 452 ] ], "normalized": [] }, { "id": "PMID-12920663_T9", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 504, 512 ] ], "normalized": [] }, { "id": "PMID-12920663_T10", "type": "Organism", "text": [ "controls" ], "offsets": [ [ 560, 568 ] ], "normalized": [] }, { "id": "PMID-12920663_T11", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 595, 629 ] ], "normalized": [] }, { "id": "PMID-12920663_T12", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "PMID-12920663_T13", "type": "Gene_or_gene_product", "text": [ "pigment epithelium-derived factor" ], "offsets": [ [ 662, 695 ] ], "normalized": [] }, { "id": "PMID-12920663_T14", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 697, 701 ] ], "normalized": [] }, { "id": "PMID-12920663_T15", "type": "Organism_substance", "text": [ "aqueous humor" ], "offsets": [ [ 747, 760 ] ], "normalized": [] }, { "id": "PMID-12920663_T16", "type": "Cell", "text": [ "capillary endothelial cells" ], "offsets": [ [ 820, 847 ] ], "normalized": [] }, { "id": "PMID-12920663_T17", "type": "Organism_substance", "text": [ "aqueous fluid" ], "offsets": [ [ 856, 869 ] ], "normalized": [] }, { "id": "PMID-12920663_T18", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 871, 875 ] ], "normalized": [] }, { "id": "PMID-12920663_T19", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 977, 981 ] ], "normalized": [] }, { "id": "PMID-12920663_T20", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1106, 1114 ] ], "normalized": [] }, { "id": "PMID-12920663_T21", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1207, 1211 ] ], "normalized": [] }, { "id": "PMID-12920663_T22", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1251, 1255 ] ], "normalized": [] }, { "id": "PMID-12920663_T23", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1291, 1299 ] ], "normalized": [] }, { "id": "PMID-12920663_T24", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1387, 1395 ] ], "normalized": [] }, { "id": "PMID-12920663_T25", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1451, 1455 ] ], "normalized": [] }, { "id": "PMID-12920663_T26", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1514, 1518 ] ], "normalized": [] }, { "id": "PMID-12920663_T27", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1620, 1624 ] ], "normalized": [] }, { "id": "PMID-12920663_T28", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1710, 1714 ] ], "normalized": [] }, { "id": "PMID-12920663_T29", "type": "Gene_or_gene_product", "text": [ "PEDF" ], "offsets": [ [ 1771, 1775 ] ], "normalized": [] }, { "id": "PMID-12920663_T30", "type": "Organism_substance", "text": [ "aqueous humor" ], "offsets": [ [ 1837, 1850 ] ], "normalized": [] } ]

[ { "id": "PMID-12920663_E1", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 93, 103 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12920663_T1" } ] }, { "id": "PMID-12920663_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 361, 371 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E3", "type": "Planned_process", "trigger": { "text": [ "collected" ], "offsets": [ [ 457, 466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_T8" } ] }, { "id": "PMID-12920663_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 584, 594 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 641, 651 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 652, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12920663_T13" }, { "role": "Theme", "ref_id": "PMID-12920663_E5" } ] }, { "id": "PMID-12920663_E7", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenic" ], "offsets": [ [ 720, 730 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E8", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 793, 799 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_E9" }, { "role": "Cause", "ref_id": "PMID-12920663_T15" } ] }, { "id": "PMID-12920663_E9", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 807, 816 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_T16" } ] }, { "id": "PMID-12920663_E10", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 888, 897 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_T18" } ] }, { "id": "PMID-12920663_E11", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 998, 1007 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_T19" } ] }, { "id": "PMID-12920663_E12", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_T21" } ] }, { "id": "PMID-12920663_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenic" ], "offsets": [ [ 1353, 1363 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1433, 1443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_E13" }, { "role": "Cause", "ref_id": "PMID-12920663_T25" } ] }, { "id": "PMID-12920663_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1461, 1471 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_E13" } ] }, { "id": "PMID-12920663_E16", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1476, 1483 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_E15" } ] }, { "id": "PMID-12920663_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1566, 1576 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E18", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1595, 1602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12920663_E17" } ] }, { "id": "PMID-12920663_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1693, 1703 ] ] }, "arguments": [] }, { "id": "PMID-12920663_E20", "type": "Negative_regulation", "trigger": { "text": [ "negative regulator" ], "offsets": [ [ 1792, 1810 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12920663_T29" }, { "role": "Theme", "ref_id": "PMID-12920663_E21" } ] }, { "id": "PMID-12920663_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1814, 1824 ] ] }, "arguments": [] } ]

[ { "id": "PMID-12920663_1", "entity_ids": [ "PMID-12920663_T2", "PMID-12920663_T3" ] }, { "id": "PMID-12920663_2", "entity_ids": [ "PMID-12920663_T11", "PMID-12920663_T12" ] }, { "id": "PMID-12920663_3", "entity_ids": [ "PMID-12920663_T13", "PMID-12920663_T14" ] } ]

[]

[ { "id": "PMID-11255762__text", "type": "abstract", "text": [ "[Study of fungus polysaccharides compounds (FPC) in inducing the apoptosis of liver cancer cell Bel-7402]. \nTo observe the influence of fungus polysaccharides compounds (FPC) in inducing human liver cancer cell Bel-7402 apoptosis in cell cultivating in vitro, the authors analyzed tumor inhibitive gene P53 expression in Bel-7402 apoptosis by applying double immuno-marker. The result showed that the multilevel of FPC could all apparently induce Bel-7402 apoptosis. With the enhancement of FPC concentration, the authors observed chromatin condensation in some phases companying with the characteristic apoptosis. In the meantime, it could also greatly reduce the G1 and S, with obviously dose-response relationship. The percentage of cell apoptosis increased with the enhancing of concentration. In the high-level group the authors found typical DNA ladder eletrophoresis stripe. The result showed that the mechanism of the FPC antineoplastic effect had an intimate relation with its induction to apoptosis and that the result of FPC inducing tumor cell apoptosis had the character of P53 independence.\n" ], "offsets": [ [ 0, 1105 ] ] } ]

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[]

[ { "id": "PMID-18319331__text", "type": "abstract", "text": [ "Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma.\nWe hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid ( less than 24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions.\n" ], "offsets": [ [ 0, 1888 ] ] } ]

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"type": "Cell", "text": [ "HT-1080" ], "offsets": [ [ 368, 375 ] ], "normalized": [] }, { "id": "PMID-18319331_T9", "type": "Cell", "text": [ "NCI" ], "offsets": [ [ 377, 380 ] ], "normalized": [] }, { "id": "PMID-18319331_T10", "type": "Cell", "text": [ "Shac fibrosarcoma-derived cell lines" ], "offsets": [ [ 386, 422 ] ], "normalized": [] }, { "id": "PMID-18319331_T11", "type": "Organism", "text": [ "anthrax" ], "offsets": [ [ 427, 434 ] ], "normalized": [] }, { "id": "PMID-18319331_T12", "type": "Simple_chemical", "text": [ "lethal toxin" ], "offsets": [ [ 435, 447 ] ], "normalized": [] }, { "id": "PMID-18319331_T13", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 449, 453 ] ], "normalized": [] }, { "id": "PMID-18319331_T14", "type": "Gene_or_gene_product", "text": [ "MKKs" ], "offsets": [ [ 491, 495 ] ], "normalized": [] }, { "id": "PMID-18319331_T15", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 526, 530 ] ], "normalized": [] }, { "id": "PMID-18319331_T16", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase" ], "offsets": [ [ 578, 615 ] ], "normalized": [] }, { "id": "PMID-18319331_T17", "type": "Gene_or_gene_product", "text": [ "p38 MAPK" ], "offsets": [ [ 620, 628 ] ], "normalized": [] }, { "id": "PMID-18319331_T18", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-18319331_T19", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 698, 702 ] ], "normalized": [] }, { "id": "PMID-18319331_T20", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 755, 759 ] ], "normalized": [] }, { "id": "PMID-18319331_T21", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-18319331_T22", "type": "Immaterial_anatomical_entity", "text": [ "extracellular" ], "offsets": [ [ 807, 820 ] ], "normalized": [] }, { "id": "PMID-18319331_T23", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 869, 903 ] ], "normalized": [] }, { "id": "PMID-18319331_T24", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 905, 918 ] ], "normalized": [] }, { "id": "PMID-18319331_T25", "type": "Gene_or_gene_product", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 924, 954 ] ], "normalized": [] }, { "id": "PMID-18319331_T26", "type": "Cell", "text": [ "cell lines" ], "offsets": [ [ 991, 1001 ] ], "normalized": [] }, { "id": "PMID-18319331_T27", "type": "Cancer", "text": [ "malignant fibrous histiocytomas" ], "offsets": [ [ 1015, 1046 ] ], "normalized": [] }, { "id": "PMID-18319331_T28", "type": "Cancer", "text": [ "leiomyosarcomas" ], "offsets": [ [ 1048, 1063 ] ], "normalized": [] }, { "id": "PMID-18319331_T29", "type": "Cancer", "text": [ "liposarcomas" ], "offsets": [ [ 1069, 1081 ] ], "normalized": [] }, { "id": "PMID-18319331_T30", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 1092, 1096 ] ], "normalized": [] }, { "id": "PMID-18319331_T31", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1107, 1111 ] ], "normalized": [] }, { "id": "PMID-18319331_T32", "type": "Cancer", "text": [ "fibrosarcoma" ], "offsets": [ [ 1133, 1145 ] ], "normalized": [] }, { "id": "PMID-18319331_T33", "type": "Cell", "text": [ "cellular" ], "offsets": [ [ 1198, 1206 ] ], "normalized": [] }, { "id": "PMID-18319331_T34", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1285, 1290 ] ], "normalized": [] }, { "id": "PMID-18319331_T35", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1296, 1302 ] ], "normalized": [] }, { "id": "PMID-18319331_T36", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1337, 1342 ] ], "normalized": [] }, { "id": "PMID-18319331_T37", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 1499, 1503 ] ], "normalized": [] }, { "id": "PMID-18319331_T38", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1507, 1512 ] ], "normalized": [] }, { "id": "PMID-18319331_T39", "type": "Cancer", "text": [ "tumor" ], "offsets": [ [ 1622, 1627 ] ], "normalized": [] }, { "id": "PMID-18319331_T40", "type": "Tissue", "text": [ "nontumor tissues" ], "offsets": [ [ 1639, 1655 ] ], "normalized": [] }, { "id": "PMID-18319331_T41", "type": "Gene_or_gene_product", "text": [ "MKK" ], "offsets": [ [ 1742, 1745 ] ], "normalized": [] }, { "id": "PMID-18319331_T42", "type": "Simple_chemical", "text": [ "LeTx" ], "offsets": [ [ 1760, 1764 ] ], "normalized": [] }, { "id": "PMID-18319331_T43", "type": "Cancer", "text": [ "fibrosarcomas" ], "offsets": [ [ 1833, 1846 ] ], "normalized": [] }, { "id": "PMID-18319331_T44", "type": "Cancer", "text": [ "proliferative lesions" ], "offsets": [ [ 1865, 1886 ] ], "normalized": [] } ]

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"arguments": [ { "role": "AtLoc", "ref_id": "PMID-18319331_T2" } ] }, { "id": "PMID-18319331_E6", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 204, 212 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18319331_T3" } ] }, { "id": "PMID-18319331_E7", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 216, 225 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18319331_E6" }, { "role": "Theme", "ref_id": "PMID-18319331_E9" } ] }, { "id": "PMID-18319331_E8", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 216, 225 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18319331_E6" }, { "role": "Theme", "ref_id": "PMID-18319331_E10" } ] }, { "id": "PMID-18319331_E9", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 234, 240 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18319331_T5" } ] }, { "id": "PMID-18319331_E10", "type": 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"ref_id": "PMID-18319331_E44" } ] }, { "id": "PMID-18319331_E43", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 1801, 1810 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18319331_E41" }, { "role": "Theme", "ref_id": "PMID-18319331_E45" } ] }, { "id": "PMID-18319331_E44", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 1811, 1829 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18319331_T43" } ] }, { "id": "PMID-18319331_E45", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 1811, 1829 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18319331_T44" } ] } ]

[ { "id": "PMID-18319331_1", "entity_ids": [ "PMID-18319331_T3", "PMID-18319331_T4" ] }, { "id": "PMID-18319331_2", "entity_ids": [ "PMID-18319331_T12", "PMID-18319331_T13" ] } ]

[]

[ { "id": "PMID-19080335__text", "type": "abstract", "text": [ "Effect of transplanted mesenchymal stem cells from rats of different ages on the improvement of heart function after acute myocardial infarction.\nBACKGROUND: Mesenchymal stem cells (MSCs) transplantation is of therapeutic potential after ischemic injury in both experimental and clinical studies. Clinically, elderly patients are more vulnerable to acute myocardial infarction (AMI). But little is known about the characteristics of young donor-derived MSCs transplanted to old patients with AMI. The present study was designed to investigate the effect of transplanted MSCs from rats of different ages on the improvement of heart function after AMI. METHODS: MSCs from Sprague-Dawley (SD) rats were isolated and cultured in vitro. The apoptosis characteristics of MSCs were observed under conditions of ischemia and anoxia. SD rats underwent MI received intramyocardial injection of MSCs from young donor rats (n = 8), old donor rats (n = 8), respectively. AMI control group received equal volume physiological saline. Immunofluorescence was used to observe the differentiation of the grafted cells into cardiomyocytes. Four weeks after cell transplantation, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry for vascular endothelial growth factor (VEGF), VIII-factor immunohistochemistry for vessel density, TUNEL, caspase-3 for cardiomyocyte apoptosis, echocardiography and hemodynamic detection for heart function were performed. RESULTS: The apoptosis rate of the old donor-derived MSCs group was significantly higher than that of the young donor-derived MSCs group under conditions of ischemia and anoxia (P less than 0.05). Engrafted MSCs survived, proliferated and differentiated into myocardium-like cells. VEGF gene expression and capillary density in the old donor-derived group were lower than those in the young donor-derived group but higher than those in the control group (P less than 0.05). The transplantation of old donor-derived MSCs attenuated apoptosis of cardiomyocytes in the peri-infarct region compared with the control group and the effect was elevated in young donor-derived MSCs (P less than 0.05). The heart functions (left ventricle ejection fraction (LVEF), left ventricle fractional shortening (LVFS)) were improved more significantly in the old donor-derived MSCs group than in the control group and the heart function in the young donor-derived MSCs group further improved (P less than 0.05). CONCLUSIONS: Young donor-derived MSCs can improve heart function significantly through angiogenesis and decreasing cardiomyocyte apoptosis when transplanted to the infarcted area.\n" ], "offsets": [ [ 0, 2648 ] ] } ]

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], "offsets": [ [ 2510, 2517 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19080335_T47" }, { "role": "Theme", "ref_id": "PMID-19080335_E30" } ] }, { "id": "PMID-19080335_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 2555, 2567 ] ] }, "arguments": [] }, { "id": "PMID-19080335_E31", "type": "Negative_regulation", "trigger": { "text": [ "decreasing" ], "offsets": [ [ 2572, 2582 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_E32" }, { "role": "Cause", "ref_id": "PMID-19080335_T47" } ] }, { "id": "PMID-19080335_E32", "type": "Cell_death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 2597, 2606 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T49" } ] }, { "id": "PMID-19080335_E33", "type": "Planned_process", "trigger": { "text": [ "transplanted" ], "offsets": [ [ 2612, 2624 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19080335_T47" } ] } ]

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[]

[ { "id": "PMID-15574223__text", "type": "abstract", "text": [ "Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. \nOBJECTIVE: Dependence on glycolysis is a hallmark of malignant tumors. As a consequence, these tumors generate more lactate, which is effluxed from cells by monocarboxylate transporters (MCTs). We hypothesized that 1) MCT expression in malignant tumors may differ from normal tissue in quantity, isoform, or both; and 2) silencing MCT expression would induce intracellular acidification, resulting in decreased proliferation and/or increased cell death. METHODS: We quantified expression of MCT isoforms in human glioblastoma multiforme and glioma-derived cells lines by Western blot analysis. MCTs that were abundant or specific to glioma then were targeted in the model U-87 MG glioma cell line via small interfering ribonucleic acid-mediated gene silencing and tested for inhibition of lactate efflux, intracellular pH changes, reduced proliferation, and/or induction of cell death. RESULTS: MCT 1 and 2 were the primary isoforms expressed in human glioblastoma multiforme and glioma-derived cell lines. In contrast, MCT 3 was the predominantly expressed isoform in normal brain. Small interfering ribonucleic acid specific for MCT 1 and 2 reduced expression of these isoforms in U-87 MG cells to barely detectable levels and reduced lactate efflux by 30% individually and 85% in combination, with a concomitant decrease of intracellular pH by 0.6 units (a fourfold increase in intracellular H(+)). Prolonged silencing of both MCTs reduced viability by 75% individually and 92% in combination, as measured by both phenotypic and flow cytometric analyses. CONCLUSION: MCT targeting significantly reduced the viability of U-87 MG cells mediated by both apoptosis and necrosis. This indicates that the strategy may be a useful therapeutic avenue for treatment of patients with malignant glioma.\n" ], "offsets": [ [ 0, 1960 ] ] } ]

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322, 350 ] ], "normalized": [] }, { "id": "PMID-15574223_T9", "type": "Gene_or_gene_product", "text": [ "MCTs" ], "offsets": [ [ 352, 356 ] ], "normalized": [] }, { "id": "PMID-15574223_T10", "type": "Gene_or_gene_product", "text": [ "MCT" ], "offsets": [ [ 383, 386 ] ], "normalized": [] }, { "id": "PMID-15574223_T11", "type": "Cancer", "text": [ "malignant tumors" ], "offsets": [ [ 401, 417 ] ], "normalized": [] }, { "id": "PMID-15574223_T12", "type": "Tissue", "text": [ "normal tissue" ], "offsets": [ [ 434, 447 ] ], "normalized": [] }, { "id": "PMID-15574223_T13", "type": "Gene_or_gene_product", "text": [ "MCT" ], "offsets": [ [ 496, 499 ] ], "normalized": [] }, { "id": "PMID-15574223_T14", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 524, 537 ] ], "normalized": [] }, { "id": "PMID-15574223_T15", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 607, 611 ] ], "normalized": [] }, { "id": "PMID-15574223_T16", "type": "Gene_or_gene_product", "text": [ "MCT" ], "offsets": [ [ 656, 659 ] ], "normalized": [] }, { "id": "PMID-15574223_T17", "type": "Organism", "text": [ "human" ], "offsets": [ [ 672, 677 ] ], "normalized": [] }, { "id": "PMID-15574223_T18", "type": "Cell", "text": [ "glioblastoma multiforme" ], "offsets": [ [ 678, 701 ] ], "normalized": [] }, { "id": "PMID-15574223_T19", "type": "Cell", "text": [ "glioma-derived cells lines" ], "offsets": [ [ 706, 732 ] ], "normalized": [] }, { "id": "PMID-15574223_T20", "type": "Gene_or_gene_product", "text": [ "MCTs" ], "offsets": [ [ 759, 763 ] ], "normalized": [] }, { "id": "PMID-15574223_T21", "type": "Cancer", "text": [ "glioma" ], "offsets": [ [ 798, 804 ] ], "normalized": [] }, { "id": "PMID-15574223_T22", "type": "Cell", "text": [ "U-87 MG glioma cell line" ], "offsets": [ [ 837, 861 ] ], "normalized": [] }, { "id": "PMID-15574223_T23", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 954, 961 ] ], "normalized": [] }, { "id": "PMID-15574223_T24", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 970, 983 ] ], "normalized": [] }, { "id": "PMID-15574223_T25", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "PMID-15574223_T26", "type": "Gene_or_gene_product", "text": [ "MCT 1" ], "offsets": [ [ 1060, 1065 ] ], "normalized": [] }, { "id": "PMID-15574223_T27", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1070, 1071 ] ], "normalized": [] }, { "id": "PMID-15574223_T28", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1111, 1116 ] ], "normalized": [] }, { "id": "PMID-15574223_T29", "type": "Cell", "text": [ "glioblastoma multiforme" ], "offsets": [ [ 1117, 1140 ] ], "normalized": [] }, { "id": "PMID-15574223_T30", "type": "Cell", "text": [ "glioma-derived cell lines" ], "offsets": [ [ 1145, 1170 ] ], "normalized": [] }, { "id": "PMID-15574223_T31", "type": "Gene_or_gene_product", "text": [ "MCT 3" ], "offsets": [ [ 1185, 1190 ] ], "normalized": [] }, { "id": "PMID-15574223_T32", "type": "Organ", "text": [ "brain" ], "offsets": [ [ 1241, 1246 ] ], "normalized": [] }, { "id": "PMID-15574223_T33", "type": "Gene_or_gene_product", "text": [ "MCT 1" ], "offsets": [ [ 1296, 1301 ] ], "normalized": [] }, { "id": "PMID-15574223_T34", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1306, 1307 ] ], "normalized": [] }, { "id": "PMID-15574223_T35", "type": "Cell", "text": [ "U-87 MG cells" ], "offsets": [ [ 1348, 1361 ] ], "normalized": [] }, { "id": "PMID-15574223_T36", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 1402, 1409 ] ], "normalized": [] }, { "id": "PMID-15574223_T37", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1492, 1505 ] ], "normalized": [] }, { "id": "PMID-15574223_T38", "type": "Immaterial_anatomical_entity", "text": [ "intracellular" ], "offsets": [ [ 1546, 1559 ] ], "normalized": [] }, { "id": "PMID-15574223_T39", "type": "Gene_or_gene_product", "text": [ "MCTs" ], "offsets": [ [ 1595, 1599 ] ], "normalized": [] }, { "id": "PMID-15574223_T40", "type": "Gene_or_gene_product", "text": [ "MCT" ], "offsets": [ [ 1735, 1738 ] ], "normalized": [] }, { "id": "PMID-15574223_T41", "type": "Cell", "text": [ "U-87 MG cells" ], "offsets": [ [ 1788, 1801 ] ], "normalized": [] }, { "id": "PMID-15574223_T42", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1928, 1936 ] ], "normalized": [] }, { "id": "PMID-15574223_T43", "type": "Cancer", "text": [ "malignant glioma" ], "offsets": [ [ 1942, 1958 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-19389366__text", "type": "abstract", "text": [ "Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. \nThe polycomb gene Bmi-1 is required for the self-renewal of stem cells from diverse tissues, including the central nervous system (CNS). Bmi-1 expression is elevated in most human gliomas, irrespective of grade, raising the question of whether Bmi-1 over-expression is sufficient to promote self-renewal or tumorigenesis by CNS stem/progenitor cells. To test this we generated Nestin-Bmi-1-GFP transgenic mice. Analysis of two independent lines with expression in the fetal and adult CNS demonstrated that transgenic neural stem cells formed larger colonies, more self-renewing divisions, and more neurons in culture. However, in vivo, Bmi-1 over-expression had little effect on CNS stem cell frequency, subventricular zone proliferation, olfactory bulb neurogenesis, or neurogenesis/gliogenesis during development. Bmi-1 transgenic mice were born with enlarged lateral ventricles and a minority developed idiopathic hydrocephalus as adults, but none of the transgenic mice formed detectable CNS tumors, even when aged. The more pronounced effects of Bmi-1 over-expression in culture were largely attributable to the attenuated induction of p16(Ink4a) and p19(Arf) in culture, proteins that are generally not expressed by neural stem/progenitor cells in young mice in vivo. Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo.\n" ], "offsets": [ [ 0, 1572 ] ] } ]

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