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[ { "id": "PMID-9648911__text", "type": "abstract", "text": [ "Induction of Ets-1 in endothelial cells during reendothelialization after denuding injury.\n\nEts-1, a transcription factor, is induced in endothelial cells (ECs) during angiogenesis. Here, we investigated the expression of Ets-1 during reendothelialization. When a confluent monolayer of human umbilical vein endothelial cell line, ECV304, was denuded, ECV304 at the wound edge expressed Ets-1. An immunohistochemical analysis revealed that Ets-1 accumulated in migrating cells at the wound edge and returned to basal level when reendothelialization was accomplished. This induction of Ets-1 could be reproduced in in vivo denudation of rat aortic endothelium by a balloon catheter. The induction of Ets-1 in ECs after denudation was regulated transcriptionally, and humeral factors released from injured ECs might not be responsible. Mitogen-activated protein kinase (MAPK) activities were investigated to explore the mechanism of this induction. Although extracellular signal-regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1 (JNK1), and p38 were activated after denudation, the activation of ERK1 and p38 was more rapid and prominent. PD98059, a specific MAPK/ERK kinase (MEK) 1 inhibitor, did not affect the induction of ets-1 mRNA, whereas SB203580, a specific p38 inhibitor, almost completely abrogated its induction. These results indicate that Ets-1 is induced in ECs after denudation through activation of p38. This induction of Ets-1 may be relevant for reendothelialization by regulating the expression of certain genes.\n" ], "offsets": [ [ 0, 1546 ] ] } ]

[ { "id": "PMID-9648911_T2", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 13, 18 ] ], "normalized": [] }, { "id": "PMID-9648911_T3", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 22, 39 ] ], "normalized": [] }, { "id": "PMID-9648911_T7", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 92, 97 ] ], "normalized": [] }, { "id": "PMID-9648911_T8", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 137, 154 ] ], "normalized": [] }, { "id": "PMID-9648911_T9", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "PMID-9648911_T13", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 222, 227 ] ], "normalized": [] }, { "id": "PMID-9648911_T18", "type": "Cell", "text": [ "human umbilical vein endothelial cell line" ], "offsets": [ [ 287, 329 ] ], "normalized": [] }, { "id": "PMID-9648911_T19", "type": "Cell", "text": [ "ECV304" ], "offsets": [ [ 331, 337 ] ], "normalized": [] }, { "id": "PMID-9648911_T20", "type": "Cell", "text": [ "ECV304" ], "offsets": [ [ 352, 358 ] ], "normalized": [] }, { "id": "PMID-9648911_T22", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 387, 392 ] ], "normalized": [] }, { "id": "PMID-9648911_T24", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 440, 445 ] ], "normalized": [] }, { "id": "PMID-9648911_T25", "type": "Cell", "text": [ "migrating cells" ], "offsets": [ [ 461, 476 ] ], "normalized": [] }, { "id": "PMID-9648911_T28", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 585, 590 ] ], "normalized": [] }, { "id": "PMID-9648911_T30", "type": "Tissue", "text": [ "aortic endothelium" ], "offsets": [ [ 640, 658 ] ], "normalized": [] }, { "id": "PMID-9648911_T33", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 699, 704 ] ], "normalized": [] }, { "id": "PMID-9648911_T34", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 708, 711 ] ], "normalized": [] }, { "id": "PMID-9648911_T35", "type": "Gene_or_gene_product", "text": [ "humeral factors" ], "offsets": [ [ 766, 781 ] ], "normalized": [] }, { "id": "PMID-9648911_T36", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 804, 807 ] ], "normalized": [] }, { "id": "PMID-9648911_T37", "type": "Gene_or_gene_product", "text": [ "Mitogen-activated protein kinase" ], "offsets": [ [ 834, 866 ] ], "normalized": [] }, { "id": "PMID-9648911_T38", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 868, 872 ] ], "normalized": [] }, { "id": "PMID-9648911_T40", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated protein kinase 1" ], "offsets": [ [ 956, 1003 ] ], "normalized": [] }, { "id": "PMID-9648911_T41", "type": "Gene_or_gene_product", "text": [ "ERK1" ], "offsets": [ [ 1007, 1011 ] ], "normalized": [] }, { "id": "PMID-9648911_T43", "type": "Gene_or_gene_product", "text": [ "c-Jun N-terminal kinase 1" ], "offsets": [ [ 1016, 1041 ] ], "normalized": [] }, { "id": "PMID-9648911_T44", "type": "Gene_or_gene_product", "text": [ "JNK1" ], "offsets": [ [ 1043, 1047 ] ], "normalized": [] }, { "id": "PMID-9648911_T46", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1054, 1057 ] ], "normalized": [] }, { "id": "PMID-9648911_T49", "type": "Gene_or_gene_product", "text": [ "ERK1" ], "offsets": [ [ 1109, 1113 ] ], "normalized": [] }, { "id": "PMID-9648911_T50", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1118, 1121 ] ], "normalized": [] }, { "id": "PMID-9648911_T51", "type": "Drug_or_compound", "text": [ "PD98059" ], "offsets": [ [ 1152, 1159 ] ], "normalized": [] }, { "id": "PMID-9648911_T52", "type": "Gene_or_gene_product", "text": [ "MAPK/ERK kinase (MEK) 1" ], "offsets": [ [ 1172, 1195 ] ], "normalized": [] }, { "id": "PMID-9648911_T54", "type": "Gene_or_gene_product", "text": [ "ets-1" ], "offsets": [ [ 1239, 1244 ] ], "normalized": [] }, { "id": "PMID-9648911_T55", "type": "Drug_or_compound", "text": [ "SB203580" ], "offsets": [ [ 1259, 1267 ] ], "normalized": [] }, { "id": "PMID-9648911_T56", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "PMID-9648911_T58", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 1366, 1371 ] ], "normalized": [] }, { "id": "PMID-9648911_T59", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1386, 1389 ] ], "normalized": [] }, { "id": "PMID-9648911_T61", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1429, 1432 ] ], "normalized": [] }, { "id": "PMID-9648911_T63", "type": "Gene_or_gene_product", "text": [ "Ets-1" ], "offsets": [ [ 1452, 1457 ] ], "normalized": [] }, { "id": "PMID-9648911_T1001", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 636, 639 ] ], "normalized": [] }, { "id": "PMID-9648911_T4", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1004, 1005 ] ], "normalized": [] }, { "id": "PMID-9648911_T10", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1012, 1013 ] ], "normalized": [] } ]

[ { "id": "PMID-9648911_E1", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T2" } ] }, { "id": "PMID-9648911_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 126, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T7" } ] }, { "id": "PMID-9648911_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 208, 218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T13" } ] }, { "id": "PMID-9648911_E17", "type": "Planned_process", "trigger": { "text": [ "denuded" ], "offsets": [ [ 343, 350 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T19" } ] }, { "id": "PMID-9648911_E21", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 377, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T22" } ] }, { "id": "PMID-9648911_E23", "type": "Positive_regulation", "trigger": { "text": [ "accumulated" ], "offsets": [ [ 446, 457 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T24" } ] }, { "id": "PMID-9648911_E27", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 572, 581 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T28" } ] }, { "id": "PMID-9648911_E29", "type": "Planned_process", "trigger": { "text": [ "denudation" ], "offsets": [ [ 622, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T30" } ] }, { "id": "PMID-9648911_E32", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 686, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T33" } ] }, { "id": "PMID-9648911_E45", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1063, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T46" } ] }, { "id": "PMID-9648911_E48", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1095, 1105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T49" } ] }, { "id": "PMID-9648911_E57", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1375, 1382 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T58" }, { "role": "Cause", "ref_id": "PMID-9648911_E60" } ] }, { "id": "PMID-9648911_E60", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1415, 1425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T61" } ] }, { "id": "PMID-9648911_E62", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1439, 1448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T63" } ] }, { "id": "PMID-9648911_E2", "type": "Planned_process", "trigger": { "text": [ "denuded" ], "offsets": [ [ 343, 350 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T18" } ] }, { "id": "PMID-9648911_E3", "type": "Positive_regulation", "trigger": { "text": [ "reproduced" ], "offsets": [ [ 600, 610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_E27" }, { "role": "Cause", "ref_id": "PMID-9648911_E29" } ] }, { "id": "PMID-9648911_E4", "type": "Planned_process", "trigger": { "text": [ "denudation" ], "offsets": [ [ 718, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T34" } ] }, { "id": "PMID-9648911_E5", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 733, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_E32" } ] }, { "id": "PMID-9648911_E7", "type": "Localization", "trigger": { "text": [ "released" ], "offsets": [ [ 782, 790 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-9648911_T36" }, { "role": "Theme", "ref_id": "PMID-9648911_T35" } ] }, { "id": "PMID-9648911_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 936, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T33" } ] }, { "id": "PMID-9648911_E9", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1063, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T43" } ] }, { "id": "PMID-9648911_E10", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1063, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T40" } ] }, { "id": "PMID-9648911_E11", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1063, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T4" } ] }, { "id": "PMID-9648911_E13", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1095, 1105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T50" } ] }, { "id": "PMID-9648911_E14", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1215, 1221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_E15" }, { "role": "Cause", "ref_id": "PMID-9648911_T51" } ] }, { "id": "PMID-9648911_E15", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1226, 1235 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T54" } ] }, { "id": "PMID-9648911_E16", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1327, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T56" } ] }, { "id": "PMID-9648911_E18", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 1313, 1322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_E16" }, { "role": "Cause", "ref_id": "PMID-9648911_T55" } ] }, { "id": "PMID-9648911_E19", "type": "Planned_process", "trigger": { "text": [ "denudation" ], "offsets": [ [ 1396, 1406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9648911_T59" } ] }, { "id": "PMID-9648911_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "reendothelialization" ], "offsets": [ [ 47, 67 ] ] }, "arguments": [] }, { "id": "PMID-9648911_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 168, 180 ] ] }, "arguments": [] }, { "id": "PMID-9648911_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "reendothelialization" ], "offsets": [ [ 235, 255 ] ] }, "arguments": [] }, { "id": "PMID-9648911_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "reendothelialization" ], "offsets": [ [ 528, 548 ] ] }, "arguments": [] }, { "id": "PMID-9648911_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "reendothelialization" ], "offsets": [ [ 1478, 1498 ] ] }, "arguments": [] } ]

[ { "id": "PMID-9648911_1", "entity_ids": [ "PMID-9648911_T43", "PMID-9648911_T44" ] }, { "id": "PMID-9648911_2", "entity_ids": [ "PMID-9648911_T37", "PMID-9648911_T38" ] }, { "id": "PMID-9648911_3", "entity_ids": [ "PMID-9648911_T40", "PMID-9648911_T41" ] }, { "id": "PMID-9648911_4", "entity_ids": [ "PMID-9648911_T8", "PMID-9648911_T9" ] }, { "id": "PMID-9648911_5", "entity_ids": [ "PMID-9648911_T10", "PMID-9648911_T4" ] } ]

[ { "id": "PMID-9648911_R1", "type": "frag", "arg1_id": "PMID-9648911_T4", "arg2_id": "PMID-9648911_T40", "normalized": [] }, { "id": "PMID-9648911_R2", "type": "frag", "arg1_id": "PMID-9648911_T10", "arg2_id": "PMID-9648911_T41", "normalized": [] } ]

[ { "id": "PMID-9891506__text", "type": "abstract", "text": [ "Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.\n\nBACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth.\n" ], "offsets": [ [ 0, 1469 ] ] } ]

[ { "id": "PMID-9891506_T2", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 10, 15 ] ], "normalized": [] }, { "id": "PMID-9891506_T3", "type": "Tissue", "text": [ "cartilage" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "PMID-9891506_T8", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 104, 109 ] ], "normalized": [] }, { "id": "PMID-9891506_T11", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 168, 173 ] ], "normalized": [] }, { "id": "PMID-9891506_T12", "type": "Tissue", "text": [ "cartilage" ], "offsets": [ [ 202, 211 ] ], "normalized": [] }, { "id": "PMID-9891506_T13", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 249, 254 ] ], "normalized": [] }, { "id": "PMID-9891506_T14", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "PMID-9891506_T19", "type": "Cell", "text": [ "human umbilical vein endothelial cell" ], "offsets": [ [ 393, 430 ] ], "normalized": [] }, { "id": "PMID-9891506_T21", "type": "Cell", "text": [ "HUVEC" ], "offsets": [ [ 432, 437 ] ], "normalized": [] }, { "id": "PMID-9891506_T23", "type": "Gene_or_gene_product", "text": [ "TNF alpha" ], "offsets": [ [ 504, 513 ] ], "normalized": [] }, { "id": "PMID-9891506_T24", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membrane" ], "offsets": [ [ 525, 549 ] ], "normalized": [] }, { "id": "PMID-9891506_T25", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-9891506_T26", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 599, 604 ] ], "normalized": [] }, { "id": "PMID-9891506_T30", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 619, 629 ] ], "normalized": [] }, { "id": "PMID-9891506_T32", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 662, 667 ] ], "normalized": [] }, { "id": "PMID-9891506_T36", "type": "Cell", "text": [ "HUVEC" ], "offsets": [ [ 713, 718 ] ], "normalized": [] }, { "id": "PMID-9891506_T38", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 851, 856 ] ], "normalized": [] }, { "id": "PMID-9891506_T40", "type": "Gene_or_gene_product", "text": [ "TNF alpha" ], "offsets": [ [ 872, 881 ] ], "normalized": [] }, { "id": "PMID-9891506_T46", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 938, 951 ] ], "normalized": [] }, { "id": "PMID-9891506_T47", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 963, 968 ] ], "normalized": [] }, { "id": "PMID-9891506_T50", "type": "Gene_or_gene_product", "text": [ "collagenase" ], "offsets": [ [ 1007, 1018 ] ], "normalized": [] }, { "id": "PMID-9891506_T53", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 1076, 1081 ] ], "normalized": [] }, { "id": "PMID-9891506_T56", "type": "Cell", "text": [ "sarcoma-180 cell" ], "offsets": [ [ 1124, 1140 ] ], "normalized": [] }, { "id": "PMID-9891506_T58", "type": "Cell", "text": [ "B16-F10 mouse melanoma cell" ], "offsets": [ [ 1152, 1179 ] ], "normalized": [] }, { "id": "PMID-9891506_T61", "type": "Gene_or_gene_product", "text": [ "U-995" ], "offsets": [ [ 1271, 1276 ] ], "normalized": [] }, { "id": "PMID-9891506_T68", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1347, 1353 ] ], "normalized": [] }, { "id": "PMID-9891506_T77", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 1450, 1460 ] ], "normalized": [] }, { "id": "PMID-9891506_T1000", "type": "Organism", "text": [ "blue shark" ], "offsets": [ [ 219, 229 ] ], "normalized": [] }, { "id": "PMID-9891506_T1001", "type": "Organism", "text": [ "Prionace glauca" ], "offsets": [ [ 231, 246 ] ], "normalized": [] }, { "id": "PMID-9891506_T1003", "type": "Organism", "text": [ "chicken" ], "offsets": [ [ 517, 524 ] ], "normalized": [] }, { "id": "PMID-9891506_T1004", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1105, 1109 ] ], "normalized": [] }, { "id": "PMID-9891506_T31", "type": "Drug_or_compound", "text": [ "thymidine" ], "offsets": [ [ 799, 808 ] ], "normalized": [] }, { "id": "PMID-9891506_T63", "type": "Organism", "text": [ "shark" ], "offsets": [ [ 26, 31 ] ], "normalized": [] } ]

[ { "id": "PMID-9891506_E7", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 110, 120 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T2" }, { "role": "Theme", "ref_id": "PMID-9891506_T8" } ] }, { "id": "PMID-9891506_E16", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 453, 466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T19" } ] }, { "id": "PMID-9891506_E18", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 439, 448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T19" } ] }, { "id": "PMID-9891506_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 608, 618 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T26" }, { "role": "Theme", "ref_id": "PMID-9891506_E29" } ] }, { "id": "PMID-9891506_E28", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 641, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T30" } ] }, { "id": "PMID-9891506_E29", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 630, 636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T30" } ] }, { "id": "PMID-9891506_E35", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 719, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T36" } ] }, { "id": "PMID-9891506_E37", "type": "Planned_process", "trigger": { "text": [ "added" ], "offsets": [ [ 863, 868 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-9891506_T38" }, { "role": "Theme", "ref_id": "PMID-9891506_E24" } ] }, { "id": "PMID-9891506_E44", "type": "Breakdown", "trigger": { "text": [ "disrupted" ], "offsets": [ [ 928, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T46" } ] }, { "id": "PMID-9891506_E48", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 997, 1006 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T47" }, { "role": "Theme", "ref_id": "PMID-9891506_E25" } ] }, { "id": "PMID-9891506_E52", "type": "Planned_process", "trigger": { "text": [ "injected" ], "offsets": [ [ 1086, 1094 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-9891506_T53" }, { "role": "Theme", "ref_id": "PMID-9891506_T1004" } ] }, { "id": "PMID-9891506_E54", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1113, 1123 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T53" }, { "role": "Theme", "ref_id": "PMID-9891506_E55" } ] }, { "id": "PMID-9891506_E55", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 1141, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T56" } ] }, { "id": "PMID-9891506_E57", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1180, 1190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T58" } ] }, { "id": "PMID-9891506_E62", "type": "Negative_regulation", "trigger": { "text": [ "interference" ], "offsets": [ [ 1294, 1306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E64" } ] }, { "id": "PMID-9891506_E64", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1316, 1329 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T68" } ] }, { "id": "PMID-9891506_E66", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1334, 1343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T68" } ] }, { "id": "PMID-9891506_E73", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1414, 1424 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_E10" }, { "role": "Theme", "ref_id": "PMID-9891506_E31" } ] }, { "id": "PMID-9891506_E76", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 1461, 1467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T77" } ] }, { "id": "PMID-9891506_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 882, 889 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T40" }, { "role": "Theme", "ref_id": "PMID-9891506_E24" } ] }, { "id": "PMID-9891506_E2", "type": "Planned_process", "trigger": { "text": [ "purified" ], "offsets": [ [ 184, 192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_T11" } ] }, { "id": "PMID-9891506_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 493, 500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E23" }, { "role": "Cause", "ref_id": "PMID-9891506_T23" } ] }, { "id": "PMID-9891506_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 608, 618 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T26" }, { "role": "Theme", "ref_id": "PMID-9891506_E28" } ] }, { "id": "PMID-9891506_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 703, 712 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E35" }, { "role": "Cause", "ref_id": "PMID-9891506_T32" } ] }, { "id": "PMID-9891506_E6", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 903, 909 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_E37" }, { "role": "Theme", "ref_id": "PMID-9891506_E44" } ] }, { "id": "PMID-9891506_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1019, 1026 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T50" }, { "role": "Theme", "ref_id": "PMID-9891506_E25" } ] }, { "id": "PMID-9891506_E9", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1113, 1123 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T53" }, { "role": "Theme", "ref_id": "PMID-9891506_E57" } ] }, { "id": "PMID-9891506_E10", "type": "Negative_regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1260, 1267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E26" }, { "role": "Cause", "ref_id": "PMID-9891506_T61" } ] }, { "id": "PMID-9891506_E11", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1287, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E10" }, { "role": "Cause", "ref_id": "PMID-9891506_E62" } ] }, { "id": "PMID-9891506_E12", "type": "Negative_regulation", "trigger": { "text": [ "interference" ], "offsets": [ [ 1294, 1306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E66" } ] }, { "id": "PMID-9891506_E13", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1287, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E10" }, { "role": "Cause", "ref_id": "PMID-9891506_E12" } ] }, { "id": "PMID-9891506_E14", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1287, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E10" }, { "role": "Cause", "ref_id": "PMID-9891506_E33" } ] }, { "id": "PMID-9891506_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1414, 1424 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_E10" }, { "role": "Theme", "ref_id": "PMID-9891506_E76" } ] }, { "id": "PMID-9891506_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 50, 62 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 82, 94 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 144, 156 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 480, 492 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 890, 902 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "collagenolysis" ], "offsets": [ [ 1027, 1041 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1249, 1259 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1433, 1445 ] ] }, "arguments": [] }, { "id": "PMID-9891506_E32", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 110, 120 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9891506_T2" }, { "role": "Theme", "ref_id": "PMID-9891506_E21" } ] }, { "id": "PMID-9891506_E33", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1365, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9891506_E15" } ] }, { "id": "PMID-9891506_E15", "type": "Pathway", "trigger": { "text": [ "collagenolysis" ], "offsets": [ [ 1379, 1393 ] ] }, "arguments": [] } ]

[ { "id": "PMID-9891506_1", "entity_ids": [ "PMID-9891506_T19", "PMID-9891506_T21" ] }, { "id": "PMID-9891506_2", "entity_ids": [ "PMID-9891506_T24", "PMID-9891506_T25" ] } ]

[]

[ { "id": "PMID-10586954__text", "type": "abstract", "text": [ "Insulin-induced vascular endothelial growth factor expression in retina.\n\nPURPOSE: Clinical studies have demonstrated that intensive insulin therapy causes a transient worsening of retinopathy. The mechanisms underlying the initial insulin-induced deterioration of retinal status in patients with diabetes remain unknown. Vascular endothelial growth factor (VEGF) is known to be operative in the pathogenesis of diabetic retinopathy. The current study was conducted to characterize the effect of insulin on retinal VEGF gene expression in vitro and in vivo. METHODS: The effect of insulin on VEGF expression in vivo was examined by in situ hybridization studies of rat retinal VEGF transcripts. To examine the mechanisms by which insulin regulates VEGF expression, human retinal pigment epithelial (RPE) cells were exposed to insulin, and VEGF mRNA levels were quantified with RNase protection assays (RPAs). Conditioned media from insulin-treated RPE cells were assayed for VEGF protein and capillary endothelial cell proliferation. The capacity of insulin to stimulate the VEGF promoter linked to a luciferase reporter gene was characterized in transient transfection assays. RESULTS: Insulin increased VEGF mRNA levels in the ganglion, inner nuclear, and RPE cell layers. In vitro, insulin increased VEGF mRNA levels in human RPE cells and enhanced VEGF promoter activity without affecting transcript stability. Insulin treatment also increased VEGF protein levels in conditioned RPE cell media in a dose-dependent manner with a median effective concentration of 5 nM. The insulin-conditioned RPE cell media stimulated capillary endothelial cell proliferation, an effect that was completely blocked by anti-VEGF neutralizing antibody. CONCLUSIONS: Insulin increases VEGF mRNA and secreted protein levels in RPE cells through enhanced transcription of the VEGF gene. Intensive insulin therapy may cause a transient worsening of retinopathy in patients with diabetes through increased retinal VEGF gene expression.\n" ], "offsets": [ [ 0, 2016 ] ] } ]

[ { "id": "PMID-10586954_T2", "type": "Gene_or_gene_product", "text": [ "Insulin" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-10586954_T3", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 16, 50 ] ], "normalized": [] }, { "id": "PMID-10586954_T4", "type": "Multi-tissue_structure", "text": [ "retina" ], "offsets": [ [ 65, 71 ] ], "normalized": [] }, { "id": "PMID-10586954_T5", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 133, 140 ] ], "normalized": [] }, { "id": "PMID-10586954_T6", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 232, 239 ] ], "normalized": [] }, { "id": "PMID-10586954_T7", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 322, 356 ] ], "normalized": [] }, { "id": "PMID-10586954_T8", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 358, 362 ] ], "normalized": [] }, { "id": "PMID-10586954_T9", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 496, 503 ] ], "normalized": [] }, { "id": "PMID-10586954_T12", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-10586954_T13", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 581, 588 ] ], "normalized": [] }, { "id": "PMID-10586954_T15", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 592, 596 ] ], "normalized": [] }, { "id": "PMID-10586954_T16", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 677, 681 ] ], "normalized": [] }, { "id": "PMID-10586954_T17", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 730, 737 ] ], "normalized": [] }, { "id": "PMID-10586954_T19", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 748, 752 ] ], "normalized": [] }, { "id": "PMID-10586954_T20", "type": "Cell", "text": [ "retinal pigment epithelial (RPE) cells" ], "offsets": 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"Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1050, 1057 ] ], "normalized": [] }, { "id": "PMID-10586954_T34", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1075, 1079 ] ], "normalized": [] }, { "id": "PMID-10586954_T35", "type": "Gene_or_gene_product", "text": [ "Insulin" ], "offsets": [ [ 1187, 1194 ] ], "normalized": [] }, { "id": "PMID-10586954_T36", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1205, 1209 ] ], "normalized": [] }, { "id": "PMID-10586954_T37", "type": "Tissue", "text": [ "ganglion" ], "offsets": [ [ 1229, 1237 ] ], "normalized": [] }, { "id": "PMID-10586954_T38", "type": "Tissue", "text": [ "inner nuclear" ], "offsets": [ [ 1239, 1252 ] ], "normalized": [] }, { "id": "PMID-10586954_T39", "type": "Tissue", "text": [ "RPE cell layers" ], "offsets": [ [ 1258, 1273 ] ], "normalized": [] }, { "id": "PMID-10586954_T40", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1285, 1292 ] ], 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"ref_id": "PMID-10586954_T41" } ] }, { "id": "PMID-10586954_E17", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1438, 1447 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10586954_E44" }, { "role": "Theme", "ref_id": "PMID-10586954_T46" } ] }, { "id": "PMID-10586954_E19", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1611, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10586954_E52" } ] }, { "id": "PMID-10586954_E20", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1694, 1701 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10586954_T56" }, { "role": "Theme", "ref_id": "PMID-10586954_E19" } ] }, { "id": "PMID-10586954_E21", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1759, 1768 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10586954_T58" }, { "role": "Cause", "ref_id": "PMID-10586954_E22" } ] }, 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[ { "id": "PMID-19636328__text", "type": "abstract", "text": [ "Targeting angiogenesis: progress with anti-VEGF treatment with large molecules.\n\nAngiogenesis--one of the hallmarks of cancer--has emerged as a valid therapeutic target in oncology. The VEGF system represents a key mediator of tumor-initiated angiogenesis and the first target of antiangiogenesis agents introduced in clinical practice. Although anti-VEGF therapies have clearly demonstrated antitumor efficacy in various malignancies, especially when combined with conventional cytotoxic chemotherapy, their mechanism of action is not fully understood. This Review will discuss the rationale for using antiangiogenic compounds and will focus on large molecules, such as antibodies, that target the VEGF system. Clinical data on bevacizumab is discussed in detail. Predictive markers for anti-VEGF agents have not yet been identified and questions regarding the usefulness of bevacizumab in the adjuvant setting as well as its continued use beyond progression remain unanswered, in spite of negative data on bevacizumab in treating patients with adjuvant colon cancer. Nonetheless, anti-VEGF therapy has enhanced the arsenal of anticancer therapies and has provided new insights into the biology of malignancy.\n" ], "offsets": [ [ 0, 1211 ] ] } ]

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[]

[]

[ { "id": "PMID-18245558__text", "type": "abstract", "text": [ "Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin.\n\nPURPOSE: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment. EXPERIMENTAL DESIGN: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models--subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models. RESULTS: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed >50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days. CONCLUSION: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.\n" ], "offsets": [ [ 0, 1834 ] ] } ]

[ { "id": "PMID-18245558_T4", "type": "Pathological_formation", "text": [ "lung tumor" ], "offsets": [ [ 15, 25 ] ], "normalized": [] }, { "id": "PMID-18245558_T6", "type": "Gene_or_gene_product", "text": [ "vasostatin" ], "offsets": [ [ 105, 115 ] ], "normalized": [] }, { "id": "PMID-18245558_T13", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 220, 225 ] ], "normalized": [] }, { "id": "PMID-18245558_T14", "type": "Gene_or_gene_product", "text": [ "Vasostatin" ], "offsets": [ [ 261, 271 ] ], "normalized": [] }, { "id": "PMID-18245558_T15", "type": "Gene_or_gene_product", "text": [ "calreticulin" ], "offsets": [ [ 298, 310 ] ], "normalized": [] }, { "id": "PMID-18245558_T19", "type": "Gene_or_gene_product", "text": [ "vasostatin" ], "offsets": [ [ 398, 408 ] ], "normalized": [] }, { "id": "PMID-18245558_T21", "type": "Pathological_formation", "text": [ "lung cancer" ], "offsets": [ [ 517, 528 ] ], "normalized": [] }, { "id": "PMID-18245558_T22", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 569, 574 ] ], "normalized": [] }, { "id": "PMID-18245558_T25", "type": "Gene_or_gene_product", "text": [ "vasostatin" ], "offsets": [ [ 588, 598 ] ], "normalized": [] }, { "id": "PMID-18245558_T26", "type": "Pathological_formation", "text": [ "lung tumor" ], "offsets": [ [ 649, 659 ] ], "normalized": [] }, { "id": "PMID-18245558_T27", "type": "Pathological_formation", "text": [ "lung tumor" ], "offsets": [ [ 731, 741 ] ], "normalized": [] }, { "id": "PMID-18245558_T29", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "PMID-18245558_T30", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 819, 824 ] ], "normalized": [] }, { "id": "PMID-18245558_T32", "type": "Pathological_formation", "text": [ "subcutaneous tumor" ], "offsets": [ [ 936, 954 ] ], "normalized": [] }, { "id": "PMID-18245558_T34", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "PMID-18245558_T35", "type": "Cell", "text": [ "Lewis lung carcinoma cells" ], "offsets": [ [ 981, 1007 ] ], "normalized": [] }, { "id": "PMID-18245558_T37", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1041, 1046 ] ], "normalized": [] }, { "id": "PMID-18245558_T41", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 1132, 1137 ] ], "normalized": [] }, { "id": "PMID-18245558_T42", "type": "Pathological_formation", "text": [ "lung tumor A549 xenograft" ], "offsets": [ [ 1166, 1191 ] ], "normalized": [] }, { "id": "PMID-18245558_T45", "type": "Tissue", "text": [ "capillary vessels" ], "offsets": [ [ 1228, 1245 ] ], "normalized": [] }, { "id": "PMID-18245558_T46", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] }, { "id": "PMID-18245558_T47", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 1292, 1297 ] ], "normalized": [] }, { "id": "PMID-18245558_T50", "type": "Pathological_formation", "text": [ "A549 tumors" ], "offsets": [ [ 1329, 1340 ] ], "normalized": [] }, { "id": "PMID-18245558_T51", "type": "Multi-tissue_structure", "text": [ "lymph nodes" ], "offsets": [ [ 1356, 1367 ] ], "normalized": [] }, { "id": "PMID-18245558_T52", "type": "Organ", "text": [ "lung" ], "offsets": [ [ 1386, 1390 ] ], "normalized": [] }, { "id": "PMID-18245558_T53", "type": "Pathological_formation", "text": [ "lung metastases" ], "offsets": [ [ 1458, 1473 ] ], "normalized": [] }, { "id": "PMID-18245558_T54", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 1485, 1490 ] ], "normalized": [] }, { "id": "PMID-18245558_T56", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1511, 1516 ] ], "normalized": [] }, { "id": "PMID-18245558_T57", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 1630, 1635 ] ], "normalized": [] }, { "id": "PMID-18245558_T62", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1686, 1691 ] ], "normalized": [] }, { "id": "PMID-18245558_T64", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1726, 1731 ] ], "normalized": [] }, { "id": "PMID-18245558_T65", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 1775, 1780 ] ], "normalized": [] }, { "id": "PMID-18245558_T66", "type": "Pathological_formation", "text": [ "lung cancer" ], "offsets": [ [ 1821, 1832 ] ], "normalized": [] }, { "id": "PMID-18245558_T1000", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 51, 55 ] ], "normalized": [] }, { "id": "PMID-18245558_T1001", "type": "Organism", "text": [ "adeno-associated virus" ], "offsets": [ [ 59, 81 ] ], "normalized": [] }, { "id": "PMID-18245558_T1002", "type": "Organism", "text": [ "recombinant pseudotype adeno-associated virus 2" ], "offsets": [ [ 422, 469 ] ], "normalized": [] }, { "id": "PMID-18245558_T1003", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 643, 648 ] ], "normalized": [] }, { "id": "PMID-18245558_T1004", "type": "Organism", "text": [ "Mice" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "PMID-18245558_T1005", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1160, 1165 ] ], "normalized": [] }, { "id": "PMID-18245558_T1006", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1434, 1438 ] ], "normalized": [] }, { "id": "PMID-18245558_T8", "type": "Organism", "text": [ "5" ], "offsets": [ [ 470, 471 ] ], "normalized": [] }, { "id": "PMID-18245558_T17", "type": "Organism", "text": [ "rAAV2" ], "offsets": [ [ 473, 478 ] ], "normalized": [] }, { "id": "PMID-18245558_T20", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 479, 484 ] ], "normalized": [] }, { "id": "PMID-18245558_T28", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 1636, 1641 ] ], "normalized": [] }, { "id": "PMID-18245558_T39", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 1781, 1786 ] ], "normalized": [] }, { "id": "PMID-18245558_T43", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 1138, 1143 ] ], "normalized": [] }, { "id": "PMID-18245558_T59", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 1298, 1303 ] ], "normalized": [] }, { "id": "PMID-18245558_T67", "type": "Organism", "text": [ "5" ], "offsets": [ [ 575, 576 ] ], "normalized": [] }, { "id": "PMID-18245558_T68", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 784, 789 ] ], "normalized": [] }, { "id": "PMID-18245558_T69", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 964, 969 ] ], "normalized": [] }, { "id": "PMID-18245558_T70", "type": "Organism", "text": [ "5-VAS" ], "offsets": [ [ 1491, 1496 ] ], "normalized": [] }, { "id": "PMID-18245558_T38", "type": "Organ", "text": [ "pulmonary" ], "offsets": [ [ 1078, 1087 ] ], "normalized": [] }, { "id": "PMID-18245558_T78", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 192, 197 ] ], "normalized": [] }, { "id": "PMID-18245558_T49", "type": "Pathological_formation", "text": [ "intratumorally" ], "offsets": [ [ 599, 613 ] ], "normalized": [] } ]

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"PMID-18245558_E33", "type": "Planned_process", "trigger": { "text": [ "pretreated" ], "offsets": [ [ 970, 980 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18245558_T69" }, { "role": "Instrument", "ref_id": "PMID-18245558_T34" }, { "role": "Theme", "ref_id": "PMID-18245558_T35" } ] }, { "id": "PMID-18245558_E36", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1020, 1029 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T37" }, { "role": "Cause", "ref_id": "PMID-18245558_E33" } ] }, { "id": "PMID-18245558_E40", "type": "Negative_regulation", "trigger": { "text": [ "tumor-suppressive action" ], "offsets": [ [ 1104, 1128 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T42" }, { "role": "Cause", "ref_id": "PMID-18245558_T41" } ] }, { "id": "PMID-18245558_E44", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1210, 1217 ] ] }, "arguments": [ { "role": "Theme", "ref_id": 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"PMID-18245558_E61", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 1692, 1698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T62" } ] }, { "id": "PMID-18245558_E63", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 1732, 1743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T64" } ] }, { "id": "PMID-18245558_E4", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 82, 90 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18245558_T1001" }, { "role": "Theme", "ref_id": "PMID-18245558_E5" } ] }, { "id": "PMID-18245558_E6", "type": "Negative_regulation", "trigger": { "text": [ "Suppression" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18245558_E5" }, { "role": "Theme", "ref_id": "PMID-18245558_E2" } ] }, { "id": "PMID-18245558_E7", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 208, 219 ] ] }, 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"PMID-18245558_T59" }, { "role": "Theme", "ref_id": "PMID-18245558_E49" } ] }, { "id": "PMID-18245558_E20", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1304, 1314 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18245558_T47" }, { "role": "Theme", "ref_id": "PMID-18245558_E49" } ] }, { "id": "PMID-18245558_E21", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1405, 1414 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T1006" } ] }, { "id": "PMID-18245558_E22", "type": "Negative_regulation", "trigger": { "text": [ "effectiveness" ], "offsets": [ [ 1613, 1626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_E31" }, { "role": "Cause", "ref_id": "PMID-18245558_T57" } ] }, { "id": "PMID-18245558_E23", "type": "Negative_regulation", "trigger": { "text": [ "effectiveness" ], "offsets": [ [ 1613, 1626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_E31" }, { "role": "Cause", "ref_id": "PMID-18245558_T28" } ] }, { "id": "PMID-18245558_E25", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 1674, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_E61" }, { "role": "Cause", "ref_id": "PMID-18245558_T57" } ] }, { "id": "PMID-18245558_E26", "type": "Planned_process", "trigger": { "text": [ "gene therapy" ], "offsets": [ [ 1787, 1799 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18245558_T39" } ] }, { "id": "PMID-18245558_E27", "type": "Planned_process", "trigger": { "text": [ "gene therapy" ], "offsets": [ [ 1787, 1799 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18245558_T65" } ] }, { "id": "PMID-18245558_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenesis" ], "offsets": [ [ 127, 139 ] ] }, "arguments": [] }, { "id": "PMID-18245558_E29", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 324, 336 ] ] }, "arguments": [] }, { "id": "PMID-18245558_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 862, 880 ] ] }, "arguments": [] }, { "id": "PMID-18245558_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1648, 1660 ] ] }, "arguments": [] }, { "id": "PMID-18245558_E32", "type": "Negative_regulation", "trigger": { "text": [ "against" ], "offsets": [ [ 1813, 1820 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T66" }, { "role": "Cause", "ref_id": "PMID-18245558_E26" } ] }, { "id": "PMID-18245558_E34", "type": "Negative_regulation", "trigger": { "text": [ "against" ], "offsets": [ [ 1813, 1820 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18245558_T66" }, { "role": "Cause", "ref_id": "PMID-18245558_E27" } ] }, { "id": "PMID-18245558_E35", "type": "Planned_process", "trigger": { "text": [ "deliver" ], "offsets": [ [ 580, 587 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18245558_T67" }, { "role": "Instrument", "ref_id": "PMID-18245558_T25" }, { "role": "Theme", "ref_id": "PMID-18245558_T26" } ] } ]

[ { "id": "PMID-18245558_1", "entity_ids": [ "PMID-18245558_T1002", "PMID-18245558_T17" ] }, { "id": "PMID-18245558_2", "entity_ids": [ "PMID-18245558_T8", "PMID-18245558_T20" ] } ]

[ { "id": "PMID-18245558_R1", "type": "frag", "arg1_id": "PMID-18245558_T8", "arg2_id": "PMID-18245558_T1002", "normalized": [] }, { "id": "PMID-18245558_R2", "type": "frag", "arg1_id": "PMID-18245558_T67", "arg2_id": "PMID-18245558_T22", "normalized": [] } ]

[ { "id": "PMID-19574426__text", "type": "abstract", "text": [ "Angiogenesis in platelet endothelial cell adhesion molecule-1-null mice.\n\nPlatelet endothelial cell adhesion molecule (PECAM)-1 has been previously implicated in endothelial cell migration; additionally, anti-PECAM-1 antibodies have been shown to inhibit in vivo angiogenesis. Studies were therefore performed with PECAM-1-null mice to further define the involvement of PECAM-1 in blood vessel formation. Vascularization of subcutaneous Matrigel implants as well as tumor angiogenesis were both inhibited in PECAM-1-null mice. Reciprocal bone marrow transplants that involved both wild-type and PECAM-1-deficient mice revealed that the impaired angiogenic response resulted from a loss of endothelial, but not leukocyte, PECAM-1. In vitro wound migration and single-cell motility by PECAM-1-null endothelial cells were also compromised. In addition, filopodia formation, a feature of motile cells, was inhibited in PECAM-1-null endothelial cells as well as in human endothelial cells treated with either anti-PECAM-1 antibody or PECAM-1 siRNA. Furthermore, the expression of PECAM-1 promoted filopodia formation and increased the protein expression levels of Cdc42, a Rho GTPase that is known to promote the formation of filopodia. In the developing retinal vasculature, numerous, long filamentous filopodia, emanating from endothelial cells at the tips of angiogenic sprouts, were observed in wild-type animals, but to a lesser extent in the PECAM-1-null mice. Together, these data further establish the involvement of endothelial PECAM-1 in angiogenesis and suggest that, in vivo, PECAM-1 may stimulate endothelial cell motility by promoting the formation of filopodia.\n" ], "offsets": [ [ 0, 1672 ] ] } ]

[ { "id": "PMID-19574426_T2", "type": "Gene_or_gene_product", "text": [ "platelet endothelial cell adhesion molecule-1" ], "offsets": [ [ 16, 61 ] ], "normalized": [] }, { "id": "PMID-19574426_T3", "type": "Gene_or_gene_product", "text": [ "Platelet endothelial cell adhesion molecule (PECAM)-1" ], "offsets": [ [ 74, 127 ] ], "normalized": [] }, { "id": "PMID-19574426_T6", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 162, 178 ] ], "normalized": [] }, { "id": "PMID-19574426_T11", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 315, 322 ] ], "normalized": [] }, { "id": "PMID-19574426_T13", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 370, 377 ] ], "normalized": [] }, { "id": "PMID-19574426_T15", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 381, 393 ] ], "normalized": [] }, { "id": "PMID-19574426_T17", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 466, 471 ] ], "normalized": [] }, { "id": "PMID-19574426_T20", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 508, 515 ] ], "normalized": [] }, { "id": "PMID-19574426_T22", "type": "Multi-tissue_structure", "text": [ "bone marrow" ], "offsets": [ [ 538, 549 ] ], "normalized": [] }, { "id": "PMID-19574426_T23", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 595, 602 ] ], "normalized": [] }, { "id": "PMID-19574426_T28", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 710, 719 ] ], "normalized": [] }, { "id": "PMID-19574426_T29", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 721, 728 ] ], "normalized": [] }, { "id": "PMID-19574426_T30", "type": "Cell", "text": [ "PECAM-1-null endothelial cells" ], "offsets": [ [ 783, 813 ] ], "normalized": [] }, { "id": "PMID-19574426_T31", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 783, 790 ] ], "normalized": [] }, { "id": "PMID-19574426_T36", "type": "Cell", "text": [ "PECAM-1-null endothelial cells" ], "offsets": [ [ 915, 945 ] ], "normalized": [] }, { "id": "PMID-19574426_T37", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 915, 922 ] ], "normalized": [] }, { "id": "PMID-19574426_T39", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 966, 983 ] ], "normalized": [] }, { "id": "PMID-19574426_T43", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1075, 1082 ] ], "normalized": [] }, { "id": "PMID-19574426_T49", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "PMID-19574426_T54", "type": "Multi-tissue_structure", "text": [ "retinal vasculature" ], "offsets": [ [ 1250, 1269 ] ], "normalized": [] }, { "id": "PMID-19574426_T56", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1324, 1341 ] ], "normalized": [] }, { "id": "PMID-19574426_T58", "type": "Tissue", "text": [ "sprouts" ], "offsets": [ [ 1368, 1375 ] ], "normalized": [] }, { "id": "PMID-19574426_T59", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1443, 1450 ] ], "normalized": [] }, { "id": "PMID-19574426_T62", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1532, 1539 ] ], "normalized": [] }, { "id": "PMID-19574426_T64", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1583, 1590 ] ], "normalized": [] }, { "id": "PMID-19574426_T67", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1605, 1621 ] ], "normalized": [] }, { "id": "PMID-19574426_T7", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1009, 1016 ] ], "normalized": [] }, { "id": "PMID-19574426_T9", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 1029, 1036 ] ], "normalized": [] }, { "id": "PMID-19574426_T12", "type": "Gene_or_gene_product", "text": [ "PECAM-1" ], "offsets": [ [ 209, 216 ] ], "normalized": [] }, { "id": "PMID-19574426_T1000", "type": "Organism", "text": [ "platelet endothelial cell adhesion molecule-1-null mice" ], "offsets": [ [ 16, 71 ] ], "normalized": [] }, { "id": "PMID-19574426_T1001", "type": "Organism", "text": [ "PECAM-1-null mice" ], "offsets": [ [ 315, 332 ] ], "normalized": [] }, { "id": "PMID-19574426_T1002", "type": "Organism", "text": [ "PECAM-1-null mice" ], "offsets": [ [ 508, 525 ] ], "normalized": [] }, { "id": "PMID-19574426_T1003", "type": "Organism", "text": [ "PECAM-1-deficient mice" ], "offsets": [ [ 595, 617 ] ], "normalized": [] }, { "id": "PMID-19574426_T1004", "type": "Organism", "text": [ "human" ], "offsets": [ [ 960, 965 ] ], "normalized": [] }, { "id": "PMID-19574426_T1005", "type": "Organism", "text": [ "PECAM-1-null mice" ], "offsets": [ [ 1443, 1460 ] ], "normalized": [] }, { "id": "PMID-19574426_T50", "type": "Gene_or_gene_product", "text": [ "Rho" ], "offsets": [ [ 1168, 1171 ] ], "normalized": [] }, { "id": "PMID-19574426_T8", "type": "Gene_or_gene_product", "text": [ "anti-PECAM-1 antibodies" ], "offsets": [ [ 204, 227 ] ], "normalized": [] }, { "id": "PMID-19574426_T40", "type": "Gene_or_gene_product", "text": [ "anti-PECAM-1 antibody" ], "offsets": [ [ 1004, 1025 ] ], "normalized": [] }, { "id": "PMID-19574426_T72", "type": "Cellular_component", "text": [ "long filamentous filopodia" ], "offsets": [ [ 1281, 1307 ] ], "normalized": [] }, { "id": "PMID-19574426_T73", "type": "Cellular_component", "text": [ "filopodia" ], "offsets": [ [ 1092, 1101 ] ], "normalized": [] }, { "id": "PMID-19574426_T75", "type": "Cellular_component", "text": [ "filopodia" ], "offsets": [ [ 850, 859 ] ], "normalized": [] }, { "id": "PMID-19574426_T77", "type": "Cellular_component", "text": [ "filopodia" ], "offsets": [ [ 1221, 1230 ] ], "normalized": [] }, { "id": "PMID-19574426_T79", "type": "Cellular_component", "text": [ "filopodia" ], "offsets": [ [ 1661, 1670 ] ], "normalized": [] }, { "id": "PMID-19574426_T81", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 766, 770 ] ], "normalized": [] }, { "id": "PMID-19574426_T83", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 891, 896 ] ], "normalized": [] }, { "id": "PMID-19574426_T4", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 689, 700 ] ], "normalized": [] } ]

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"PMID-19574426_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 247, 254 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E35" }, { "role": "Cause", "ref_id": "PMID-19574426_T8" } ] }, { "id": "PMID-19574426_E3", "type": "Gene_expression", "trigger": { "text": [ "null" ], "offsets": [ [ 323, 327 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T11" } ] }, { "id": "PMID-19574426_E6", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 355, 366 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_T13" }, { "role": "Theme", "ref_id": "PMID-19574426_E7" } ] }, { "id": "PMID-19574426_E7", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 394, 403 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T15" } ] }, { "id": "PMID-19574426_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 495, 504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E37" } ] }, { "id": "PMID-19574426_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 495, 504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E36" } ] }, { "id": "PMID-19574426_E10", "type": "Gene_expression", "trigger": { "text": [ "null" ], "offsets": [ [ 516, 520 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T20" } ] }, { "id": "PMID-19574426_E11", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 603, 612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T23" } ] }, { "id": "PMID-19574426_E12", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 636, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E38" }, { "role": "Cause", "ref_id": "PMID-19574426_E13" } ] }, { "id": "PMID-19574426_E13", "type": "Localization", "trigger": { "text": [ "loss" ], "offsets": [ [ 681, 685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T29" }, { "role": "AtLoc", "ref_id": "PMID-19574426_T4" } ] }, { "id": "PMID-19574426_E15", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 984, 991 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T39" }, { "role": "Instrument", "ref_id": "PMID-19574426_T40" } ] }, { "id": "PMID-19574426_E17", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1116, 1125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E48" }, { "role": "Cause", "ref_id": "PMID-19574426_E42" } ] }, { "id": "PMID-19574426_E18", "type": "Positive_regulation", "trigger": { "text": [ "promoted" ], "offsets": [ [ 1083, 1091 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_E42" }, { "role": "Theme", "ref_id": "PMID-19574426_E27" } ] }, { "id": "PMID-19574426_E19", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 1196, 1203 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_T49" }, { "role": "Theme", "ref_id": "PMID-19574426_E29" } ] }, { "id": "PMID-19574426_E20", "type": "Gene_expression", "trigger": { "text": [ "null" ], "offsets": [ [ 1451, 1455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T59" } ] }, { "id": "PMID-19574426_E22", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 1595, 1604 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_E24" }, { "role": "Theme", "ref_id": "PMID-19574426_E23" } ] }, { "id": "PMID-19574426_E23", "type": "Localization", "trigger": { "text": [ "motility" ], "offsets": [ [ 1622, 1630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T67" } ] }, { "id": "PMID-19574426_E24", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 1634, 1643 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_T64" }, { "role": "Theme", "ref_id": "PMID-19574426_E30" } ] }, { "id": "PMID-19574426_E25", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 1505, 1516 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19574426_T62" }, { "role": "Theme", "ref_id": "PMID-19574426_E40" } ] }, { "id": "PMID-19574426_E26", "type": "Development", "trigger": { "text": [ "developing" ], "offsets": [ [ 1239, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T54" } ] }, { "id": "PMID-19574426_E27", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1102, 1111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T73" } ] }, { "id": "PMID-19574426_E28", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 860, 869 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T75" } ] }, { "id": "PMID-19574426_E29", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1208, 1217 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T77" } ] }, { "id": "PMID-19574426_E30", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1648, 1657 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T79" } ] }, { "id": "PMID-19574426_E31", "type": "Localization", "trigger": { "text": [ "motility" ], "offsets": [ [ 771, 779 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T81" } ] }, { "id": "PMID-19574426_E32", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 902, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E28" } ] }, { "id": "PMID-19574426_E34", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenesis" ], "offsets": [ [ 0, 12 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19574426_T1000" } ] }, { "id": "PMID-19574426_E35", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 263, 275 ] ] }, "arguments": [] }, { "id": "PMID-19574426_E36", "type": "Blood_vessel_development", "trigger": { "text": [ "Vascularization" ], "offsets": [ [ 405, 420 ] ] }, "arguments": [] }, { "id": "PMID-19574426_E37", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 472, 484 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19574426_T17" } ] }, { "id": "PMID-19574426_E38", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 645, 655 ] ] }, "arguments": [] }, { "id": "PMID-19574426_E39", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1357, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T58" } ] }, { "id": "PMID-19574426_E40", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1543, 1555 ] ] }, "arguments": [] }, { "id": "PMID-19574426_E4", "type": "Localization", "trigger": { "text": [ "loss" ], "offsets": [ [ 681, 685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_T29" }, { "role": "AtLoc", "ref_id": "PMID-19574426_T28" } ] }, { "id": "PMID-19574426_E14", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 636, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19574426_E38" }, { "role": "Cause", "ref_id": "PMID-19574426_E4" } ] } ]

[]

[]

[ { "id": "PMID-18505892__text", "type": "abstract", "text": [ "Adenomatoid tumour of the liver.\n\nAn unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.\n" ], "offsets": [ [ 0, 1212 ] ] } ]

[ { "id": "PMID-18505892_T1", "type": "Pathological_formation", "text": [ "Adenomatoid tumour" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "PMID-18505892_T2", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 26, 31 ] ], "normalized": [] }, { "id": "PMID-18505892_T3", "type": "Pathological_formation", "text": [ "adenomatoid tumour" ], "offsets": [ [ 53, 71 ] ], "normalized": [] }, { "id": "PMID-18505892_T4", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 94, 99 ] ], "normalized": [] }, { "id": "PMID-18505892_T5", "type": "Pathological_formation", "text": [ "tumour" ], "offsets": [ [ 219, 225 ] ], "normalized": [] }, { "id": "PMID-18505892_T8", "type": "Cell", "text": [ "epithelioid cells" ], "offsets": [ [ 424, 441 ] ], "normalized": [] }, { "id": "PMID-18505892_T9", "type": "Cellular_component", "text": [ "vacuolated cytoplasm" ], "offsets": [ [ 447, 467 ] ], "normalized": [] }, { "id": "PMID-18505892_T11", "type": "Cell", "text": [ "epithelioid cells" ], "offsets": [ [ 498, 515 ] ], "normalized": [] }, { "id": "PMID-18505892_T15", "type": "Tissue", "text": [ "capillaries" ], "offsets": [ [ 556, 567 ] ], "normalized": [] }, { "id": "PMID-18505892_T16", "type": "Multi-tissue_structure", "text": [ "arteries" ], "offsets": [ [ 572, 580 ] ], "normalized": [] }, { "id": "PMID-18505892_T17", "type": "Tissue", "text": [ "collagenous stroma" ], "offsets": [ [ 595, 613 ] ], "normalized": [] }, { "id": "PMID-18505892_T18", "type": "Cell", "text": [ "epithelioid cells" ], "offsets": [ [ 659, 676 ] ], "normalized": [] }, { "id": "PMID-18505892_T19", "type": "Gene_or_gene_product", "text": [ "cytokeratins" ], "offsets": [ [ 724, 736 ] ], "normalized": [] }, { "id": "PMID-18505892_T20", "type": "Gene_or_gene_product", "text": [ "AE1" ], "offsets": [ [ 738, 741 ] ], "normalized": [] }, { "id": "PMID-18505892_T21", "type": "Gene_or_gene_product", "text": [ "AE3" ], "offsets": [ [ 742, 745 ] ], "normalized": [] }, { "id": "PMID-18505892_T22", "type": "Gene_or_gene_product", "text": [ "CAM5.2" ], "offsets": [ [ 747, 753 ] ], "normalized": [] }, { "id": "PMID-18505892_T23", "type": "Gene_or_gene_product", "text": [ "epithelial membrane antigen" ], "offsets": [ [ 755, 782 ] ], "normalized": [] }, { "id": "PMID-18505892_T24", "type": "Gene_or_gene_product", "text": [ "cytokeratin 7" ], "offsets": [ [ 787, 800 ] ], "normalized": [] }, { "id": "PMID-18505892_T25", "type": "Tissue", "text": [ "mesothelial" ], "offsets": [ [ 806, 817 ] ], "normalized": [] }, { "id": "PMID-18505892_T26", "type": "Gene_or_gene_product", "text": [ "calretinin" ], "offsets": [ [ 827, 837 ] ], "normalized": [] }, { "id": "PMID-18505892_T27", "type": "Gene_or_gene_product", "text": [ "Wilms' tumour 1" ], "offsets": [ [ 839, 854 ] ], "normalized": [] }, { "id": "PMID-18505892_T28", "type": "Gene_or_gene_product", "text": [ "D2-40" ], "offsets": [ [ 859, 864 ] ], "normalized": [] }, { "id": "PMID-18505892_T29", "type": "Gene_or_gene_product", "text": [ "Hep par-1" 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"PMID-18505892_T44", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 873, 878 ] ], "normalized": [] } ]

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[]

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[ { "id": "PMID-7586219__text", "type": "abstract", "text": [ "VEGF165 expressed by a replication-deficient recombinant adenovirus vector induces angiogenesis in vivo.\n\nTo evaluate the concept that localized delivery of angiogenic factors via virus-mediated gene transfer may be useful in the treatment of ischemic disorders, the replication-deficient adenovirus (Ad) vector AdCMV.VEGF165 (where CMV is cytomegalovirus and VEGF is vascular endothelial growth factor) containing the cDNA for human VEGF165, a secreted endothelial cell-specific angiogenic growth factor, was constructed. Human umbilical vein endothelial cells (HUVECs) and rat aorta smooth muscle cells (RASMCs) infected with AdCMV.VEGF165 (5 and 20 plaque-forming units [pfu] per cell) demonstrated VEGF mRNA expression and protein secretion into the supernatant. Furthermore, the conditioned medium from these cells enhanced vascular permeability in vivo. In contrast, neither VEGF mRNA nor secreted protein was found in uninfected HUVECs or RASMCs or in cells infected with the control vector AdCMV.beta gal (where beta gal is beta-galactosidase). Assessment of starved HUVECs at 14 days demonstrated sixfold more cells for AdCMV.VEGF165-infected HUVECs (20 pfu per cell) than for either infected or uninfected control cells. RASMC proliferation was unaffected by infection with AdCMV.VEGF165. When plated in 2% serum on dishes precoated with reconstituted basement membrane (Matrigel), HUVECs infected with AdCMV.VEGF165 (20 pfu per cell) differentiated into capillary-like structures. Under similar conditions, both uninfected HUVECs and HUVECs infected with AdCMV.beta gal did not differentiate. To evaluate the ability of AdCMV.VEGF165 to function in vivo, either AdCMV. VEGF165 or AdCMV.beta gal (2 x 10(10) pfu) was resuspended in 0.5 mL Matrigel and injected subcutaneously into mice. Immunohistochemical staining demonstrated VEGF in the tissues surrounding the Matrigel plugs containing AdCMV.VEGF165 up to 3 weeks after injection, whereas no VEGF was found in the control plugs with AdCMV.beta gal. Two weeks after injection, there was histological evidence of neovascularization in the tissues surrounding the Matrigel containing AdCMV.VEGF165, whereas no significant angiogenesis was observed in response to AdCMV.beta gal. Furthermore, the Matrigel plugs with AdCMV.VEGF165 demonstrated hemoglobin content fourfold higher than the plugs with AdCMV.beta gal. Together, these in vitro and in vivo studies are consistent with the concept that Ad vectors may provide a useful strategy for efficient local delivery of VEGF165 in the treatment of ischemic diseases.\n" ], "offsets": [ [ 0, 2578 ] ] } ]

[ { "id": "PMID-7586219_T2", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-7586219_T6", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 318, 325 ] ], "normalized": [] }, { "id": "PMID-7586219_T7", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 360, 364 ] ], "normalized": [] }, { "id": "PMID-7586219_T8", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 368, 402 ] ], "normalized": [] }, { "id": "PMID-7586219_T9", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 434, 441 ] ], "normalized": [] }, { "id": "PMID-7586219_T10", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 454, 470 ] ], "normalized": [] }, { "id": "PMID-7586219_T13", "type": "Cell", "text": [ "Human umbilical vein endothelial cells" ], "offsets": [ [ 523, 561 ] ], "normalized": [] }, { "id": "PMID-7586219_T14", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 563, 569 ] ], "normalized": [] }, { "id": "PMID-7586219_T16", "type": "Cell", "text": [ "rat aorta smooth muscle cells" ], "offsets": [ [ 575, 604 ] ], "normalized": [] }, { "id": "PMID-7586219_T17", "type": "Cell", "text": [ "RASMCs" ], "offsets": [ [ 606, 612 ] ], "normalized": [] }, { "id": "PMID-7586219_T18", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 634, 641 ] ], "normalized": [] }, { "id": "PMID-7586219_T20", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-7586219_T22", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 829, 837 ] ], "normalized": [] }, { "id": "PMID-7586219_T23", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 881, 885 ] ], "normalized": [] }, { "id": "PMID-7586219_T24", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 936, 942 ] ], "normalized": [] }, { "id": "PMID-7586219_T25", "type": "Cell", "text": [ "RASMCs" ], "offsets": [ [ 946, 952 ] ], "normalized": [] }, { "id": "PMID-7586219_T26", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 998, 1012 ] ], "normalized": [] }, { "id": "PMID-7586219_T27", "type": "Gene_or_gene_product", "text": [ "beta gal" ], "offsets": [ [ 1020, 1028 ] ], "normalized": [] }, { "id": "PMID-7586219_T28", "type": "Gene_or_gene_product", "text": [ "beta-galactosidase" ], "offsets": [ [ 1032, 1050 ] ], "normalized": [] }, { "id": "PMID-7586219_T29", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1075, 1081 ] ], "normalized": [] }, { "id": "PMID-7586219_T30", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 1129, 1142 ] ], "normalized": [] }, { "id": "PMID-7586219_T31", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1152, 1158 ] ], "normalized": [] }, { "id": "PMID-7586219_T32", "type": "Cell", "text": [ "RASMC" ], "offsets": [ [ 1231, 1236 ] ], "normalized": [] }, { "id": "PMID-7586219_T33", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 1284, 1297 ] ], "normalized": [] }, { "id": "PMID-7586219_T34", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1392, 1398 ] ], "normalized": [] }, { "id": "PMID-7586219_T35", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 1413, 1426 ] ], "normalized": [] }, { "id": "PMID-7586219_T36", "type": "Tissue", "text": [ "capillary-like structures" ], "offsets": [ [ 1465, 1490 ] ], "normalized": [] }, { "id": "PMID-7586219_T37", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1534, 1540 ] ], "normalized": [] }, { "id": "PMID-7586219_T38", "type": "Cell", "text": [ "HUVECs" ], "offsets": [ [ 1545, 1551 ] ], "normalized": [] }, { "id": "PMID-7586219_T39", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 1566, 1580 ] ], "normalized": [] }, { "id": "PMID-7586219_T40", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 1631, 1644 ] ], "normalized": [] }, { "id": "PMID-7586219_T41", "type": "Organism", "text": [ "AdCMV. VEGF165" ], "offsets": [ [ 1673, 1687 ] ], "normalized": [] }, { "id": "PMID-7586219_T42", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 1691, 1705 ] ], "normalized": [] }, { "id": "PMID-7586219_T43", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1839, 1843 ] ], "normalized": [] }, { "id": "PMID-7586219_T44", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 1901, 1914 ] ], "normalized": [] }, { "id": "PMID-7586219_T45", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1957, 1961 ] ], "normalized": [] }, { "id": "PMID-7586219_T46", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 1998, 2012 ] ], "normalized": [] }, { "id": "PMID-7586219_T48", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 2146, 2159 ] ], "normalized": [] }, { "id": "PMID-7586219_T50", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 2225, 2239 ] ], "normalized": [] }, { "id": "PMID-7586219_T51", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 2278, 2291 ] ], "normalized": [] }, { "id": "PMID-7586219_T52", "type": "Gene_or_gene_product", "text": [ "hemoglobin" ], "offsets": [ [ 2305, 2315 ] ], "normalized": [] }, { "id": "PMID-7586219_T53", "type": "Organism", "text": [ "AdCMV.beta gal" ], "offsets": [ [ 2360, 2374 ] ], "normalized": [] }, { "id": "PMID-7586219_T54", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 2531, 2538 ] ], "normalized": [] }, { "id": "PMID-7586219_T3", "type": "Cellular_component", "text": [ "basement membrane" ], "offsets": [ [ 1362, 1379 ] ], "normalized": [] }, { "id": "PMID-7586219_T1000", "type": "Organism", "text": [ "CMV" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "PMID-7586219_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 428, 433 ] ], "normalized": [] }, { "id": "PMID-7586219_T1004", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1791, 1795 ] ], "normalized": [] }, { "id": "PMID-7586219_T12", "type": "Organism", "text": [ "cytomegalovirus" ], "offsets": [ [ 340, 355 ] ], "normalized": [] }, { "id": "PMID-7586219_T15", "type": "Organism", "text": [ "adenovirus" ], "offsets": [ [ 57, 67 ] ], "normalized": [] }, { "id": "PMID-7586219_T61", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 628, 641 ] ], "normalized": [] }, { "id": "PMID-7586219_T62", "type": "Organism", "text": [ "AdCMV.VEGF165" ], "offsets": [ [ 312, 325 ] ], "normalized": [] }, { "id": "PMID-7586219_T63", "type": "Gene_or_gene_product", "text": [ "beta gal" ], "offsets": [ [ 1004, 1012 ] ], "normalized": [] }, { "id": "PMID-7586219_T64", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 1290, 1297 ] ], "normalized": [] }, { "id": "PMID-7586219_T65", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 1637, 1644 ] ], "normalized": [] }, { "id": "PMID-7586219_T66", "type": "Gene_or_gene_product", "text": [ "beta gal" ], "offsets": [ 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"PMID-7586219_T74", "type": "Gene_or_gene_product", "text": [ "beta gal" ], "offsets": [ [ 2231, 2239 ] ], "normalized": [] }, { "id": "PMID-7586219_T75", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 2284, 2291 ] ], "normalized": [] }, { "id": "PMID-7586219_T76", "type": "Gene_or_gene_product", "text": [ "VEGF165" ], "offsets": [ [ 1135, 1142 ] ], "normalized": [] }, { "id": "PMID-7586219_T91", "type": "Organism", "text": [ "adenovirus" ], "offsets": [ [ 289, 299 ] ], "normalized": [] }, { "id": "PMID-7586219_T92", "type": "Organism", "text": [ "Ad" ], "offsets": [ [ 301, 303 ] ], "normalized": [] }, { "id": "PMID-7586219_T93", "type": "Organism", "text": [ "Ad" ], "offsets": [ [ 2458, 2460 ] ], "normalized": [] }, { "id": "PMID-7586219_T94", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 1851, 1858 ] ], "normalized": [] }, { "id": "PMID-7586219_T96", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 2102, 2109 ] ], "normalized": [] }, { "id": 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"Instrument", "ref_id": "PMID-7586219_T44" } ] }, { "id": "PMID-7586219_E26", "type": "Regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 2213, 2221 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7586219_T50" }, { "role": "Theme", "ref_id": "PMID-7586219_E33" } ] }, { "id": "PMID-7586219_E10", "type": "Planned_process", "trigger": { "text": [ "uninfected" ], "offsets": [ [ 1205, 1215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7586219_T103" } ] }, { "id": "PMID-7586219_E28", "type": "Planned_process", "trigger": { "text": [ "infected" ], "offsets": [ [ 1193, 1201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7586219_T103" } ] }, { "id": "PMID-7586219_E29", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 83, 95 ] ] }, "arguments": [] }, { "id": "PMID-7586219_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 157, 167 ] ] }, "arguments": [] }, { "id": "PMID-7586219_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 480, 490 ] ] }, "arguments": [] }, { "id": "PMID-7586219_E32", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 2076, 2094 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-7586219_T96" } ] }, { "id": "PMID-7586219_E33", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 2184, 2196 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-7586219_T96" } ] }, { "id": "PMID-7586219_E21", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 820, 828 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7586219_T22" } ] }, { "id": "PMID-7586219_E27", "type": "Planned_process", "trigger": { "text": [ "Immunohistochemical staining" ], "offsets": [ [ 1797, 1825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7586219_T43" } ] } ]

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[]

[ { "id": "PMID-11387198__text", "type": "abstract", "text": [ "Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism.\n\nThe angiogenic switch during tumorigenesis is thought to be induced by a change in the balance of pro- angiogenic and anti-angiogenic factors. To elucidate the biological role of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, we subjected TSP-2-deficient and wild-type mice to a chemical skin carcinogenesis regimen. Surprisingly, TSP-2 expression was strongly upregulated in the mesenchymal stroma of wild-type mice throughout the consecutive stages of tumorigenesis whereas the angiogenesis factor, vascular endothelial growth factor, was induced predominantly in tumor cells. TSP-2 deficiency dramatically enhanced susceptibility to skin carcinogenesis and resulted in accelerated and increased tumor formation. The angiogenic switch occurred in early stages of pre-malignant tumor formation, and tumor angiogenesis was significantly enhanced in TSP-2-deficient mice. While TSP-2 deficiency did not affect tumor differentiation or proliferation, tumor cell apoptosis was significantly reduced. These results reveal upregulation of an endogenous angiogenesis inhibitor during multi step tumorigenesis and identify enhanced stromal TSP-2 expression as a novel host anti-tumor defense mechanism.\n" ], "offsets": [ [ 0, 1359 ] ] } ]

[ { "id": "PMID-11387198_T1", "type": "Gene_or_gene_product", "text": [ "Thrombospondin-2" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "PMID-11387198_T2", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 88, 93 ] ], "normalized": [] }, { "id": "PMID-11387198_T8", "type": "Gene_or_gene_product", "text": [ "thrombospondin-2" ], "offsets": [ [ 331, 347 ] ], "normalized": [] }, { "id": "PMID-11387198_T9", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 349, 354 ] ], "normalized": [] }, { "id": "PMID-11387198_T11", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 402, 407 ] ], "normalized": [] }, { "id": "PMID-11387198_T14", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 494, 499 ] ], "normalized": [] }, { "id": "PMID-11387198_T15", "type": "Tissue", "text": [ "mesenchymal stroma" ], "offsets": [ [ 543, 561 ] ], "normalized": [] }, { "id": "PMID-11387198_T19", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 664, 698 ] ], "normalized": [] }, { "id": "PMID-11387198_T20", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 729, 740 ] ], "normalized": [] }, { "id": "PMID-11387198_T23", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "PMID-11387198_T26", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 861, 866 ] ], "normalized": [] }, { "id": "PMID-11387198_T29", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 942, 947 ] ], "normalized": [] }, { "id": "PMID-11387198_T30", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 963, 968 ] ], "normalized": [] }, { "id": "PMID-11387198_T34", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 1012, 1017 ] ], "normalized": [] }, { "id": "PMID-11387198_T36", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 1040, 1045 ] ], "normalized": [] }, { "id": "PMID-11387198_T39", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1072, 1077 ] ], "normalized": [] }, { "id": "PMID-11387198_T42", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 1112, 1122 ] ], "normalized": [] }, { "id": "PMID-11387198_T48", "type": "Gene_or_gene_product", "text": [ "TSP-2" ], "offsets": [ [ 1296, 1301 ] ], "normalized": [] }, { "id": "PMID-11387198_T49", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1334, 1339 ] ], "normalized": [] }, { "id": "PMID-11387198_T7", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 451, 455 ] ], "normalized": [] }, { "id": "PMID-11387198_T17", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 799, 803 ] ], "normalized": [] }, { "id": "PMID-11387198_T1000", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 432, 436 ] ], "normalized": [] }, { "id": "PMID-11387198_T1001", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 575, 579 ] ], "normalized": [] }, { "id": "PMID-11387198_T1002", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1028, 1032 ] ], "normalized": [] } ]

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"Theme", "ref_id": "PMID-11387198_T26" } ] }, { "id": "PMID-11387198_E28", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 948, 957 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T29" } ] }, { "id": "PMID-11387198_E37", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1097, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T39" } ] }, { "id": "PMID-11387198_E38", "type": "Development", "trigger": { "text": [ "differentiation" ], "offsets": [ [ 1078, 1093 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T39" } ] }, { "id": "PMID-11387198_E40", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1151, 1158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E41" }, { "role": "Cause", "ref_id": "PMID-11387198_E10" } ] }, { "id": "PMID-11387198_E41", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1123, 1132 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T42" } ] }, { "id": "PMID-11387198_E46", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1279, 1287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E47" } ] }, { "id": "PMID-11387198_E47", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1302, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T48" } ] }, { "id": "PMID-11387198_E1", "type": "Negative_regulation", "trigger": { "text": [ "defense" ], "offsets": [ [ 94, 101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T2" } ] }, { "id": "PMID-11387198_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 174, 181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E16" } ] }, { "id": "PMID-11387198_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 321, 330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E20" }, { "role": "Cause", "ref_id": "PMID-11387198_T8" } ] }, { "id": "PMID-11387198_E4", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 408, 417 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T11" } ] }, { "id": "PMID-11387198_E5", "type": "Planned_process", "trigger": { "text": [ "subjected" ], "offsets": [ [ 392, 401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T1000" } ] }, { "id": "PMID-11387198_E6", "type": "Gene_expression", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 748, 758 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T23" } ] }, { "id": "PMID-11387198_E7", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1000, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E23" } ] }, { "id": "PMID-11387198_E8", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1000, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_E28" } ] }, { "id": "PMID-11387198_E9", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 1018, 1027 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T34" } ] }, { "id": "PMID-11387198_E10", "type": "Gene_expression", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 1046, 1056 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T36" } ] }, { "id": "PMID-11387198_E11", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1065, 1071 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11387198_E10" }, { "role": "Theme", "ref_id": "PMID-11387198_E38" } ] }, { "id": "PMID-11387198_E14", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1065, 1071 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11387198_E10" }, { "role": "Theme", "ref_id": "PMID-11387198_E37" } ] }, { "id": "PMID-11387198_E15", "type": "Negative_regulation", "trigger": { "text": [ "defense" ], "offsets": [ [ 1340, 1347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11387198_T49" } ] }, { "id": "PMID-11387198_E16", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 118, 128 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 217, 227 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 237, 247 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 308, 320 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 643, 655 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 882, 892 ] ] }, "arguments": [] }, { "id": "PMID-11387198_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 969, 981 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-11387198_T30" } ] }, { "id": "PMID-11387198_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1211, 1223 ] ] }, "arguments": [] } ]

[ { "id": "PMID-11387198_1", "entity_ids": [ "PMID-11387198_T8", "PMID-11387198_T9" ] } ]

[]

[ { "id": "PMID-18194650__text", "type": "abstract", "text": [ "Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.\n\nVascular endothelial growth factor (VEGF) and Angiopoietin 1 (Ang1) are both potent proangiogenic factors, but, whereas VEGF causes vascular permeability, Ang1 stabilizes blood vessels and protects them from VEGF-induced plasma leakage. The antivascular permeability mechanisms deployed by Ang1 are still undefined. Here, we demonstrate that Ang1 halts the ability of VEGF to induce the phosphorylation-dependent redistribution of the adhesion molecule VE-cadherin, thereby rescuing the endothelial barrier function. Ang1 inhibits the activation of Src by VEGF, the most upstream component of the pathway linking VEGF receptors to VE-cadherin internalization. Indeed, Ang1 promotes the activation of mDia through RhoA, resulting in the association of mDia with Src. This ultimately deprives VEGF receptors of an essential molecule required for promoting the disruption of endothelial cell-cell contacts and paracellular permeability.\n" ], "offsets": [ [ 0, 1031 ] ] } ]

[ { "id": "PMID-18194650_T1", "type": "Gene_or_gene_product", "text": [ "Angiopoietin-1" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "PMID-18194650_T2", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "PMID-18194650_T3", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 78, 81 ] ], "normalized": [] }, { "id": "PMID-18194650_T4", "type": "Gene_or_gene_product", "text": [ "mDia" ], "offsets": [ [ 90, 94 ] ], "normalized": [] }, { "id": "PMID-18194650_T5", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 97, 131 ] ], "normalized": [] }, { "id": "PMID-18194650_T6", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 133, 137 ] ], "normalized": [] }, { "id": "PMID-18194650_T7", "type": "Gene_or_gene_product", "text": [ "Angiopoietin 1" ], "offsets": [ [ 143, 157 ] ], "normalized": [] }, { "id": "PMID-18194650_T8", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 159, 163 ] ], "normalized": [] }, { "id": "PMID-18194650_T11", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 217, 221 ] ], "normalized": [] }, { "id": "PMID-18194650_T12", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 252, 256 ] ], "normalized": [] }, { "id": "PMID-18194650_T13", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 268, 281 ] ], "normalized": [] }, { "id": "PMID-18194650_T14", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 305, 309 ] ], "normalized": [] }, { "id": "PMID-18194650_T15", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 387, 391 ] ], "normalized": [] }, { "id": "PMID-18194650_T16", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-18194650_T18", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 465, 469 ] ], "normalized": [] }, { "id": "PMID-18194650_T20", "type": "Gene_or_gene_product", "text": [ "VE-cadherin" ], "offsets": [ [ 550, 561 ] ], "normalized": [] }, { "id": "PMID-18194650_T22", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "PMID-18194650_T24", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 646, 649 ] ], "normalized": [] }, { "id": "PMID-18194650_T25", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "PMID-18194650_T26", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 710, 714 ] ], "normalized": [] }, { "id": "PMID-18194650_T28", "type": "Gene_or_gene_product", "text": [ "VE-cadherin" ], "offsets": [ [ 728, 739 ] ], "normalized": [] }, { "id": "PMID-18194650_T30", "type": "Gene_or_gene_product", "text": [ "Ang1" ], "offsets": [ [ 765, 769 ] ], "normalized": [] }, { "id": "PMID-18194650_T32", "type": "Gene_or_gene_product", "text": [ "mDia" ], "offsets": [ [ 797, 801 ] ], "normalized": [] }, { "id": "PMID-18194650_T33", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "PMID-18194650_T35", "type": "Gene_or_gene_product", "text": [ "mDia" ], "offsets": [ [ 848, 852 ] ], "normalized": [] }, { "id": "PMID-18194650_T36", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 858, 861 ] ], "normalized": [] }, { "id": "PMID-18194650_T38", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 888, 892 ] ], "normalized": [] }, { "id": "PMID-18194650_T42", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 969, 980 ] ], "normalized": [] }, { "id": "PMID-18194650_T9", "type": "Organism_substance", "text": [ "plasma" ], "offsets": [ [ 318, 324 ] ], "normalized": [] }, { "id": "PMID-18194650_T43", "type": "Tissue", "text": [ "endothelial" ], "offsets": [ [ 37, 48 ] ], "normalized": [] }, { "id": "PMID-18194650_T44", "type": "Tissue", "text": [ "endothelial" ], "offsets": [ [ 584, 595 ] ], "normalized": [] } ]

[ { "id": "PMID-18194650_E17", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 473, 479 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E19" }, { "role": "Cause", "ref_id": "PMID-18194650_T18" } ] }, { "id": "PMID-18194650_E19", "type": "Localization", "trigger": { "text": [ "redistribution" ], "offsets": [ [ 510, 524 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T20" } ] }, { "id": "PMID-18194650_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 619, 627 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E23" }, { "role": "Cause", "ref_id": "PMID-18194650_T22" } ] }, { "id": "PMID-18194650_E23", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 632, 642 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T24" }, { "role": "Cause", "ref_id": "PMID-18194650_T25" } ] }, { "id": "PMID-18194650_E27", "type": "Localization", "trigger": { "text": [ "internalization" ], "offsets": [ [ 740, 755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T28" } ] }, { "id": "PMID-18194650_E29", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 770, 778 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_E11" }, { "role": "Theme", "ref_id": "PMID-18194650_E31" } ] }, { "id": "PMID-18194650_E31", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 783, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T32" } ] }, { "id": "PMID-18194650_E34", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 833, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T35" }, { "role": "Theme", "ref_id": "PMID-18194650_T36" } ] }, { "id": "PMID-18194650_E39", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 941, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E40" } ] }, { "id": "PMID-18194650_E40", "type": "Negative_regulation", "trigger": { "text": [ "disruption" ], "offsets": [ [ 955, 965 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E41" } ] }, { "id": "PMID-18194650_E41", "type": "Binding", "trigger": { "text": [ "cell-cell contacts" ], "offsets": [ [ 981, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T42" } ] }, { "id": "PMID-18194650_E1", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 15, 23 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_E3" }, { "role": "Theme", "ref_id": "PMID-18194650_E2" } ] }, { "id": "PMID-18194650_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 29, 36 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T43" }, { "role": "Cause", "ref_id": "PMID-18194650_T2" } ] }, { "id": "PMID-18194650_E3", "type": "Negative_regulation", "trigger": { "text": [ "sequestering" ], "offsets": [ [ 65, 77 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T3" }, { "role": "Cause", "ref_id": "PMID-18194650_E4" } ] }, { "id": "PMID-18194650_E4", "type": "Regulation", "trigger": { "text": [ "sequestering" ], "offsets": [ [ 65, 77 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T4" }, { "role": "Cause", "ref_id": "PMID-18194650_T1" } ] }, { "id": "PMID-18194650_E5", "type": "Negative_regulation", "trigger": { "text": [ "protects" ], "offsets": [ [ 286, 294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E7" }, { "role": "Cause", "ref_id": "PMID-18194650_T12" } ] }, { "id": "PMID-18194650_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 310, 317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E7" }, { "role": "Cause", "ref_id": "PMID-18194650_T14" } ] }, { "id": "PMID-18194650_E7", "type": "Localization", "trigger": { "text": [ "leakage" ], "offsets": [ [ 325, 332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T9" } ] }, { "id": "PMID-18194650_E8", "type": "Negative_regulation", "trigger": { "text": [ "halts" ], "offsets": [ [ 444, 449 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E17" }, { "role": "Cause", "ref_id": "PMID-18194650_T16" } ] }, { "id": "PMID-18194650_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 484, 499 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_T20" } ] }, { "id": "PMID-18194650_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 500, 509 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_E9" }, { "role": "Theme", "ref_id": "PMID-18194650_E19" } ] }, { "id": "PMID-18194650_E11", "type": "Regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 770, 778 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_T30" }, { "role": "Theme", "ref_id": "PMID-18194650_T33" } ] }, { "id": "PMID-18194650_E12", "type": "Positive_regulation", "trigger": { "text": [ "resulting" ], "offsets": [ [ 816, 825 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_E29" }, { "role": "Theme", "ref_id": "PMID-18194650_E34" } ] }, { "id": "PMID-18194650_E13", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 928, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18194650_E39" } ] }, { "id": "PMID-18194650_E14", "type": "Regulation", "trigger": { "text": [ "stabilizes" ], "offsets": [ [ 257, 267 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18194650_T12" }, { "role": "Theme", "ref_id": "PMID-18194650_T13" } ] }, { "id": "PMID-18194650_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 184, 194 ] ] }, "arguments": [] } ]

[ { "id": "PMID-18194650_1", "entity_ids": [ "PMID-18194650_T5", "PMID-18194650_T6" ] }, { "id": "PMID-18194650_2", "entity_ids": [ "PMID-18194650_T7", "PMID-18194650_T8" ] } ]

[]

[ { "id": "PMID-17608264__text", "type": "abstract", "text": [ "An assay to measure angiogenesis in human fat tissue.\n\nBACKGROUND: Inhibition of angiogenesis reverses rodent obesity. A validated assay in human fat tissue is needed to study the role of angiogenesis in human obesity. METHODS: Human fat tissue fragments from surgery were placed in 96-well plates, embedded in fibrin thrombin clot and overlaid with cell culture media containing 20% fetal bovine serum. After 15 days, the clots were examined by histology and electron microscopy. The effect of taxol, cobalt chloride and a heparin-steroid combination was tested in the fat tissue assay and compared to the validated human placental vein angiogenesis model (HPVAM). RESULTS: Blood vessels initiated growth and elongated from the fat tissue fragments over 15 days. Presence of blood vessels was confirmed with histology and electron microscopy. Taxol at 10(-6) and 10(-7) M completely inhibited angiogenesis, while Taxol 10(-8) and 10(-9) M and the heparin-steroid partially inhibited angiogenesis. The response to taxol and heparin-steroid was similar to that of the HPVAM, a validated angiogenesis assay. Cobalt chloride, a stimulator of vascular endothelial growth factor (VEGF) stimulated angiogenesis initiation at 10(-9) M in fat tissue and the HPVAM, but at 10(-10) M blood vessel growth was stimulated only in the fat assay. CONCLUSION: This angiogenesis assay based on human fat tissue uses three-dimensionally intact human tissue. The vessels are derived from quiescient vessels within the fat. These properties allow the angiogenic switch to be evaluated in an in vitro setting. The angiogenic response of fat tissue is not identical to placental tissue. This assay allows exploration of angiogenesis in fat tissue.\n" ], "offsets": [ [ 0, 1726 ] ] } ]

[ { "id": "PMID-17608264_T3", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 42, 52 ] ], "normalized": [] }, { "id": "PMID-17608264_T5", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 146, 156 ] ], "normalized": [] }, { "id": "PMID-17608264_T7", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 234, 244 ] ], "normalized": [] }, { "id": "PMID-17608264_T8", "type": "Organism_substance", "text": [ "clot" ], "offsets": [ [ 327, 331 ] ], "normalized": [] }, { "id": "PMID-17608264_T9", "type": "Gene_or_gene_product", "text": [ "fibrin" ], "offsets": [ [ 311, 317 ] ], "normalized": [] }, { "id": "PMID-17608264_T10", "type": "Gene_or_gene_product", "text": [ "thrombin" ], "offsets": [ [ 318, 326 ] ], "normalized": [] }, { "id": "PMID-17608264_T11", "type": "Organism_substance", "text": [ "clots" ], "offsets": [ [ 423, 428 ] ], "normalized": [] }, { "id": "PMID-17608264_T12", "type": "Drug_or_compound", "text": [ "taxol" ], "offsets": [ [ 495, 500 ] ], "normalized": [] }, { "id": "PMID-17608264_T13", "type": "Drug_or_compound", "text": [ "cobalt chloride" ], "offsets": [ [ 502, 517 ] ], "normalized": [] }, { "id": "PMID-17608264_T14", "type": "Drug_or_compound", "text": [ "heparin-steroid" ], "offsets": [ [ 524, 539 ] ], "normalized": [] }, { "id": "PMID-17608264_T15", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 570, 580 ] ], "normalized": [] }, { "id": "PMID-17608264_T17", "type": "Multi-tissue_structure", "text": [ "placental vein" ], "offsets": [ [ 623, 637 ] ], "normalized": [] }, { "id": "PMID-17608264_T21", "type": "Multi-tissue_structure", "text": [ "Blood vessels" ], "offsets": [ [ 675, 688 ] ], "normalized": [] }, { "id": "PMID-17608264_T22", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 729, 739 ] ], "normalized": [] }, { "id": "PMID-17608264_T23", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 776, 789 ] ], "normalized": [] }, { "id": "PMID-17608264_T24", "type": "Drug_or_compound", "text": [ "Taxol" ], "offsets": [ [ 844, 849 ] ], "normalized": [] }, { "id": "PMID-17608264_T27", "type": "Drug_or_compound", "text": [ "Taxol" ], "offsets": [ [ 914, 919 ] ], "normalized": [] }, { "id": "PMID-17608264_T28", "type": "Drug_or_compound", "text": [ "heparin-steroid" ], "offsets": [ [ 948, 963 ] ], "normalized": [] }, { "id": "PMID-17608264_T31", "type": "Drug_or_compound", "text": [ "taxol" ], "offsets": [ [ 1014, 1019 ] ], "normalized": [] }, { "id": "PMID-17608264_T32", "type": "Drug_or_compound", "text": [ "heparin-steroid" ], "offsets": [ [ 1024, 1039 ] ], "normalized": [] }, { "id": "PMID-17608264_T36", "type": "Drug_or_compound", "text": [ "Cobalt chloride" ], "offsets": [ [ 1106, 1121 ] ], "normalized": [] }, { "id": "PMID-17608264_T37", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1139, 1173 ] ], "normalized": [] }, { "id": "PMID-17608264_T38", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1175, 1179 ] ], "normalized": [] }, { "id": "PMID-17608264_T41", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 1231, 1241 ] ], "normalized": [] }, { "id": "PMID-17608264_T44", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 1274, 1286 ] ], "normalized": [] }, { "id": "PMID-17608264_T45", "type": "Tissue", "text": [ "fat" ], "offsets": [ [ 1321, 1324 ] ], "normalized": [] }, { "id": "PMID-17608264_T47", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 1383, 1393 ] ], "normalized": [] }, { "id": "PMID-17608264_T48", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 1444, 1451 ] ], "normalized": [] }, { "id": "PMID-17608264_T49", "type": "Multi-tissue_structure", "text": [ "quiescient vessels" ], "offsets": [ [ 1469, 1487 ] ], "normalized": [] }, { "id": "PMID-17608264_T50", "type": "Tissue", "text": [ "fat" ], "offsets": [ [ 1499, 1502 ] ], "normalized": [] }, { "id": "PMID-17608264_T53", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 1616, 1626 ] ], "normalized": [] }, { "id": "PMID-17608264_T55", "type": "Tissue", "text": [ "placental tissue" ], "offsets": [ [ 1647, 1663 ] ], "normalized": [] }, { "id": "PMID-17608264_T58", "type": "Tissue", "text": [ "fat tissue" ], "offsets": [ [ 1714, 1724 ] ], "normalized": [] }, { "id": "PMID-17608264_T1", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 397, 402 ] ], "normalized": [] }, { "id": "PMID-17608264_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 36, 41 ] ], "normalized": [] }, { "id": "PMID-17608264_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 140, 145 ] ], "normalized": [] }, { "id": "PMID-17608264_T1002", "type": "Organism", "text": [ "human" ], "offsets": [ [ 204, 209 ] ], "normalized": [] }, { "id": "PMID-17608264_T1003", "type": "Organism", "text": [ "Human" ], "offsets": [ [ 228, 233 ] ], "normalized": [] }, { "id": "PMID-17608264_T1004", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 390, 396 ] ], "normalized": [] }, { "id": "PMID-17608264_T1005", "type": "Organism", "text": [ "human" ], "offsets": [ [ 617, 622 ] ], "normalized": [] }, { "id": "PMID-17608264_T1006", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1377, 1382 ] ], "normalized": [] }, { "id": "PMID-17608264_T1007", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1426, 1431 ] ], "normalized": [] }, { "id": "PMID-17608264_T66", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 1432, 1438 ] ], "normalized": [] }, { "id": "PMID-17608264_T67", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 350, 354 ] ], "normalized": [] } ]

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"PMID-17608264_T8" } ] }, { "id": "PMID-17608264_E6", "type": "Planned_process", "trigger": { "text": [ "overlaid" ], "offsets": [ [ 336, 344 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17608264_T1" }, { "role": "Theme", "ref_id": "PMID-17608264_T7" } ] }, { "id": "PMID-17608264_E7", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 699, 705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_T21" } ] }, { "id": "PMID-17608264_E8", "type": "Positive_regulation", "trigger": { "text": [ "initiated" ], "offsets": [ [ 689, 698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E7" } ] }, { "id": "PMID-17608264_E9", "type": "Growth", "trigger": { "text": [ "elongated" ], "offsets": [ [ 710, 719 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_T21" } ] }, { "id": "PMID-17608264_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 884, 893 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17608264_T24" }, { "role": "Theme", "ref_id": "PMID-17608264_E25" } ] }, { "id": "PMID-17608264_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 974, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E26" }, { "role": "Cause", "ref_id": "PMID-17608264_T28" } ] }, { "id": "PMID-17608264_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 974, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E26" }, { "role": "Cause", "ref_id": "PMID-17608264_T27" } ] }, { "id": "PMID-17608264_E14", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1181, 1191 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17608264_T36" }, { "role": "Theme", "ref_id": "PMID-17608264_E15" } ] }, { "id": "PMID-17608264_E15", "type": "Positive_regulation", "trigger": { "text": [ "initiation" ], "offsets": [ [ 1205, 1215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E28" } ] }, { "id": "PMID-17608264_E16", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 1287, 1293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_T44" } ] }, { "id": "PMID-17608264_E17", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1298, 1308 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E16" }, { "role": "Cause", "ref_id": "PMID-17608264_T36" } ] }, { "id": "PMID-17608264_E19", "type": "Positive_regulation", "trigger": { "text": [ "exploration" ], "offsets": [ [ 1683, 1694 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_E32" } ] }, { "id": "PMID-17608264_E20", "type": "Planned_process", "trigger": { "text": [ "culture" ], "offsets": [ [ 355, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_T67" } ] }, { "id": "PMID-17608264_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 20, 32 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17608264_T3" } ] }, { "id": "PMID-17608264_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 81, 93 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 188, 200 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 638, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17608264_T17" } ] }, { "id": "PMID-17608264_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 894, 906 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 984, 996 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E27", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1086, 1098 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1192, 1204 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E29", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1349, 1361 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1531, 1541 ] ] }, "arguments": [] }, { "id": "PMID-17608264_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1593, 1603 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17608264_T53" } ] }, { "id": "PMID-17608264_E32", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1698, 1710 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17608264_T58" } ] }, { "id": "PMID-17608264_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1593, 1603 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17608264_T55" } ] } ]

[ { "id": "PMID-17608264_1", "entity_ids": [ "PMID-17608264_T37", "PMID-17608264_T38" ] } ]

[]

[ { "id": "PMID-10417401__text", "type": "abstract", "text": [ "Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial growth factor.\n\nA marked coronary angiogenesis is known to occur with chronic bradycardia. We tested the hypothesis that vascular endothelial growth factor (VEGF), an endothelial cell mitogen and a major regulator of angiogenesis, is upregulated in response to low heart rate and consequential increased stroke volume. Bradycardia was induced in rats by administering the bradycardic drug alinidine (3 mg/kg body weight) twice daily. Heart rate decreased by 32% for 20 to 40 minutes after injection and was chronically reduced by 10%, 14%, and 18.5% after 1, 2, and 3 weeks of treatment, respectively. Arterial pressure and cardiac output were unchanged. Left ventricular capillary length density (mm/mm(3)) increased gradually with alinidine administration; a 15% increase after 2 weeks and a 40% increase after 3 weeks of alinidine treatment were documented. Left ventricular weight, body weight, and their ratio were not significantly altered by alinidine treatment. After 1 week of treatment, before an increase in capillary length density, VEGF mRNA increased greater than 2-fold and then declined to control levels after 3 weeks of treatment. VEGF protein was higher in alinidine-treated rats than in controls after 2 weeks and increased further after 3 weeks of treatment. Injection of VEGF-neutralizing antibodies over a 2-week period completely blocked alinidine-stimulated angiogenesis. In contrast, bFGF mRNA was not altered by alinidine treatment. These data suggest that VEGF plays a key role in the angiogenic response that occurs with chronic bradycardia. The mechanism underlying this VEGF-associated angiogenesis may be an increase in stretch due to enhanced diastolic filling.\n" ], "offsets": [ [ 0, 1775 ] ] } ]

[ { "id": "PMID-10417401_T3", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 58, 92 ] ], "normalized": [] }, { "id": "PMID-10417401_T6", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 200, 234 ] ], "normalized": [] }, { "id": "PMID-10417401_T7", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 236, 240 ] ], "normalized": [] }, { "id": "PMID-10417401_T8", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 246, 262 ] ], "normalized": [] }, { "id": "PMID-10417401_T12", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 468, 477 ] ], "normalized": [] }, { "id": "PMID-10417401_T15", "type": "Tissue", "text": [ "Left ventricular capillary" ], "offsets": [ [ 734, 760 ] ], "normalized": [] }, { "id": "PMID-10417401_T17", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 812, 821 ] ], "normalized": [] }, { "id": "PMID-10417401_T19", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 903, 912 ] ], "normalized": [] }, { "id": "PMID-10417401_T20", "type": "Multi-tissue_structure", "text": [ "Left ventricular" ], "offsets": [ [ 940, 956 ] ], "normalized": [] }, { "id": "PMID-10417401_T22", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 1028, 1037 ] ], "normalized": [] }, { "id": "PMID-10417401_T25", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 1098, 1107 ] ], "normalized": [] }, { "id": "PMID-10417401_T27", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1124, 1128 ] ], "normalized": [] }, { "id": "PMID-10417401_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "PMID-10417401_T30", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 1256, 1265 ] ], "normalized": [] }, { "id": "PMID-10417401_T32", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1373, 1377 ] ], "normalized": [] }, { "id": "PMID-10417401_T34", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 1442, 1451 ] ], "normalized": [] }, { "id": "PMID-10417401_T37", "type": "Gene_or_gene_product", "text": [ "bFGF" ], "offsets": [ [ 1490, 1494 ] ], "normalized": [] }, { "id": "PMID-10417401_T39", "type": "Drug_or_compound", "text": [ "alinidine" ], "offsets": [ [ 1519, 1528 ] ], "normalized": [] }, { "id": "PMID-10417401_T40", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1564, 1568 ] ], "normalized": [] }, { "id": "PMID-10417401_T43", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1681, 1685 ] ], "normalized": [] }, { "id": "PMID-10417401_T2", "type": "Multi-tissue_structure", "text": [ "Arterial" ], "offsets": [ [ 681, 689 ] ], "normalized": [] }, { "id": "PMID-10417401_T9", "type": "Organ", "text": [ "heart" ], "offsets": [ [ 344, 349 ] ], "normalized": [] }, { "id": "PMID-10417401_T1000", "type": "Organism", "text": [ "rats" ], "offsets": [ [ 425, 429 ] ], "normalized": [] }, { "id": "PMID-10417401_T1001", "type": "Organism", "text": [ "rats" ], "offsets": [ [ 1274, 1278 ] ], "normalized": [] }, { "id": "PMID-10417401_T48", "type": "Gene_or_gene_product", "text": [ "VEGF-neutralizing antibodies" ], "offsets": [ [ 1373, 1401 ] ], "normalized": [] }, { "id": "PMID-10417401_T54", "type": "Multi-tissue_structure", "text": [ "coronary" ], "offsets": [ [ 20, 28 ] ], "normalized": [] }, { "id": "PMID-10417401_T55", "type": "Multi-tissue_structure", "text": [ "coronary" ], "offsets": [ [ 104, 112 ] ], "normalized": [] } ]

[ { "id": "PMID-10417401_E5", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 313, 324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T6" } ] }, { "id": "PMID-10417401_E11", "type": "Planned_process", "trigger": { "text": [ "administering" ], "offsets": [ [ 433, 446 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T12" }, { "role": "Theme", "ref_id": "PMID-10417401_T1000" } ] }, { "id": "PMID-10417401_E13", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 787, 796 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T15" }, { "role": "Cause", "ref_id": "PMID-10417401_E16" } ] }, { "id": "PMID-10417401_E16", "type": "Planned_process", "trigger": { "text": [ "administration" ], "offsets": [ [ 822, 836 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T17" } ] }, { "id": "PMID-10417401_E18", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 913, 922 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T19" } ] }, { "id": "PMID-10417401_E21", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1038, 1047 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T22" } ] }, { "id": "PMID-10417401_E26", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1134, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T27" } ] }, { "id": "PMID-10417401_E29", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1266, 1273 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T30" }, { "role": "Theme", "ref_id": "PMID-10417401_T1001" } ] }, { "id": "PMID-10417401_E31", "type": "Planned_process", "trigger": { "text": [ "Injection" ], "offsets": [ [ 1360, 1369 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T48" } ] }, { "id": "PMID-10417401_E38", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1529, 1538 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10417401_T39" } ] }, { "id": "PMID-10417401_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 12, 19 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_E19" } ] }, { "id": "PMID-10417401_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 45, 54 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_E19" }, { "role": "Cause", "ref_id": "PMID-10417401_T3" } ] }, { "id": "PMID-10417401_E3", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 844, 852 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T15" } ] }, { "id": "PMID-10417401_E4", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 877, 885 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T15" } ] }, { "id": "PMID-10417401_E6", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1086, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T25" } ] }, { "id": "PMID-10417401_E7", "type": "Negative_regulation", "trigger": { "text": [ "declined" ], "offsets": [ [ 1174, 1182 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T27" } ] }, { "id": "PMID-10417401_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1314, 1323 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T28" } ] }, { "id": "PMID-10417401_E9", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1434, 1441 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10417401_E31" }, { "role": "Theme", "ref_id": "PMID-10417401_E23" } ] }, { "id": "PMID-10417401_E10", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1452, 1462 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10417401_T34" }, { "role": "Theme", "ref_id": "PMID-10417401_E23" } ] }, { "id": "PMID-10417401_E12", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 1508, 1515 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10417401_E38" }, { "role": "Theme", "ref_id": "PMID-10417401_T37" } ] }, { "id": "PMID-10417401_E15", "type": "Regulation", "trigger": { "text": [ "plays a key role" ], "offsets": [ [ 1569, 1585 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10417401_T40" }, { "role": "Theme", "ref_id": "PMID-10417401_E25" } ] }, { "id": "PMID-10417401_E17", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 1686, 1696 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10417401_T43" }, { "role": "Theme", "ref_id": "PMID-10417401_E27" } ] }, { "id": "PMID-10417401_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 29, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T54" } ] }, { "id": "PMID-10417401_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 113, 125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10417401_T55" } ] }, { "id": "PMID-10417401_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 296, 308 ] ] }, "arguments": [] }, { "id": "PMID-10417401_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1463, 1475 ] ] }, "arguments": [] }, { "id": "PMID-10417401_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1593, 1603 ] ] }, "arguments": [] }, { "id": "PMID-10417401_E27", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1697, 1709 ] ] }, "arguments": [] } ]

[ { "id": "PMID-10417401_1", "entity_ids": [ "PMID-10417401_T6", "PMID-10417401_T7" ] } ]

[]

[ { "id": "PMID-18188789__text", "type": "abstract", "text": [ "[Photodynamic therapy in severe chronic central serous chorioretinopaty]\n\nOBJECTIVE: To determine the efficacy of Photodynamic Therapy (PDT) in chronic Central Serous Chorioretinopathy (CSC). METHODS: Patients diagnosed with chronic CSC, with clinical evidence of activity and treated with Photodynamic Therapy, are included in this report. All were assessed by a complete ophthalmological examination, including assessment of the best corrected visual acuity (BCVA) using an ETDRS chart, fluorescein and indocyanine angiography and optical coherence tomography (OCT). The main objective of the study was to determine the mean visual acuity change. RESULTS: 11 eyes of 11 patients were included in the study, which had a mean follow-up period of 11 months. The mean BCVA increased from 20/76 to 20/64. 35% of eyes improved their BCVA by 2 lines or more, 45% remained stable and 18% lost 2 lines or more. Choroidal hyperpermeability was reduced in every case. Neurosensorial retinal detachment decreased in 80% of cases. Only one eye received a second PDT treatment due to choroidal neovascularization. An increase of atrophy over the Retinal Pigment Epithelium (RPE) was observed in another patient. CONCLUSIONS: PDT can reduce the clinical signs of activity, such as choroidal hyperpermeability or neurosensorial retinal detachment, in patients affected by chronic CSC. However, the increase in visual acuity is variable, probably due to the extent of RPE damage.\n" ], "offsets": [ [ 0, 1465 ] ] } ]

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[ { "id": "PMID-18188789_1", "entity_ids": [ "PMID-18188789_T8", "PMID-18188789_T9" ] } ]

[]

[ { "id": "PMID-18852899__text", "type": "abstract", "text": [ "M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo.\n\nBACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo.\n" ], "offsets": [ [ 0, 1810 ] ] } ]

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[]

[]

[ { "id": "PMID-15029197__text", "type": "abstract", "text": [ "The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis.\n\nGliomas are the most common primary tumours of the central nervous system, with nearly 15,000 diagnosed annually in the United States and a lethality approaching 80% within the first year of glioblastoma diagnosis. The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression; however, the precise molecular mechanisms underlying the regulation of brain tumour growth and angiogenesis remain unresolved. Here we report that a candidate tumour suppressor gene, ING4, is involved in regulating brain tumour growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours. We show that ING4 physically interacts with p65 (RelA) subunit of nuclear factor NF-kappaB, and that ING4 regulates brain tumour angiogenesis through transcriptional repression of NF-kappaB-responsive genes. These results indicate that ING4 has an important role in brain tumour pathogenesis.\n" ], "offsets": [ [ 0, 1350 ] ] } ]

[ { "id": "PMID-15029197_T1", "type": "Pathological_formation", "text": [ "tumour" ], "offsets": [ [ 14, 20 ] ], "normalized": [] }, { "id": "PMID-15029197_T2", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 40, 44 ] ], "normalized": [] }, { "id": "PMID-15029197_T6", "type": "Pathological_formation", "text": [ "brain tumour" ], "offsets": [ [ 55, 67 ] ], "normalized": [] }, { "id": "PMID-15029197_T9", "type": "Pathological_formation", "text": [ "Gliomas" ], "offsets": [ [ 94, 101 ] ], "normalized": [] }, { "id": "PMID-15029197_T10", "type": "Pathological_formation", "text": [ "tumours" ], "offsets": [ [ 130, 137 ] ], "normalized": [] }, { "id": "PMID-15029197_T11", "type": "Anatomical_system", "text": [ "central nervous system" ], "offsets": [ [ 145, 167 ] ], "normalized": [] }, { "id": "PMID-15029197_T12", "type": "Pathological_formation", "text": [ "glioblastoma" ], "offsets": [ [ 285, 297 ] ], "normalized": [] }, { "id": "PMID-15029197_T14", "type": "Pathological_formation", "text": [ "glioblastomas" ], "offsets": [ [ 349, 362 ] ], "normalized": [] }, { "id": "PMID-15029197_T16", "type": "Pathological_formation", "text": [ "brain tumour" ], "offsets": [ [ 497, 509 ] ], "normalized": [] }, { "id": "PMID-15029197_T19", "type": "Pathological_formation", "text": [ "tumour" ], "offsets": [ [ 585, 591 ] ], "normalized": [] }, { "id": "PMID-15029197_T20", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 609, 613 ] ], "normalized": [] }, { "id": "PMID-15029197_T23", "type": "Pathological_formation", "text": [ "brain tumour" ], "offsets": [ [ 641, 653 ] ], "normalized": [] }, { "id": "PMID-15029197_T27", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 693, 697 ] ], "normalized": [] }, { "id": "PMID-15029197_T28", "type": "Pathological_formation", "text": [ "gliomas" ], "offsets": [ [ 726, 733 ] ], "normalized": [] }, { "id": "PMID-15029197_T29", "type": "Tissue", "text": [ "brain tissue" ], "offsets": [ [ 764, 776 ] ], "normalized": [] }, { "id": "PMID-15029197_T30", "type": "Pathological_formation", "text": [ "tumours" ], "offsets": [ [ 869, 876 ] ], "normalized": [] }, { "id": "PMID-15029197_T32", "type": "Pathological_formation", "text": [ "glioblastoma U87MG" ], "offsets": [ [ 907, 925 ] ], "normalized": [] }, { "id": "PMID-15029197_T35", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 961, 965 ] ], "normalized": [] }, { "id": "PMID-15029197_T36", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1009, 1017 ] ], "normalized": [] }, { "id": "PMID-15029197_T37", "type": "Pathological_formation", "text": [ "tumours" ], "offsets": [ [ 1048, 1055 ] ], "normalized": [] }, { "id": "PMID-15029197_T39", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 1070, 1074 ] ], "normalized": [] }, { "id": "PMID-15029197_T40", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "PMID-15029197_T41", "type": "Gene_or_gene_product", "text": [ "RelA" ], "offsets": [ [ 1106, 1110 ] ], "normalized": [] }, { "id": "PMID-15029197_T42", "type": "Gene_or_gene_product", "text": [ "NF-kappaB" ], "offsets": [ [ 1138, 1147 ] ], "normalized": [] }, { "id": "PMID-15029197_T43", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 1158, 1162 ] ], "normalized": [] }, { "id": "PMID-15029197_T45", "type": "Pathological_formation", "text": [ "brain tumour" ], "offsets": [ [ 1173, 1185 ] ], "normalized": [] }, { "id": "PMID-15029197_T50", "type": "Gene_or_gene_product", "text": [ "ING4" ], "offsets": [ [ 1293, 1297 ] ], "normalized": [] }, { "id": "PMID-15029197_T51", "type": "Pathological_formation", "text": [ "brain tumour" ], "offsets": [ [ 1323, 1335 ] ], "normalized": [] }, { "id": "PMID-15029197_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 758, 763 ] ], "normalized": [] }, { "id": "PMID-15029197_T1001", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 881, 885 ] ], "normalized": [] }, { "id": "PMID-15029197_T1002", "type": "Organism", "text": [ "human" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-15029197_T4", "type": "Gene_or_gene_product", "text": [ "NF-kappaB" ], "offsets": [ [ 1237, 1246 ] ], "normalized": [] } ]

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"PMID-15029197_E33", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 937, 946 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E34" } ] }, { "id": "PMID-15029197_E34", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 947, 957 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T35" } ] }, { "id": "PMID-15029197_E1", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 45, 54 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15029197_T2" }, { "role": "Theme", "ref_id": "PMID-15029197_E20" } ] }, { "id": "PMID-15029197_E2", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 320, 329 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E21" } ] }, { "id": "PMID-15029197_E4", "type": "Development", "trigger": { "text": [ "malignant progression" ], "offsets": [ [ 403, 424 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T14" } ] }, { "id": "PMID-15029197_E6", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 483, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E15" } ] }, { "id": "PMID-15029197_E7", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 483, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E23" } ] }, { "id": "PMID-15029197_E8", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 630, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E22" } ] }, { "id": "PMID-15029197_E9", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 630, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E24" } ] }, { "id": "PMID-15029197_E10", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 715, 722 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15029197_E26" }, { "role": "Theme", "ref_id": "PMID-15029197_T28" } ] }, { "id": "PMID-15029197_E11", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 796, 805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T28" } ] }, { "id": "PMID-15029197_E12", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 826, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T30" } ] }, { "id": "PMID-15029197_E13", "type": "Growth", "trigger": { "text": [ "grow" ], "offsets": [ [ 967, 971 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T36" } ] }, { "id": "PMID-15029197_E14", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T39" }, { "role": "Theme", "ref_id": "PMID-15029197_T40" } ] }, { "id": "PMID-15029197_E16", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1163, 1172 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_E25" } ] }, { "id": "PMID-15029197_E17", "type": "Regulation", "trigger": { "text": [ "has an important role" ], "offsets": [ [ 1298, 1319 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15029197_T50" }, { "role": "Theme", "ref_id": "PMID-15029197_E18" } ] }, { "id": "PMID-15029197_E18", "type": "Development", "trigger": { "text": [ "pathogenesis" ], "offsets": [ [ 1336, 1348 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T51" } ] }, { "id": "PMID-15029197_E19", "type": "Negative_regulation", "trigger": { "text": [ "suppressor" ], "offsets": [ [ 21, 31 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15029197_T1" }, { "role": "Cause", "ref_id": "PMID-15029197_T2" } ] }, { "id": "PMID-15029197_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 79, 91 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15029197_T6" } ] }, { "id": "PMID-15029197_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 333, 345 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15029197_T14" } ] }, { "id": "PMID-15029197_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 521, 533 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15029197_T16" } ] }, { "id": "PMID-15029197_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 665, 677 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15029197_T23" } ] }, { "id": "PMID-15029197_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1186, 1198 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15029197_T45" } ] } ]

[ { "id": "PMID-15029197_1", "entity_ids": [ "PMID-15029197_T40", "PMID-15029197_T41" ] } ]

[]

[ { "id": "PMID-15723619__text", "type": "abstract", "text": [ "Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC).\n\nHormone-refractory prostate cancer (HRPC) is an inevitable evolution of prostate carcinogenesis, through which the normal dependence on hormones for growth and survival is bypassed. Although advances in terms of symptoms palliation and quality of life improvement have been addressed with current treatment options, innovative approaches are needed to improve survival rates. A thorough understanding of HRPC-associated molecular pathways and mechanisms of resistance are a prerequisite for novel potential therapeutic interventions. Preclinical and early clinical studies are ongoing to evaluate new therapies that target specific molecular entities. Agents under development include growth factor receptor inhibitors, small molecules targeting signal transduction pathways, apoptosis and cell-cycle regulators, angiogenesis and metastasis inhibitors, differentiation agents, telomerase inactivators, and epigenetic therapeutics. Incorporation of these agents into existing treatment regimens will guide us in the development of a multidisciplinary treatment strategy of HRPC. This article critically reviews published data on new biological agents that are being tested in HRPC clinical trials, highlights ongoing research and considers the future perspectives of this new class of agents.\n" ], "offsets": [ [ 0, 1381 ] ] } ]

[ { "id": "PMID-15723619_T1", "type": "Pathological_formation", "text": [ "hormone-refractory prostate cancer" ], "offsets": [ [ 45, 79 ] ], "normalized": [] }, { "id": "PMID-15723619_T3", "type": "Pathological_formation", "text": [ "HRPC" ], "offsets": [ [ 81, 85 ] ], "normalized": [] }, { "id": "PMID-15723619_T4", "type": "Pathological_formation", "text": [ "Hormone-refractory prostate cancer" ], "offsets": [ [ 89, 123 ] ], "normalized": [] }, { "id": "PMID-15723619_T6", "type": "Pathological_formation", "text": [ "HRPC" ], "offsets": [ [ 125, 129 ] ], "normalized": [] }, { "id": "PMID-15723619_T7", "type": "Organ", "text": [ "prostate" ], "offsets": [ [ 161, 169 ] ], "normalized": [] }, { "id": "PMID-15723619_T8", "type": "Pathological_formation", "text": [ "HRPC" ], "offsets": [ [ 493, 497 ] ], "normalized": [] }, { "id": "PMID-15723619_T10", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 966, 976 ] ], "normalized": [] }, { "id": "PMID-15723619_T11", "type": "Pathological_formation", "text": [ "HRPC" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "PMID-15723619_T12", "type": "Pathological_formation", "text": [ "HRPC" ], "offsets": [ [ 1264, 1268 ] ], "normalized": [] }, { "id": "PMID-15723619_T13", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 879, 883 ] ], "normalized": [] } ]

[ { "id": "PMID-15723619_E1", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 32, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15723619_T1" } ] }, { "id": "PMID-15723619_E2", "type": "Development", "trigger": { "text": [ "carcinogenesis" ], "offsets": [ [ 170, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15723619_T7" } ] }, { "id": "PMID-15723619_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 902, 914 ] ] }, "arguments": [] } ]

[ { "id": "PMID-15723619_1", "entity_ids": [ "PMID-15723619_T1", "PMID-15723619_T3" ] }, { "id": "PMID-15723619_2", "entity_ids": [ "PMID-15723619_T4", "PMID-15723619_T6" ] } ]

[]

[ { "id": "PMID-19760065__text", "type": "abstract", "text": [ "Targeting TNF for Treatment of Cancer and Autoimmunity.\n\nTumor necrosis factor-alpha (TNF-alpha) was first isolated two decades ago as a macrophageproduced protein that can effectively kill tumor cells. TNF-alpha is also an essential component of the immune system and is required for hematopoiesis, for protection from bacterial infection and for immune cell-mediated cytotoxicity. Extensive research, however, has revealed that TNF-alpha is one of the major players in tumor initiation, proliferation, invasion, angiogenesis and metastasis. The proinflammatory activities link TNF-alpha with a wide variety of autoimmune diseases, including psoriasis, inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, diabetes and ankylosing spondylitis. Systemic inhibitors of TNF such as etanercept (Enbrel) (a soluble TNF receptor) and infliximab (Remicade) and adalimumab (Humira) (anti-TNF antibodies) have been approved for the treatment inflammatory bowel disease, psoriasis and rheumatoid arthritis. These drugs, however, exhibit severe side effects and are expensive. Hence orally active blockers of TNF-alpha that are safe, efficacious and inexpensive are urgently needed. Numerous products from fruits, vegetable and traditional medicinal plants have been described which can suppress TNF expression and TNF signaling but their clinical potential is yet uncertain.\n" ], "offsets": [ [ 0, 1432 ] ] } ]

[ { "id": "PMID-19760065_T2", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 10, 13 ] ], "normalized": [] }, { "id": "PMID-19760065_T3", "type": "Gene_or_gene_product", "text": [ "Tumor necrosis factor-alpha" ], "offsets": [ [ 57, 84 ] ], "normalized": [] }, { "id": "PMID-19760065_T4", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 86, 95 ] ], "normalized": [] }, { "id": "PMID-19760065_T6", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 190, 201 ] ], "normalized": [] }, { "id": "PMID-19760065_T7", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 203, 212 ] ], "normalized": [] }, { "id": "PMID-19760065_T9", "type": "Cell", "text": [ "immune cell" ], "offsets": [ [ 348, 359 ] ], "normalized": [] }, { "id": "PMID-19760065_T10", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 430, 439 ] ], "normalized": [] }, { "id": "PMID-19760065_T17", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 471, 476 ] ], "normalized": [] }, { "id": "PMID-19760065_T19", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 579, 588 ] ], "normalized": [] }, { "id": "PMID-19760065_T20", "type": "Organ", "text": [ "bowel" ], "offsets": [ [ 667, 672 ] ], "normalized": [] }, { "id": "PMID-19760065_T21", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "PMID-19760065_T22", "type": "Drug_or_compound", "text": [ "etanercept" ], "offsets": [ [ 846, 856 ] ], "normalized": [] }, { "id": "PMID-19760065_T23", "type": "Drug_or_compound", "text": [ "Enbrel" ], "offsets": [ [ 858, 864 ] ], "normalized": [] }, { "id": "PMID-19760065_T25", "type": "Drug_or_compound", "text": [ "infliximab" ], "offsets": [ [ 895, 905 ] ], "normalized": [] }, { "id": "PMID-19760065_T26", "type": "Drug_or_compound", "text": [ "Remicade" ], "offsets": [ [ 907, 915 ] ], "normalized": [] }, { "id": "PMID-19760065_T27", "type": "Drug_or_compound", "text": [ "adalimumab" ], "offsets": [ [ 921, 931 ] ], "normalized": [] }, { "id": "PMID-19760065_T28", "type": "Drug_or_compound", "text": [ "Humira" ], "offsets": [ [ 933, 939 ] ], "normalized": [] }, { "id": "PMID-19760065_T30", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1165, 1174 ] ], "normalized": [] }, { "id": "PMID-19760065_T34", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 1352, 1355 ] ], "normalized": [] }, { "id": "PMID-19760065_T36", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 1371, 1374 ] ], "normalized": [] }, { "id": "PMID-19760065_T11", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 877, 880 ] ], "normalized": [] }, { "id": "PMID-19760065_T37", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 947, 950 ] ], "normalized": [] }, { "id": "PMID-19760065_T38", "type": "Organ", "text": [ "bowel" ], "offsets": [ [ 1013, 1018 ] ], "normalized": [] }, { "id": "PMID-19760065_T1000", "type": "Pathological_formation", "text": [ "Cancer" ], "offsets": [ [ 31, 37 ] ], "normalized": [] }, { "id": "PMID-19760065_T29", "type": "Gene_or_gene_product", "text": [ "anti-TNF antibodies" ], "offsets": [ [ 942, 961 ] ], "normalized": [] } ]

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[ { "id": "PMID-19760065_1", "entity_ids": [ "PMID-19760065_T3", "PMID-19760065_T4" ] }, { "id": "PMID-19760065_2", "entity_ids": [ "PMID-19760065_T22", "PMID-19760065_T23" ] }, { "id": "PMID-19760065_3", "entity_ids": [ "PMID-19760065_T25", "PMID-19760065_T26" ] }, { "id": "PMID-19760065_4", "entity_ids": [ "PMID-19760065_T27", "PMID-19760065_T28" ] } ]

[]

[ { "id": "PMID-17311993__text", "type": "abstract", "text": [ "Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion.\n\nVascular development is dependent on various growth factors and certain modifiers critical for providing arterial or venous identity, interaction with the surrounding stroma and tissues, hierarchic network formation, and recruitment of pericytes. Notch receptors and ligands (Jagged and Delta-like) play a critical role in this process in addition to VEGF. Dll4 is one of the Notch ligands that regulates arterial specification and maturation events. In the current study, we have shown that loss of function by either targeted allele deletion or use of a soluble form of Dll4 extracellular domain leads to inhibition of Notch signaling, resulting in increased vascular proliferation but defective maturation. Newly forming vessels have thin caliber, a markedly reduced vessel lumen, markedly reduced pericyte recruitment, and deficient vascular perfusion. sDll4 similarly induced defective vascular response in tumor implants leading to reduced tumor growth. Interference with Dll4-Notch signaling may be particularly desirable in tumors that have highly induced Dll4-Notch pathway.\n" ], "offsets": [ [ 0, 1203 ] ] } ]

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"PMID-17311993_T20" } ] }, { "id": "PMID-17311993_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 726, 736 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E36" } ] }, { "id": "PMID-17311993_E24", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 770, 779 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E10" } ] }, { "id": "PMID-17311993_E28", "type": "Negative_regulation", "trigger": { "text": [ "defective" ], "offsets": [ [ 807, 816 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E13" } ] }, { "id": "PMID-17311993_E32", "type": "Localization", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 929, 940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T34" } ] }, { "id": "PMID-17311993_E39", "type": "Negative_regulation", "trigger": { "text": [ "defective" ], "offsets": [ [ 1000, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": 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514, 523 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17311993_T15" }, { "role": "Theme", "ref_id": "PMID-17311993_E27" } ] }, { "id": "PMID-17311993_E10", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 789, 802 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T27" } ] }, { "id": "PMID-17311993_E13", "type": "Development", "trigger": { "text": [ "maturation" ], "offsets": [ [ 817, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T27" } ] }, { "id": "PMID-17311993_E14", "type": "Development", "trigger": { "text": [ "forming" ], "offsets": [ [ 835, 842 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T30" } ] }, { "id": "PMID-17311993_E15", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 881, 888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T31" } ] }, { "id": "PMID-17311993_E16", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 912, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E32" } ] }, { "id": "PMID-17311993_E18", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 992, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E39" }, { "role": "Cause", "ref_id": "PMID-17311993_T37" } ] }, { "id": "PMID-17311993_E20", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1057, 1064 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E43" } ] }, { "id": "PMID-17311993_E22", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1046, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E43" }, { "role": "Cause", "ref_id": "PMID-17311993_E39" } ] }, { "id": "PMID-17311993_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1175, 1182 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E38" } ] }, { "id": "PMID-17311993_E27", "type": "Development", "trigger": { "text": [ "maturation" ], "offsets": [ [ 551, 561 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T66" } ] }, { "id": "PMID-17311993_E30", "type": "Development", "trigger": { "text": [ "specification" ], "offsets": [ [ 533, 546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T66" } ] }, { "id": "PMID-17311993_E31", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 514, 523 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17311993_T15" }, { "role": "Theme", "ref_id": "PMID-17311993_E30" } ] }, { "id": "PMID-17311993_E34", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 28, 37 ] ] }, "arguments": [] }, { "id": "PMID-17311993_E36", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 746, 755 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17311993_T63" } ] }, { "id": "PMID-17311993_E37", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1108, 1117 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17311993_T46" }, { "role": "Participant", "ref_id": "PMID-17311993_T64" } ] }, { "id": "PMID-17311993_E38", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17311993_T49" }, { "role": "Participant", "ref_id": "PMID-17311993_T65" } ] }, { "id": "PMID-17311993_E41", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 19, 27 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17311993_T3" }, { "role": "Theme", "ref_id": "PMID-17311993_E34" } ] }, { "id": "PMID-17311993_E5", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 325, 334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T5" } ] }, { "id": "PMID-17311993_E9", "type": "Regulation", "trigger": { "text": [ "play a critical role" ], "offsets": [ [ 418, 438 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E8" }, { "role": "Cause", "ref_id": "PMID-17311993_T60" } ] }, { "id": "PMID-17311993_E12", "type": "Regulation", "trigger": { "text": [ "play a critical role" ], "offsets": [ [ 418, 438 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_E8" }, { "role": "Cause", "ref_id": "PMID-17311993_T61" } ] }, { "id": "PMID-17311993_E25", "type": "Development", "trigger": { "text": [ "response" ], "offsets": [ [ 1019, 1027 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17311993_T41" } ] } ]

[]

[]

[ { "id": "PMID-15034302__text", "type": "abstract", "text": [ "TGFbeta1, back to the future: revisiting its role as a transforming growth factor.\n\nTGFbeta1 was initially identified in culture media from transformed cells as part of a factor that could produce a transformed phenotype in a nontransformed cell line. Subsequently this activity was separated into TGFbeta and TGFalpha an EGF receptor ligand. With the discovery that TGFbeta1 was a potent growth inhibitor of epithelial cells, and the identification of inactivating mutations within the TGFbeta1 signaling pathway in cancers it became clear that TGFbeta1 signaling is a tumor suppressor pathway for early stages of cancer. However many human carcinomas overexpress TGFbeta1 and this is associated with poor patient prognosis and increased frequency of metastasis. Similar results have been obtained with tumor cell lines and experimental animal models. Thus stage specific duality of function is the emerging paradigm for the role of TGFbeta1 in cancer. This review will focus on the evidence for TGFbeta1 as a tumor promoting and metastasis factor and examine the biological and molecular basis for these effects. It is proposed that the switch from tumor suppressor to oncogene reflects genetic or epigenetic alterations in signaling pathways in tumor cells that alter the readout from the TGFbeta1 pathway.\n" ], "offsets": [ [ 0, 1310 ] ] } ]

[ { "id": "PMID-15034302_T1", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-15034302_T2", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 84, 92 ] ], "normalized": [] }, { "id": "PMID-15034302_T3", "type": "Cell", "text": [ "transformed cells" ], "offsets": [ [ 140, 157 ] ], "normalized": [] }, { "id": "PMID-15034302_T4", "type": "Gene_or_gene_product", "text": [ "TGFbeta" ], "offsets": [ [ 298, 305 ] ], "normalized": [] }, { "id": "PMID-15034302_T5", "type": "Gene_or_gene_product", "text": [ "TGFalpha" ], "offsets": [ [ 310, 318 ] ], "normalized": [] }, { "id": "PMID-15034302_T6", "type": "Gene_or_gene_product", "text": [ "EGF" ], "offsets": [ [ 322, 325 ] ], "normalized": [] }, { "id": "PMID-15034302_T8", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 367, 375 ] ], "normalized": [] }, { "id": "PMID-15034302_T9", "type": "Cell", "text": [ "epithelial cells" ], "offsets": [ [ 409, 425 ] ], "normalized": [] }, { "id": "PMID-15034302_T11", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 487, 495 ] ], "normalized": [] }, { "id": "PMID-15034302_T12", "type": "Pathological_formation", "text": [ "cancers" ], "offsets": [ [ 517, 524 ] ], "normalized": [] }, { "id": "PMID-15034302_T14", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 546, 554 ] ], "normalized": [] }, { "id": "PMID-15034302_T15", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 570, 575 ] ], "normalized": [] }, { "id": "PMID-15034302_T16", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 615, 621 ] ], "normalized": [] }, { "id": "PMID-15034302_T18", "type": "Pathological_formation", "text": [ "carcinomas" ], "offsets": [ [ 642, 652 ] ], "normalized": [] }, { "id": "PMID-15034302_T19", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 665, 673 ] ], "normalized": [] }, { "id": "PMID-15034302_T21", "type": "Cell", "text": [ "tumor cell lines" ], "offsets": [ [ 804, 820 ] ], "normalized": [] }, { "id": "PMID-15034302_T22", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 934, 942 ] ], "normalized": [] }, { "id": "PMID-15034302_T23", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 946, 952 ] ], "normalized": [] }, { "id": "PMID-15034302_T25", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 997, 1005 ] ], "normalized": [] }, { "id": "PMID-15034302_T26", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1011, 1016 ] ], "normalized": [] }, { "id": "PMID-15034302_T27", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1151, 1156 ] ], "normalized": [] }, { "id": "PMID-15034302_T28", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 1248, 1259 ] ], "normalized": [] }, { "id": "PMID-15034302_T31", "type": "Gene_or_gene_product", "text": [ "TGFbeta1" ], "offsets": [ [ 1292, 1300 ] ], "normalized": [] }, { "id": "PMID-15034302_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 636, 641 ] ], "normalized": [] }, { "id": "PMID-15034302_T1001", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 707, 714 ] ], "normalized": [] }, { "id": "PMID-15034302_T36", "type": "Cell", "text": [ "nontransformed cell" ], "offsets": [ [ 226, 245 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-16485028__text", "type": "abstract", "text": [ "NF-kappaB and IKK as therapeutic targets in cancer.\n\nThe transcription factor NF-kappaB and associated regulatory factors (including IkappaB kinase subunits and the IkappaB family member Bcl-3) are strongly implicated in a variety of hematologic and solid tumor malignancies. A role for NF-kappaB in cancer cells appears to involve regulation of cell proliferation, control of apoptosis, promotion of angiogenesis, and stimulation of invasion/metastasis. Consistent with a role for NF-kappaB in oncogenesis are observations that inhibition of NF-kappaB alone or in combination with cancer therapies leads to tumor cell death or growth inhibition. However, other experimental data indicate that NF-kappaB can play a tumor suppressor role in certain settings and that it can be important in promoting an apoptotic signal downstream of certain cancer therapy regimens. In order to appropriately move NF-kappaB inhibitors in the clinic, thorough approaches must be initiated to determine the molecular mechanisms that dictate the complexity of oncologic and therapeutic outcomes that are controlled by NF-kappaB.\n" ], "offsets": [ [ 0, 1109 ] ] } ]

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[]

[]

[ { "id": "PMID-19542562__text", "type": "abstract", "text": [ "Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase.\n\nSmooth muscle-rich tissues respond to mechanical overload by an adaptive hypertrophic growth combined with activation of angiogenesis, which potentiates their mechanical overload-bearing capabilities. Neovascularization is associated with mechanical strain-dependent induction of angiogenic factors such as CCN1, an immediate-early gene-encoded matricellular molecule critical for vascular development and repair. Here we have demonstrated that mechanical strain-dependent induction of the CCN1 gene involves signaling cascades through RhoA-mediated actin remodeling and the p38 stress-activated protein kinase (SAPK). Actin signaling controls serum response factor (SRF) activity via SRF interaction with the myocardin-related transcriptional activator (MRTF)-A and tethering to a single CArG box sequence within the CCN1 promoter. Such activity was abolished in mechanically stimulated mouse MRTF-A(-/-) cells or upon inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) either pharmacologically or by siRNAs. Mechanical strain induced CBP-mediated acetylation of histones 3 and 4 at the SRF-binding site and within the CCN1 gene coding region. Inhibition of p38 SAPK reduced CBP HAT activity and its recruitment to the SRF.MRTF-A complex, whereas enforced induction of p38 by upstream activators (e.g. MKK3 and MKK6) enhanced both CBP HAT and CCN1 promoter activities. Similarly, mechanical overload-induced CCN1 gene expression in vivo was associated with nuclear localization of MRTF-A and enrichment of the CCN1 promoter with both MRTF-A and acetylated histone H3. Taken together, these data suggest that signal-controlled activation of SRF, MRTF-A, and CBP provides a novel connection between mechanical stimuli and angiogenic gene expression.\n" ], "offsets": [ [ 0, 1933 ] ] } ]

[ { "id": "PMID-19542562_T3", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 50, 54 ] ], "normalized": [] }, { "id": "PMID-19542562_T4", "type": "Gene_or_gene_product", "text": [ "CYR61" ], "offsets": [ [ 55, 60 ] ], "normalized": [] }, { "id": "PMID-19542562_T6", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 102, 108 ] ], "normalized": [] }, { "id": "PMID-19542562_T7", "type": "Gene_or_gene_product", "text": [ "CREB-binding protein histone acetyltransferase" ], "offsets": [ [ 113, 159 ] ], "normalized": [] }, { "id": "PMID-19542562_T13", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 469, 473 ] ], "normalized": [] }, { "id": "PMID-19542562_T18", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "PMID-19542562_T20", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 698, 702 ] ], "normalized": [] }, { "id": "PMID-19542562_T21", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 712, 717 ] ], "normalized": [] }, { "id": "PMID-19542562_T22", "type": "Gene_or_gene_product", "text": [ "p38 stress-activated protein kinase" ], "offsets": [ [ 737, 772 ] ], "normalized": [] }, { "id": "PMID-19542562_T23", "type": "Gene_or_gene_product", "text": [ "SAPK" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-19542562_T25", "type": "Gene_or_gene_product", "text": [ "Actin" ], "offsets": [ [ 781, 786 ] ], "normalized": [] }, { "id": "PMID-19542562_T26", "type": "Gene_or_gene_product", "text": [ "serum response factor" ], "offsets": [ [ 806, 827 ] ], "normalized": [] }, { "id": "PMID-19542562_T27", "type": "Gene_or_gene_product", "text": [ "SRF" ], "offsets": [ [ 829, 832 ] ], "normalized": [] }, { "id": "PMID-19542562_T28", "type": "Gene_or_gene_product", "text": [ "SRF" ], "offsets": [ [ 847, 850 ] ], "normalized": [] }, { "id": "PMID-19542562_T29", "type": "Gene_or_gene_product", "text": [ "myocardin-related transcriptional activator (MRTF)-A" ], "offsets": [ [ 872, 924 ] ], "normalized": [] }, { "id": "PMID-19542562_T32", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 980, 984 ] ], "normalized": [] }, { "id": "PMID-19542562_T34", "type": "Cell", "text": [ "MRTF-A(-/-) cells" ], "offsets": [ [ 1056, 1073 ] ], "normalized": [] }, { "id": "PMID-19542562_T35", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 1056, 1062 ] ], "normalized": [] }, { "id": "PMID-19542562_T38", "type": "Gene_or_gene_product", "text": [ "CREB-binding protein (CBP) histone acetyltransferase (HAT)" ], "offsets": [ [ 1096, 1154 ] ], "normalized": [] }, { "id": "PMID-19542562_T44", "type": "Gene_or_gene_product", "text": [ "CBP" ], "offsets": [ [ 1220, 1223 ] ], "normalized": [] }, { "id": "PMID-19542562_T45", "type": "Gene_or_gene_product", "text": [ "histones 3" ], "offsets": [ [ 1248, 1258 ] ], "normalized": [] }, { "id": "PMID-19542562_T46", "type": "Gene_or_gene_product", "text": [ "SRF" ], "offsets": [ [ 1272, 1275 ] ], "normalized": [] }, { "id": "PMID-19542562_T47", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 1304, 1308 ] ], "normalized": [] }, { "id": "PMID-19542562_T49", "type": "Gene_or_gene_product", "text": [ "p38 SAPK" ], "offsets": [ [ 1343, 1351 ] ], "normalized": [] }, { "id": "PMID-19542562_T52", "type": "Gene_or_gene_product", "text": [ "CBP HAT" ], "offsets": [ [ 1360, 1367 ] ], "normalized": [] }, { "id": "PMID-19542562_T55", "type": "Gene_or_gene_product", "text": [ "SRF" ], "offsets": [ [ 1404, 1407 ] ], "normalized": [] }, { "id": "PMID-19542562_T56", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 1408, 1414 ] ], "normalized": [] }, { "id": "PMID-19542562_T58", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1454, 1457 ] ], "normalized": [] }, { "id": "PMID-19542562_T59", "type": "Gene_or_gene_product", "text": [ "MKK3" ], "offsets": [ [ 1487, 1491 ] ], "normalized": [] }, { "id": "PMID-19542562_T60", "type": "Gene_or_gene_product", "text": [ "MKK6" ], "offsets": [ [ 1496, 1500 ] ], "normalized": [] }, { "id": "PMID-19542562_T62", "type": "Gene_or_gene_product", "text": [ "CBP HAT" ], "offsets": [ [ 1516, 1523 ] ], "normalized": [] }, { "id": "PMID-19542562_T64", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 1528, 1532 ] ], "normalized": [] }, { "id": "PMID-19542562_T67", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 1593, 1597 ] ], "normalized": [] }, { "id": "PMID-19542562_T69", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 1666, 1672 ] ], "normalized": [] }, { "id": "PMID-19542562_T70", "type": "Gene_or_gene_product", "text": [ "CCN1" ], "offsets": [ [ 1695, 1699 ] ], "normalized": [] }, { "id": "PMID-19542562_T71", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 1719, 1725 ] ], "normalized": [] }, { "id": "PMID-19542562_T73", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 1741, 1751 ] ], "normalized": [] }, { "id": "PMID-19542562_T75", "type": "Gene_or_gene_product", "text": [ "SRF" ], "offsets": [ [ 1825, 1828 ] ], "normalized": [] }, { "id": "PMID-19542562_T76", "type": "Gene_or_gene_product", "text": [ "MRTF-A" ], "offsets": [ [ 1830, 1836 ] ], "normalized": [] }, { "id": "PMID-19542562_T77", "type": "Gene_or_gene_product", "text": [ "CBP" ], "offsets": [ [ 1842, 1845 ] ], "normalized": [] }, { "id": "PMID-19542562_T30", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1263, 1264 ] ], "normalized": [] }, { "id": "PMID-19542562_T1000", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [] }, { "id": "PMID-19542562_T37", "type": "Tissue", "text": [ "Smooth muscle-rich tissues" ], "offsets": [ [ 162, 188 ] ], "normalized": [] }, { "id": "PMID-19542562_T61", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 543, 551 ] ], "normalized": [] }, { "id": "PMID-19542562_T84", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 985, 993 ] ], "normalized": [] }, { "id": "PMID-19542562_T40", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1533, 1541 ] ], "normalized": [] } ]

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"ref_id": "PMID-19542562_T18" } ] }, { "id": "PMID-19542562_E19", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 703, 711 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19542562_T20" }, { "role": "Theme", "ref_id": "PMID-19542562_T21" } ] }, { "id": "PMID-19542562_E33", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1039, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19542562_T34" } ] }, { "id": "PMID-19542562_E36", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1082, 1092 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19542562_T38" } ] }, { "id": "PMID-19542562_E42", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1212, 1219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19542562_E43" } ] }, { "id": "PMID-19542562_E43", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1233, 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[ { "id": "PMID-9728053__text", "type": "abstract", "text": [ "Store-operated calcium entry promotes shape change in pulmonary endothelial cells expressing Trp1.\n\nActivation of Ca2+ entry is known to produce endothelial cell shape change, leading to increased permeability, leukocyte migration, and initiation of angiogenesis in conduit-vessel endothelial cells. The mode of Ca2+ entry regulating cell shape is unknown. We hypothesized that activation of store-operated Ca2+ channels (SOCs) is sufficient to promote cell shape change necessary for these processes. SOC activation in rat pulmonary arterial endothelial cells increased free cytosolic Ca2+ that was dependent on a membrane current having a net inward component of 5.45 +/- 0.90 pA/pF at -80 mV. Changes in endothelial cell shape accompanied SOC activation and were dependent on Ca2+ entry-induced reconfiguration of peripheral (cortical) filamentous actin (F-actin). Because the identity of pulmonary endothelial SOCs is unknown, but mammalian homologues of the Drosophila melanogaster transient receptor potential (trp) gene have been proposed to form Ca2+ entry channels in nonexcitable cells, we performed RT-PCR using Trp oligonucleotide primers in both rat and human pulmonary arterial endothelial cells. Both cell types were found to express Trp1, but neither expressed Trp3 nor Trp6. Our study indicates that 1) Ca2+ entry in pulmonary endothelial cells through SOCs produces cell shape change that is dependent on site-specific rearrangement of the microfilamentous cytoskeleton and 2) Trp1 may be a component of pulmonary endothelial SOCs.\n" ], "offsets": [ [ 0, 1550 ] ] } ]

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[ { "id": "PMID-9728053_1", "entity_ids": [ "PMID-9728053_T18", "PMID-9728053_T19" ] }, { "id": "PMID-9728053_2", "entity_ids": [ "PMID-9728053_T21", "PMID-9728053_T22" ] } ]

[]

[ { "id": "PMID-15975645__text", "type": "abstract", "text": [ "Thalidomide and angiostatin inhibit tumor growth in a murine xenograft model of human cervical cancer.\n\nOBJECTIVE: To determine the impact of thalidomide and angiostatin on tumor growth, angiogenesis, and apoptosis in a xenograft model of cervical cancer. METHODS: Human umbilical endothelial cells were treated with angiostatin or thalidomide and bFGF-induced proliferation was assessed with the MTT assay. Human cervical cancer cells (CaSki and SiHa) were injected into the flanks of nude mice. After tumors developed, mice were treated with angiostatin 20 mg/kg/day or thalidomide 200 mg/kg/day for 30 days. Fractional tumor growth was determined and immunohistochemical analysis of tumors was used to determine degree of angiogenesis. TUNEL assay was used to assess apoptosis. RESULTS: Angiostatin inhibited endothelial cell proliferation by 50-60%. Thalidomide had no direct effect on endothelial cells. Angiostatin and thalidomide both inhibited tumor growth by about 55%. We found no additive or synergistic effect when the two agents were combined. Both agents inhibited angiogenesis and induced apoptosis when compared to tumors from control animals. CONCLUSIONS: Angiostatin and thalidomide inhibit tumor growth, angiogenesis, and induce apoptosis in this xenograft model of cervical cancer.\n" ], "offsets": [ [ 0, 1302 ] ] } ]

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"angiostatin" ], "offsets": [ [ 317, 328 ] ], "normalized": [] }, { "id": "PMID-15975645_T15", "type": "Drug_or_compound", "text": [ "thalidomide" ], "offsets": [ [ 332, 343 ] ], "normalized": [] }, { "id": "PMID-15975645_T16", "type": "Gene_or_gene_product", "text": [ "bFGF" ], "offsets": [ [ 348, 352 ] ], "normalized": [] }, { "id": "PMID-15975645_T17", "type": "Cell", "text": [ "cervical cancer cells" ], "offsets": [ [ 414, 435 ] ], "normalized": [] }, { "id": "PMID-15975645_T18", "type": "Cell", "text": [ "CaSki" ], "offsets": [ [ 437, 442 ] ], "normalized": [] }, { "id": "PMID-15975645_T19", "type": "Cell", "text": [ "SiHa" ], "offsets": [ [ 447, 451 ] ], "normalized": [] }, { "id": "PMID-15975645_T20", "type": "Organism_subdivision", "text": [ "flanks" ], "offsets": [ [ 476, 482 ] ], "normalized": [] }, { "id": "PMID-15975645_T21", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 503, 509 ] ], "normalized": [] }, { "id": "PMID-15975645_T24", "type": "Gene_or_gene_product", "text": [ "angiostatin" ], "offsets": [ [ 544, 555 ] ], "normalized": [] }, { "id": "PMID-15975645_T25", "type": "Drug_or_compound", "text": [ "thalidomide" ], "offsets": [ [ 572, 583 ] ], "normalized": [] }, { "id": "PMID-15975645_T27", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 622, 627 ] ], "normalized": [] }, { "id": "PMID-15975645_T28", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 686, 692 ] ], "normalized": [] }, { "id": "PMID-15975645_T30", "type": "Gene_or_gene_product", "text": [ "Angiostatin" ], "offsets": [ [ 790, 801 ] ], "normalized": [] }, { "id": "PMID-15975645_T34", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 812, 828 ] ], "normalized": [] }, { "id": "PMID-15975645_T35", "type": "Drug_or_compound", "text": [ "Thalidomide" ], "offsets": [ [ 854, 865 ] ], "normalized": [] }, { "id": "PMID-15975645_T36", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 890, 907 ] ], "normalized": [] }, { "id": "PMID-15975645_T37", "type": "Gene_or_gene_product", "text": [ "Angiostatin" ], "offsets": [ [ 909, 920 ] ], "normalized": [] }, { "id": "PMID-15975645_T38", "type": "Drug_or_compound", "text": [ "thalidomide" ], "offsets": [ [ 925, 936 ] ], "normalized": [] }, { "id": "PMID-15975645_T41", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 952, 957 ] ], "normalized": [] }, { "id": "PMID-15975645_T43", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 1131, 1137 ] ], "normalized": [] }, { "id": "PMID-15975645_T44", "type": "Gene_or_gene_product", "text": [ "Angiostatin" ], "offsets": [ [ 1173, 1184 ] ], "normalized": [] }, { "id": "PMID-15975645_T45", "type": "Drug_or_compound", "text": [ "thalidomide" ], "offsets": [ [ 1189, 1200 ] ], "normalized": [] }, { "id": "PMID-15975645_T31", "type": "Pathological_formation", "text": [ "cervical cancer" ], "offsets": [ [ 86, 101 ] ], "normalized": [] }, { "id": "PMID-15975645_T46", "type": "Pathological_formation", "text": [ "cervical cancer" ], "offsets": [ [ 239, 254 ] ], "normalized": [] }, { "id": "PMID-15975645_T49", "type": "Pathological_formation", "text": [ "cervical cancer" ], "offsets": [ [ 1285, 1300 ] ], "normalized": [] }, { "id": "PMID-15975645_T1000", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 54, 60 ] ], "normalized": [] }, { "id": "PMID-15975645_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 80, 85 ] ], "normalized": [] }, { "id": "PMID-15975645_T1002", "type": "Organism", "text": [ "Human" ], "offsets": [ [ 265, 270 ] ], "normalized": [] }, { "id": "PMID-15975645_T1003", "type": "Organism", "text": [ "Human" ], "offsets": [ [ 408, 413 ] ], "normalized": [] }, { "id": "PMID-15975645_T1004", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 486, 495 ] ], "normalized": [] }, { "id": "PMID-15975645_T1005", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 521, 525 ] ], "normalized": 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[]

[]

[ { "id": "PMID-17289834__text", "type": "abstract", "text": [ "Hyperforin blocks neutrophil activation of matrix metalloproteinase-9, motility and recruitment, and restrains inflammation-triggered angiogenesis and lung fibrosis.\n\nHyperforin (Hyp), a polyphenol-derivative of St. John's wort (Hypericum perforatum), has emerged as key player not only in the antidepressant activity of the plant but also as an inhibitor of bacteria lymphocyte and tumor cell proliferation, and matrix proteinases. We tested whether as well as inhibiting leukocyte elastase (LE) activity, Hyp might be effective in containing both polymorphonuclear neutrophil (PMN) leukocyte recruitment and unfavorable eventual tissue responses. The results show that, without affecting in vitro human PMN viability and chemokine-receptor expression, Hyp (as stable dicyclohexylammonium salt) was able to inhibit in a dose-dependent manner their chemotaxis and chemoinvasion (IC50=1 microM for both); this effect was associated with a reduced expression of the adhesion molecule CD11b by formyl-Met-Leu-Phe-stimulated neutrophils and block of LE-triggered activation of the gelatinase matrix metalloproteinase-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an interleukin-8-induced murine model. Furthermore, i.p. treatment with Hyp reduces acute PMN recruitment and enhances resolution in a pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis. These results indicate that Hyp is a powerful anti-inflammatory compound with therapeutic potential, and they elucidate mechanistic keys.\n" ], "offsets": [ [ 0, 1597 ] ] } ]

[ { "id": "PMID-17289834_T2", "type": "Drug_or_compound", "text": [ "Hyperforin" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-17289834_T4", "type": "Cell", "text": [ "neutrophil" ], "offsets": [ [ 18, 28 ] ], "normalized": [] }, { "id": "PMID-17289834_T5", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 43, 69 ] ], "normalized": [] }, { "id": "PMID-17289834_T9", "type": "Organ", "text": [ "lung" ], "offsets": [ [ 151, 155 ] ], "normalized": [] }, { "id": "PMID-17289834_T10", "type": "Drug_or_compound", "text": [ "Hyperforin" ], "offsets": [ [ 167, 177 ] ], "normalized": [] }, { "id": "PMID-17289834_T11", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "PMID-17289834_T13", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 368, 378 ] ], "normalized": [] }, { "id": "PMID-17289834_T14", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 383, 393 ] ], "normalized": [] }, { "id": "PMID-17289834_T15", "type": "Gene_or_gene_product", "text": [ "matrix proteinases" ], "offsets": [ [ 413, 431 ] ], "normalized": [] }, { "id": "PMID-17289834_T17", "type": "Gene_or_gene_product", "text": [ "leukocyte elastase" ], "offsets": [ [ 473, 491 ] ], "normalized": [] }, { "id": "PMID-17289834_T18", "type": "Gene_or_gene_product", "text": [ "LE" ], "offsets": [ [ 493, 495 ] ], "normalized": [] }, { "id": "PMID-17289834_T19", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 507, 510 ] ], "normalized": [] }, { "id": "PMID-17289834_T21", "type": "Cell", "text": [ "polymorphonuclear neutrophil (PMN) leukocyte" ], "offsets": [ [ 549, 593 ] ], "normalized": [] }, { "id": "PMID-17289834_T24", "type": "Cell", "text": [ "PMN" ], "offsets": [ [ 705, 708 ] ], "normalized": [] }, { "id": "PMID-17289834_T27", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 754, 757 ] ], "normalized": [] }, { "id": "PMID-17289834_T28", "type": "Drug_or_compound", "text": [ "dicyclohexylammonium salt" ], "offsets": [ [ 769, 794 ] ], "normalized": [] }, { "id": "PMID-17289834_T31", "type": "Gene_or_gene_product", "text": [ "CD11b" ], "offsets": [ [ 982, 987 ] ], "normalized": [] }, { "id": "PMID-17289834_T33", "type": "Drug_or_compound", "text": [ "formyl-Met-Leu-Phe" ], "offsets": [ [ 991, 1009 ] ], "normalized": [] }, { "id": "PMID-17289834_T34", "type": "Cell", "text": [ "neutrophils" ], "offsets": [ [ 1021, 1032 ] ], "normalized": [] }, { "id": "PMID-17289834_T37", "type": "Gene_or_gene_product", "text": [ "LE" ], "offsets": [ [ 1046, 1048 ] ], "normalized": [] }, { "id": "PMID-17289834_T38", "type": "Gene_or_gene_product", "text": [ "gelatinase matrix metalloproteinase-9" ], "offsets": [ [ 1077, 1114 ] ], "normalized": [] }, { "id": "PMID-17289834_T39", "type": "Cell", "text": [ "PMN" ], "offsets": [ [ 1116, 1119 ] ], "normalized": [] }, { "id": "PMID-17289834_T44", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 1220, 1223 ] ], "normalized": [] }, { "id": "PMID-17289834_T46", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 1235, 1248 ] ], "normalized": [] }, { "id": "PMID-17289834_T47", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 1304, 1307 ] ], "normalized": [] }, { "id": "PMID-17289834_T50", "type": "Cell", "text": [ "PMN" ], "offsets": [ [ 1322, 1325 ] ], "normalized": [] }, { "id": "PMID-17289834_T53", "type": "Drug_or_compound", "text": [ "bleomycin" ], "offsets": [ [ 1377, 1386 ] ], "normalized": [] }, { "id": "PMID-17289834_T54", "type": "Drug_or_compound", "text": [ "Hyp" ], "offsets": [ [ 1487, 1490 ] ], "normalized": [] }, { "id": "PMID-17289834_T1000", "type": "Organism", "text": [ "Hypericum perforatum" ], "offsets": [ [ 229, 249 ] ], "normalized": [] }, { "id": "PMID-17289834_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 699, 704 ] ], "normalized": [] }, { "id": "PMID-17289834_T1002", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 1257, 1263 ] ], "normalized": [] }, { "id": "PMID-17289834_T58", "type": "Organism", "text": [ "John's wort" ], "offsets": [ [ 216, 227 ] ], "normalized": [] }, { "id": "PMID-17289834_T59", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 631, 637 ] ], "normalized": [] } ]

[ { "id": "PMID-17289834_E1", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 11, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T2" }, { "role": "Theme", "ref_id": "PMID-17289834_E3" } ] }, { "id": "PMID-17289834_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 29, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T5" }, { "role": "Cause", "ref_id": "PMID-17289834_T4" } ] }, { "id": "PMID-17289834_E12", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 394, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T14" } ] }, { "id": "PMID-17289834_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 462, 472 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T19" }, { "role": "Theme", "ref_id": "PMID-17289834_T17" } ] }, { "id": "PMID-17289834_E20", "type": "Localization", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 594, 605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T21" } ] }, { "id": "PMID-17289834_E29", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 938, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_E30" }, { "role": "Cause", "ref_id": "PMID-17289834_T34" } ] }, { "id": "PMID-17289834_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T31" } ] }, { "id": "PMID-17289834_E32", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1010, 1020 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T33" }, { "role": "Theme", "ref_id": "PMID-17289834_T34" } ] }, { "id": "PMID-17289834_E35", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1037, 1042 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T38" } ] }, { "id": "PMID-17289834_E36", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1059, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T38" } ] }, { "id": "PMID-17289834_E43", "type": "Planned_process", "trigger": { "text": [ "injection" ], "offsets": [ [ 1173, 1182 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17289834_T44" }, { "role": "Theme", "ref_id": "PMID-17289834_T1002" } ] }, { "id": "PMID-17289834_E48", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1308, 1315 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_E25" }, { "role": "Theme", "ref_id": "PMID-17289834_E49" } ] }, { "id": "PMID-17289834_E49", "type": "Localization", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 1326, 1337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T50" } ] }, { "id": "PMID-17289834_E2", "type": "Localization", "trigger": { "text": [ "motility" ], "offsets": [ [ 71, 79 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T4" } ] }, { "id": "PMID-17289834_E4", "type": "Localization", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 84, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T4" } ] }, { "id": "PMID-17289834_E5", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 124, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_E8" } ] }, { "id": "PMID-17289834_E6", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 11, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T2" }, { "role": "Theme", "ref_id": "PMID-17289834_E2" } ] }, { "id": "PMID-17289834_E7", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 11, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T2" }, { "role": "Theme", "ref_id": "PMID-17289834_E4" } ] }, { "id": "PMID-17289834_E9", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 11, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T2" }, { "role": "Theme", "ref_id": "PMID-17289834_E8" } ] }, { "id": "PMID-17289834_E10", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 394, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T13" } ] }, { "id": "PMID-17289834_E11", "type": "Regulation", "trigger": { "text": [ "effective" ], "offsets": [ [ 520, 529 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T19" }, { "role": "Theme", "ref_id": "PMID-17289834_E20" } ] }, { "id": "PMID-17289834_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 808, 815 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T27" }, { "role": "Theme", "ref_id": "PMID-17289834_E14" } ] }, { "id": "PMID-17289834_E14", "type": "Localization", "trigger": { "text": [ "chemotaxis" ], "offsets": [ [ 849, 859 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T24" } ] }, { "id": "PMID-17289834_E15", "type": "Localization", "trigger": { "text": [ "chemoinvasion" ], "offsets": [ [ 864, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_T24" } ] }, { "id": "PMID-17289834_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 808, 815 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T27" }, { "role": "Theme", "ref_id": "PMID-17289834_E15" } ] }, { "id": "PMID-17289834_E18", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1049, 1058 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T37" }, { "role": "Theme", "ref_id": "PMID-17289834_E36" } ] }, { "id": "PMID-17289834_E19", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1120, 1129 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T39" }, { "role": "Theme", "ref_id": "PMID-17289834_E26" } ] }, { "id": "PMID-17289834_E21", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1151, 1158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_E26" }, { "role": "Cause", "ref_id": "PMID-17289834_E43" } ] }, { "id": "PMID-17289834_E22", "type": "Planned_process", "trigger": { "text": [ "administration" ], "offsets": [ [ 1198, 1212 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17289834_T44" }, { "role": "Theme", "ref_id": "PMID-17289834_T1002" } ] }, { "id": "PMID-17289834_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1249, 1256 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17289834_T46" }, { "role": "Theme", "ref_id": "PMID-17289834_T1002" } ] }, { "id": "PMID-17289834_E24", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1151, 1158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17289834_E26" }, { "role": "Cause", "ref_id": "PMID-17289834_E22" } ] }, { "id": "PMID-17289834_E25", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1289, 1298 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17289834_T47" } ] }, { "id": "PMID-17289834_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 134, 146 ] ] }, "arguments": [] }, { "id": "PMID-17289834_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1130, 1142 ] ] }, "arguments": [] } ]

[ { "id": "PMID-17289834_1", "entity_ids": [ "PMID-17289834_T17", "PMID-17289834_T18" ] }, { "id": "PMID-17289834_2", "entity_ids": [ "PMID-17289834_T10", "PMID-17289834_T11" ] }, { "id": "PMID-17289834_3", "entity_ids": [ "PMID-17289834_T58", "PMID-17289834_T1000" ] } ]

[]

[ { "id": "PMID-16045802__text", "type": "abstract", "text": [ "Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis.\n\nBACKGROUND: The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1alpha (HIF). RESULTS: Most tumors less than 35 mm3 were white but tumors greater than 35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at greater than 100 microns from the capsule (subcortex). Tumors greater than 35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. CONCLUSION: TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis.\n" ], "offsets": [ [ 0, 1771 ] ] } ]

[ { "id": "PMID-16045802_T2", "type": "Pathological_formation", "text": [ "breast cancer xenograft" ], "offsets": [ [ 72, 95 ] ], "normalized": [] }, { "id": "PMID-16045802_T5", "type": "Pathological_formation", "text": [ "MDA MB231 breast cancer xenograft" ], "offsets": [ [ 356, 389 ] ], "normalized": [] }, { "id": "PMID-16045802_T7", "type": "Gene_or_gene_product", "text": [ "Green fluorescence protein" ], "offsets": [ [ 403, 429 ] ], "normalized": [] }, { "id": "PMID-16045802_T8", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 442, 454 ] ], "normalized": [] }, { "id": "PMID-16045802_T9", "type": "Tissue", "text": [ "mammary fat pad" ], "offsets": [ [ 478, 493 ] ], "normalized": [] }, { "id": "PMID-16045802_T10", "type": "Pathological_formation", "text": [ "Tumor sections" ], "offsets": [ [ 816, 830 ] ], "normalized": [] }, { "id": "PMID-16045802_T11", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 849, 866 ] ], "normalized": [] }, { "id": "PMID-16045802_T12", "type": "Gene_or_gene_product", "text": [ "CD31" ], "offsets": [ [ 872, 876 ] ], "normalized": [] }, { "id": "PMID-16045802_T13", "type": "Drug_or_compound", "text": [ "PAS" ], "offsets": [ [ 881, 884 ] ], "normalized": [] }, { "id": "PMID-16045802_T14", "type": "Gene_or_gene_product", "text": [ "hypoxia inducible factor 1alpha" ], "offsets": [ [ 888, 919 ] ], "normalized": [] }, { "id": "PMID-16045802_T15", "type": "Gene_or_gene_product", "text": [ "HIF" ], "offsets": [ [ 921, 924 ] ], "normalized": [] }, { "id": "PMID-16045802_T16", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 941, 947 ] ], "normalized": [] }, { "id": "PMID-16045802_T17", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 981, 987 ] ], "normalized": [] }, { "id": "PMID-16045802_T18", "type": "Pathological_formation", "text": [ "vascularized capsule" ], "offsets": [ [ 1029, 1049 ] ], "normalized": [] }, { "id": "PMID-16045802_T19", "type": "Pathological_formation", "text": [ "cortex" ], "offsets": [ [ 1055, 1061 ] ], "normalized": [] }, { "id": "PMID-16045802_T20", "type": "Pathological_formation", "text": [ "capsule" ], "offsets": [ [ 1088, 1095 ] ], "normalized": [] }, { "id": "PMID-16045802_T23", "type": "Multi-tissue_structure", "text": [ "Blood vessels" ], "offsets": [ [ 1124, 1137 ] ], "normalized": [] }, { "id": "PMID-16045802_T24", "type": "Tissue", "text": [ "capillaries" ], "offsets": [ [ 1139, 1150 ] ], "normalized": [] }, { "id": "PMID-16045802_T25", "type": "Cellular_component", "text": [ "endothelial pseudopods" ], "offsets": [ [ 1156, 1178 ] ], "normalized": [] }, { "id": "PMID-16045802_T26", "type": "Pathological_formation", "text": [ "capsule" ], "offsets": [ [ 1228, 1235 ] ], "normalized": [] }, { "id": "PMID-16045802_T27", "type": "Pathological_formation", "text": [ "subcortex" ], "offsets": [ [ 1237, 1246 ] ], "normalized": [] }, { "id": "PMID-16045802_T28", "type": "Pathological_formation", "text": [ "Tumors" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] }, { "id": "PMID-16045802_T29", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 1340, 1353 ] ], "normalized": [] }, { "id": "PMID-16045802_T30", "type": "Pathological_formation", "text": [ "subcortex" ], "offsets": [ [ 1361, 1370 ] ], "normalized": [] }, { "id": "PMID-16045802_T31", "type": "Cellular_component", "text": [ "endothelial pseudopods" ], "offsets": [ [ 1380, 1402 ] ], "normalized": [] }, { "id": "PMID-16045802_T32", "type": "Gene_or_gene_product", "text": [ "HIF" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "PMID-16045802_T33", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 1452, 1458 ] ], "normalized": [] }, { "id": "PMID-16045802_T34", "type": "Organ", "text": [ "lung" ], "offsets": [ [ 1544, 1548 ] ], "normalized": [] }, { "id": "PMID-16045802_T36", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1577, 1582 ] ], "normalized": [] }, { "id": "PMID-16045802_T37", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1725, 1730 ] ], "normalized": [] }, { "id": "PMID-16045802_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 66, 71 ] ], "normalized": [] }, { "id": "PMID-16045802_T1001", "type": "Organism", "text": [ "nude mice" ], "offsets": [ [ 330, 339 ] ], "normalized": [] }, { "id": "PMID-16045802_T1002", "type": "Organism", "text": [ "human" ], "offsets": [ [ 350, 355 ] ], "normalized": [] }, { "id": "PMID-16045802_T1003", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 510, 514 ] ], "normalized": [] }, { "id": "PMID-16045802_T1004", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 533, 537 ] ], "normalized": [] }, { "id": "PMID-16045802_T1005", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-16045802_T1006", "type": "Organism", "text": [ "Mice" ], "offsets": [ [ 1483, 1487 ] ], "normalized": [] }, { "id": "PMID-16045802_T1007", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1609, 1613 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-7897308__text", "type": "abstract", "text": [ "Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells.\n\nMetastatic disease is one of the major causes of death from cancer in human beings. Several enzyme systems have been implicated in the metastatic process, but the metalloproteinases (MPs) appear to be the major group involved in most instances of neoplastic invasion. Increased MP activity has been correlated with the metastatic potential of many cancers, including breast cancer. MPs also play a role in tumor angiogenesis. Tetracyclines are antimicrobial agents that can suppress MP activity in a variety of tissues, including gingiva, bone, and cartilage. Several reports have indicated that tetracyclines can suppress tumor MPs as well. A synthetic tetracycline, doxycycline, inhibits migration of human MDA-MB-435 breast adenocarcinoma cells through a reconstituted basement membrane (Matrigel), an assay used as an in vitro surrogate for the in vivo process of tumor invasion through basement membranes. Additionally, doxycycline diminishes the proliferation of this breast cancer cell line and also decreases its gelatinolytic activity, as determined by gel zymography.\n" ], "offsets": [ [ 0, 1184 ] ] } ]

[ { "id": "PMID-7897308_T1", "type": "Drug_or_compound", "text": [ "doxycycline" ], "offsets": [ [ 11, 22 ] ], "normalized": [] }, { "id": "PMID-7897308_T4", "type": "Cell", "text": [ "breast carcinoma cells" ], "offsets": [ [ 81, 103 ] ], "normalized": [] }, { "id": "PMID-7897308_T6", "type": "Gene_or_gene_product", "text": [ "metalloproteinases" ], "offsets": [ [ 269, 287 ] ], "normalized": [] }, { "id": "PMID-7897308_T7", "type": "Gene_or_gene_product", "text": [ "MPs" ], "offsets": [ [ 289, 292 ] ], "normalized": [] }, { "id": "PMID-7897308_T9", "type": "Gene_or_gene_product", "text": [ "MP" ], "offsets": [ [ 384, 386 ] ], "normalized": [] }, { "id": "PMID-7897308_T11", "type": "Pathological_formation", "text": [ "breast cancer" ], "offsets": [ [ 473, 486 ] ], "normalized": [] }, { "id": "PMID-7897308_T12", "type": "Gene_or_gene_product", "text": [ "MPs" ], "offsets": [ [ 488, 491 ] ], "normalized": [] }, { "id": "PMID-7897308_T14", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 512, 517 ] ], "normalized": [] }, { "id": "PMID-7897308_T16", "type": "Drug_or_compound", "text": [ "Tetracyclines" ], "offsets": [ [ 532, 545 ] ], "normalized": [] }, { "id": "PMID-7897308_T18", "type": "Gene_or_gene_product", "text": [ "MP" ], "offsets": [ [ 589, 591 ] ], "normalized": [] }, { "id": "PMID-7897308_T19", "type": "Multi-tissue_structure", "text": [ "gingiva" ], "offsets": [ [ 636, 643 ] ], "normalized": [] }, { "id": "PMID-7897308_T20", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "PMID-7897308_T21", "type": "Tissue", "text": [ "cartilage" ], "offsets": [ [ 655, 664 ] ], "normalized": [] }, { "id": "PMID-7897308_T22", "type": "Drug_or_compound", "text": [ "tetracyclines" ], "offsets": [ [ 702, 715 ] ], "normalized": [] }, { "id": "PMID-7897308_T24", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 729, 734 ] ], "normalized": [] }, { "id": "PMID-7897308_T25", "type": "Gene_or_gene_product", "text": [ "MPs" ], "offsets": [ [ 735, 738 ] ], "normalized": [] }, { "id": "PMID-7897308_T26", "type": "Drug_or_compound", "text": [ "tetracycline" ], "offsets": [ [ 760, 772 ] ], "normalized": [] }, { "id": "PMID-7897308_T27", "type": "Drug_or_compound", "text": [ "doxycycline" ], "offsets": [ [ 774, 785 ] ], "normalized": [] }, { "id": "PMID-7897308_T30", "type": "Cell", "text": [ "MDA-MB-435 breast adenocarcinoma cells" ], "offsets": [ [ 815, 853 ] ], "normalized": [] }, { "id": "PMID-7897308_T32", "type": "Cellular_component", "text": [ "basement membrane" ], "offsets": [ [ 878, 895 ] ], "normalized": [] }, { "id": "PMID-7897308_T34", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 974, 979 ] ], "normalized": [] }, { "id": "PMID-7897308_T35", "type": "Cellular_component", "text": [ "basement membranes" ], "offsets": [ [ 997, 1015 ] ], "normalized": [] }, { "id": "PMID-7897308_T36", "type": "Drug_or_compound", "text": [ "doxycycline" ], "offsets": [ [ 1031, 1042 ] ], "normalized": [] }, { "id": "PMID-7897308_T39", "type": "Cell", "text": [ "breast cancer cell line" ], "offsets": [ [ 1080, 1103 ] ], "normalized": [] }, { "id": "PMID-7897308_T5", "type": "Pathological_formation", "text": [ "cancers" ], "offsets": [ [ 454, 461 ] ], "normalized": [] }, { "id": "PMID-7897308_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 176, 181 ] ], "normalized": [] }, { "id": "PMID-7897308_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 809, 814 ] ], "normalized": [] }, { "id": "PMID-7897308_T31", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 166, 172 ] ], "normalized": [] }, { "id": "PMID-7897308_T42", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 617, 624 ] ], "normalized": [] } ]

[ { "id": "PMID-7897308_E2", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 35, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T4" } ] }, { "id": "PMID-7897308_E3", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 43, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T4" } ] }, { "id": "PMID-7897308_E8", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 374, 383 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T9" } ] }, { "id": "PMID-7897308_E17", "type": "Negative_regulation", "trigger": { "text": [ "suppress" ], "offsets": [ [ 580, 588 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7897308_T16" }, { "role": "Theme", "ref_id": "PMID-7897308_T18" } ] }, { "id": "PMID-7897308_E23", "type": "Negative_regulation", "trigger": { "text": [ "suppress" ], "offsets": [ [ 720, 728 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7897308_T22" }, { "role": "Theme", "ref_id": "PMID-7897308_T25" } ] }, { "id": "PMID-7897308_E28", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 787, 795 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_E29" }, { "role": "Cause", "ref_id": "PMID-7897308_T27" } ] }, { "id": "PMID-7897308_E29", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 796, 805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T30" } ] }, { "id": "PMID-7897308_E33", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 980, 988 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T34" } ] }, { "id": "PMID-7897308_E37", "type": "Negative_regulation", "trigger": { "text": [ "diminishes" ], "offsets": [ [ 1043, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_E38" }, { "role": "Cause", "ref_id": "PMID-7897308_T36" } ] }, { "id": "PMID-7897308_E38", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1058, 1071 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T39" } ] }, { "id": "PMID-7897308_E1", "type": "Regulation", "trigger": { "text": [ "Effects" ], "offsets": [ [ 0, 7 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7897308_T1" }, { "role": "Theme", "ref_id": "PMID-7897308_E2" } ] }, { "id": "PMID-7897308_E4", "type": "Regulation", "trigger": { "text": [ "Effects" ], "offsets": [ [ 0, 7 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7897308_T1" }, { "role": "Theme", "ref_id": "PMID-7897308_E3" } ] }, { "id": "PMID-7897308_E5", "type": "Death", "trigger": { "text": [ "death" ], "offsets": [ [ 155, 160 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T1000" } ] }, { "id": "PMID-7897308_E6", "type": "Regulation", "trigger": { "text": [ "play a role" ], "offsets": [ [ 497, 508 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7897308_T12" }, { "role": "Theme", "ref_id": "PMID-7897308_E10" } ] }, { "id": "PMID-7897308_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 787, 795 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_E29" }, { "role": "Cause", "ref_id": "PMID-7897308_T26" } ] }, { "id": "PMID-7897308_E9", "type": "Remodeling", "trigger": { "text": [ "reconstituted" ], "offsets": [ [ 864, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7897308_T32" } ] }, { "id": "PMID-7897308_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 518, 530 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-7897308_T14" } ] } ]

[ { "id": "PMID-7897308_1", "entity_ids": [ "PMID-7897308_T6", "PMID-7897308_T7" ] } ]

[]

[ { "id": "PMID-19742300__text", "type": "abstract", "text": [ "Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.\n\nBACKGROUND: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra). METHODOLOGY/PRINCIPAL FINDINGS: Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia. CONCLUSIONS/SIGNIFICANCE: GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.\n" ], "offsets": [ [ 0, 2407 ] ] } ]

[ { "id": "PMID-19742300_T2", "type": "Tissue", "text": [ "Islet endothelial" ], "offsets": [ [ 0, 17 ] ], "normalized": [] }, { "id": "PMID-19742300_T3", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 80, 86 ] ], "normalized": [] }, { "id": "PMID-19742300_T5", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 193, 198 ] ], "normalized": [] }, { "id": "PMID-19742300_T7", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 261, 266 ] ], "normalized": [] }, { "id": "PMID-19742300_T8", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 299, 316 ] ], "normalized": [] }, { "id": "PMID-19742300_T11", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 375, 391 ] ], "normalized": [] }, { "id": "PMID-19742300_T12", "type": "Multi-tissue_structure", "text": [ "islets" ], "offsets": [ [ 406, 412 ] ], "normalized": [] }, { "id": "PMID-19742300_T13", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 582, 587 ] ], "normalized": [] }, { "id": "PMID-19742300_T15", "type": "Drug_or_compound", "text": [ "interleukin-1 (IL-1) receptor antagonist" ], "offsets": [ [ 642, 682 ] ], "normalized": [] }, { "id": "PMID-19742300_T18", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 684, 690 ] ], "normalized": [] }, { "id": "PMID-19742300_T19", "type": "Multi-tissue_structure", "text": [ "islets" ], "offsets": [ [ 780, 786 ] ], "normalized": [] }, { "id": "PMID-19742300_T20", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 905, 911 ] ], "normalized": [] }, { "id": "PMID-19742300_T21", "type": "Drug_or_compound", "text": [ "Kineret" ], "offsets": [ [ 913, 920 ] ], "normalized": [] }, { "id": "PMID-19742300_T22", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 1022, 1027 ] ], "normalized": [] }, { "id": "PMID-19742300_T23", "type": "Organ", "text": [ "pancreas" ], "offsets": [ [ 1046, 1054 ] ], "normalized": [] }, { "id": "PMID-19742300_T26", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1149, 1165 ] ], "normalized": [] }, { "id": "PMID-19742300_T28", "type": "Gene_or_gene_product", "text": [ "angiotensinogen" ], "offsets": [ [ 1292, 1307 ] ], "normalized": [] }, { "id": "PMID-19742300_T29", "type": "Gene_or_gene_product", "text": [ "epoxide hydrolase" ], "offsets": [ [ 1312, 1329 ] ], "normalized": [] }, { "id": "PMID-19742300_T30", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1357, 1372 ] ], "normalized": [] }, { "id": "PMID-19742300_T31", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1377, 1411 ] ], "normalized": [] }, { "id": "PMID-19742300_T32", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 1489, 1495 ] ], "normalized": [] }, { "id": "PMID-19742300_T33", "type": "Tissue", "text": [ "endothelium" ], "offsets": [ [ 1557, 1568 ] ], "normalized": [] }, { "id": "PMID-19742300_T34", "type": "Cell", "text": [ "immune cells" ], "offsets": [ [ 1572, 1584 ] ], "normalized": [] }, { "id": "PMID-19742300_T35", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 1629, 1635 ] ], "normalized": [] }, { "id": "PMID-19742300_T37", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 1650, 1655 ] ], "normalized": [] }, { "id": "PMID-19742300_T39", "type": "Multi-tissue_structure", "text": [ "islets" ], "offsets": [ [ 1749, 1755 ] ], "normalized": [] }, { "id": "PMID-19742300_T43", "type": "Cell", "text": [ "islet endothelial cell" ], "offsets": [ [ 1807, 1829 ] ], "normalized": [] }, { "id": "PMID-19742300_T44", "type": "Drug_or_compound", "text": [ "IL-1Ra" ], "offsets": [ [ 1950, 1956 ] ], "normalized": [] }, { "id": "PMID-19742300_T46", "type": "Cell", "text": [ "immune cells" ], "offsets": [ [ 1986, 1998 ] ], "normalized": [] }, { "id": "PMID-19742300_T48", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 2076, 2080 ] ], "normalized": [] }, { "id": "PMID-19742300_T50", "type": "Multi-tissue_structure", "text": [ "islet" ], "offsets": [ [ 2087, 2092 ] ], "normalized": [] }, { "id": "PMID-19742300_T51", "type": "Tissue", "text": [ "islet endothelium" ], "offsets": [ [ 2134, 2151 ] ], "normalized": [] }, { "id": "PMID-19742300_T52", "type": "Cell", "text": [ "beta-cell" ], "offsets": [ [ 2169, 2178 ] ], "normalized": [] }, { "id": "PMID-19742300_T54", "type": "Cell", "text": [ "beta-cell" ], "offsets": [ [ 2242, 2251 ] ], "normalized": [] }, { "id": "PMID-19742300_T56", "type": "Cell", "text": [ "islet endothelial cell" ], "offsets": [ [ 2290, 2312 ] ], "normalized": [] }, { "id": "PMID-19742300_T58", "type": "Cell", "text": [ "beta-cell" ], "offsets": [ [ 2365, 2374 ] ], "normalized": [] }, { "id": "PMID-19742300_T16", "type": "Cell", "text": [ "islet endothelial" ], "offsets": [ [ 1965, 1982 ] ], "normalized": [] }, { "id": "PMID-19742300_T17", "type": "Tissue", "text": [ "islet endotheliuml" ], "offsets": [ [ 503, 521 ] ], "normalized": [] }, { "id": "PMID-19742300_T36", "type": "Multi-tissue_structure", "text": [ "islets" ], "offsets": [ [ 1475, 1481 ] ], "normalized": [] }, { "id": "PMID-19742300_T1000", "type": "Organism", "text": [ "GK rat" ], "offsets": [ [ 120, 126 ] ], "normalized": [] }, { "id": "PMID-19742300_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 230, 235 ] ], "normalized": [] }, { "id": "PMID-19742300_T1002", "type": "Organism", "text": [ "Goto-Kakizaki (GK) rat" ], "offsets": [ [ 462, 484 ] ], "normalized": [] }, { "id": "PMID-19742300_T1003", "type": "Organism", "text": [ "Wistar rats" ], "offsets": [ [ 837, 848 ] ], "normalized": [] }, { "id": "PMID-19742300_T1004", "type": "Organism", "text": [ "GK rats" ], "offsets": [ [ 863, 870 ] ], "normalized": [] }, { "id": "PMID-19742300_T1005", "type": "Organism", "text": [ "GK rats" ], "offsets": [ [ 1509, 1516 ] ], "normalized": [] }, { "id": "PMID-19742300_T1006", "type": "Organism", "text": [ "GK rat" ], "offsets": [ [ 1742, 1748 ] ], "normalized": [] }, { "id": "PMID-19742300_T1007", "type": "Organism", "text": [ "GK rats" ], "offsets": [ [ 2267, 2274 ] ], "normalized": [] }, { "id": "PMID-19742300_T62", "type": "Drug_or_compound", "text": [ "saline" ], "offsets": [ [ 947, 953 ] ], "normalized": [] }, { "id": "PMID-19742300_T71", "type": "Organism", "text": [ "GK" ], "offsets": [ [ 822, 824 ] ], "normalized": [] }, { "id": "PMID-19742300_T72", "type": "Organism", "text": [ "GK" ], "offsets": [ [ 1472, 1474 ] ], "normalized": [] }, { "id": "PMID-19742300_T73", "type": "Organism", "text": [ "GK" ], "offsets": [ [ 2084, 2086 ] ], "normalized": [] } ]

[ { "id": "PMID-19742300_E1", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 18, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T2" } ] }, { "id": "PMID-19742300_E4", "type": "Breakdown", "trigger": { "text": [ "dysfunction" ], "offsets": [ [ 199, 210 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T5" } ] }, { "id": "PMID-19742300_E10", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 392, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T11" } ] }, { "id": "PMID-19742300_E25", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1166, 1176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T26" } ] }, { "id": "PMID-19742300_E42", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1830, 1840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T43" } ] }, { "id": "PMID-19742300_E49", "type": "Development", "trigger": { "text": [ "alterations" ], "offsets": [ [ 2093, 2104 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T50" } ] }, { "id": "PMID-19742300_E2", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 69, 76 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_E3" }, { "role": "Theme", "ref_id": "PMID-19742300_E1" } ] }, { "id": "PMID-19742300_E3", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 87, 96 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T1000" }, { "role": "Instrument", "ref_id": "PMID-19742300_T3" } ] }, { "id": "PMID-19742300_E5", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 623, 632 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19742300_T15" } ] }, { "id": "PMID-19742300_E7", "type": "Planned_process", "trigger": { "text": [ "isolated" ], "offsets": [ [ 787, 795 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T19" } ] }, { "id": "PMID-19742300_E8", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 876, 883 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T1004" }, { "role": "Instrument", "ref_id": "PMID-19742300_T20" } ] }, { "id": "PMID-19742300_E11", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 876, 883 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T1004" }, { "role": "Instrument", "ref_id": "PMID-19742300_T62" } ] }, { "id": "PMID-19742300_E12", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 1456, 1468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T28" } ] }, { "id": "PMID-19742300_E13", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1341, 1350 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T29" } ] }, { "id": "PMID-19742300_E14", "type": "Regulation", "trigger": { "text": [ "showed no change" ], "offsets": [ [ 1418, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T30" } ] }, { "id": "PMID-19742300_E15", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1341, 1350 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T28" } ] }, { "id": "PMID-19742300_E16", "type": "Regulation", "trigger": { "text": [ "showed no change" ], "offsets": [ [ 1418, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T31" } ] }, { "id": "PMID-19742300_E17", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 1456, 1468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T29" } ] }, { "id": "PMID-19742300_E18", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 1456, 1468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T30" } ] }, { "id": "PMID-19742300_E19", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 1456, 1468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T31" } ] }, { "id": "PMID-19742300_E20", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1496, 1505 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T1005" }, { "role": "Instrument", "ref_id": "PMID-19742300_T32" } ] }, { "id": "PMID-19742300_E21", "type": "Positive_regulation", "trigger": { "text": [ "improved" ], "offsets": [ [ 1641, 1649 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_T35" }, { "role": "Theme", "ref_id": "PMID-19742300_E31" } ] }, { "id": "PMID-19742300_E22", "type": "Positive_regulation", "trigger": { "text": [ "beneficial effect" ], "offsets": [ [ 1929, 1946 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_T44" }, { "role": "Theme", "ref_id": "PMID-19742300_T16" } ] }, { "id": "PMID-19742300_E23", "type": "Positive_regulation", "trigger": { "text": [ "beneficial effect" ], "offsets": [ [ 1929, 1946 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_T44" }, { "role": "Theme", "ref_id": "PMID-19742300_T46" } ] }, { "id": "PMID-19742300_E26", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 2067, 2071 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_T48" }, { "role": "Theme", "ref_id": "PMID-19742300_E49" } ] }, { "id": "PMID-19742300_E27", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 2126, 2133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19742300_T51" } ] }, { "id": "PMID-19742300_E28", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 2158, 2164 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19742300_E27" }, { "role": "Theme", "ref_id": "PMID-19742300_T52" } ] }, { "id": "PMID-19742300_E29", "type": "Blood_vessel_development", "trigger": { "text": [ "vascularization" ], "offsets": [ [ 588, 603 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19742300_T13" } ] }, { "id": "PMID-19742300_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1224, 1236 ] ] }, "arguments": [] }, { "id": "PMID-19742300_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "vascularization" ], "offsets": [ [ 1656, 1671 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19742300_T37" } ] } ]

[ { "id": "PMID-19742300_1", "entity_ids": [ "PMID-19742300_T15", "PMID-19742300_T18" ] }, { "id": "PMID-19742300_2", "entity_ids": [ "PMID-19742300_T20", "PMID-19742300_T21" ] } ]

[ { "id": "PMID-19742300_R1", "type": "frag", "arg1_id": "PMID-19742300_T16", "arg2_id": "PMID-19742300_T46", "normalized": [] }, { "id": "PMID-19742300_R2", "type": "frag", "arg1_id": "PMID-19742300_T71", "arg2_id": "PMID-19742300_T1003", "normalized": [] } ]

[ { "id": "PMID-15715968__text", "type": "abstract", "text": [ "Expression and purification of the catalytic domain of human vascular endothelial growth factor receptor 2 for inhibitor screening.\n\nVascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, can act in tumor-induced angiogenesis by binding to specific receptors on the surface of endothelial cells. One such receptor, VEGFR-2/KDR, plays a key role in VEGF-induced angiogenesis. Here, we expressed the catalytic domain of VEGFR-2 as a soluble active kinase using Bac-to-Bac expression system, and investigated correlations between VEGFR-2 activity and enzyme concentration, ATP concentration, substrate concentration and divalent cation type. We used these data to establish a convenient, effective and non-radioactive ELISA screening technique for the identification and evaluation of potential inhibitors for VEGFR-2 kinase. We screened 200 RTK target-based compounds and identified one (TKI-31) that potently inhibited VEGFR-2 kinase activity (IC50=0.596 microM). Treatment of NIH3T3/KDR cells with TKI-31 blocked VEGF-induced phosphorylation of KDR in a dose-dependent manner. Moreover, TKI-31 dose-dependently suppressed HUVEC tube formation. Thus, we herein report a novel, efficient method for identifying VEGFR-2 kinase inhibitors and introduce one, TKI-31, that may prove to be a useful new angiogenesis inhibitor.\n" ], "offsets": [ [ 0, 1346 ] ] } ]

[ { "id": "PMID-15715968_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptor 2" ], "offsets": [ [ 61, 106 ] ], "normalized": [] }, { "id": "PMID-15715968_T3", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 133, 167 ] ], "normalized": [] }, { "id": "PMID-15715968_T4", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 169, 173 ] ], "normalized": [] }, { "id": "PMID-15715968_T5", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 179, 195 ] ], "normalized": [] }, { "id": "PMID-15715968_T7", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 225, 230 ] ], "normalized": [] }, { "id": "PMID-15715968_T9", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 303, 320 ] ], "normalized": [] }, { "id": "PMID-15715968_T10", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 341, 348 ] ], "normalized": [] }, { "id": "PMID-15715968_T11", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 349, 352 ] ], "normalized": [] }, { "id": "PMID-15715968_T12", "type": "Drug_or_compound", "text": [ "ATP" ], "offsets": [ [ 596, 599 ] ], "normalized": [] }, { "id": "PMID-15715968_T13", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 374, 378 ] ], "normalized": [] }, { "id": "PMID-15715968_T15", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 444, 451 ] ], "normalized": [] }, { "id": "PMID-15715968_T16", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 553, 560 ] ], "normalized": [] }, { "id": "PMID-15715968_T17", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 833, 840 ] ], "normalized": [] }, { "id": "PMID-15715968_T19", "type": "Drug_or_compound", "text": [ "TKI-31" ], "offsets": [ [ 912, 918 ] ], "normalized": [] }, { "id": "PMID-15715968_T21", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 944, 951 ] ], "normalized": [] }, { "id": "PMID-15715968_T23", "type": "Cell", "text": [ "NIH3T3/KDR cells" ], "offsets": [ [ 1002, 1018 ] ], "normalized": [] }, { "id": "PMID-15715968_T24", "type": "Drug_or_compound", "text": [ "TKI-31" ], "offsets": [ [ 1024, 1030 ] ], "normalized": [] }, { "id": "PMID-15715968_T26", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "PMID-15715968_T27", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 1071, 1074 ] ], "normalized": [] }, { "id": "PMID-15715968_T28", "type": "Drug_or_compound", "text": [ "TKI-31" ], "offsets": [ [ 1113, 1119 ] ], "normalized": [] }, { "id": "PMID-15715968_T32", "type": "Tissue", "text": [ "HUVEC tube" ], "offsets": [ [ 1148, 1158 ] ], "normalized": [] }, { "id": "PMID-15715968_T33", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 1235, 1242 ] ], "normalized": [] }, { "id": "PMID-15715968_T34", "type": "Drug_or_compound", "text": [ "TKI-31" ], "offsets": [ [ 1280, 1286 ] ], "normalized": [] }, { "id": "PMID-15715968_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 55, 60 ] ], "normalized": [] } ]

[ { "id": "PMID-15715968_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T2" } ] }, { "id": "PMID-15715968_E2", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 410, 419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T15" } ] }, { "id": "PMID-15715968_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 934, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15715968_T19" }, { "role": "Theme", "ref_id": "PMID-15715968_T21" } ] }, { "id": "PMID-15715968_E22", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1031, 1038 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15715968_E10" }, { "role": "Theme", "ref_id": "PMID-15715968_E25" } ] }, { "id": "PMID-15715968_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1052, 1067 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T27" } ] }, { "id": "PMID-15715968_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 255, 262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T9" }, { "role": "Theme", "ref_id": "PMID-15715968_T3" } ] }, { "id": "PMID-15715968_E5", "type": "Regulation", "trigger": { "text": [ "act" ], "offsets": [ [ 218, 221 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15715968_E4" }, { "role": "Theme", "ref_id": "PMID-15715968_E14" } ] }, { "id": "PMID-15715968_E6", "type": "Regulation", "trigger": { "text": [ "plays a key role" ], "offsets": [ [ 354, 370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_E15" }, { "role": "Cause", "ref_id": "PMID-15715968_T11" } ] }, { "id": "PMID-15715968_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 379, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_E15" }, { "role": "Cause", "ref_id": "PMID-15715968_T13" } ] }, { "id": "PMID-15715968_E8", "type": "Regulation", "trigger": { "text": [ "plays a key role" ], "offsets": [ [ 354, 370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_E15" }, { "role": "Cause", "ref_id": "PMID-15715968_T10" } ] }, { "id": "PMID-15715968_E10", "type": "Planned_process", "trigger": { "text": [ "Treatment" ], "offsets": [ [ 989, 998 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T23" }, { "role": "Instrument", "ref_id": "PMID-15715968_T24" } ] }, { "id": "PMID-15715968_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1044, 1051 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15715968_T26" }, { "role": "Theme", "ref_id": "PMID-15715968_E25" } ] }, { "id": "PMID-15715968_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1137, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_E13" }, { "role": "Cause", "ref_id": "PMID-15715968_T28" } ] }, { "id": "PMID-15715968_E13", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1159, 1168 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15715968_T32" } ] }, { "id": "PMID-15715968_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 239, 251 ] ] }, "arguments": [] }, { "id": "PMID-15715968_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 387, 399 ] ] }, "arguments": [] }, { "id": "PMID-15715968_E16", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1322, 1334 ] ] }, "arguments": [] }, { "id": "PMID-15715968_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 231, 238 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15715968_T7" }, { "role": "Theme", "ref_id": "PMID-15715968_E14" } ] } ]

[ { "id": "PMID-15715968_1", "entity_ids": [ "PMID-15715968_T3", "PMID-15715968_T4" ] } ]

[]

[ { "id": "PMID-12167423__text", "type": "abstract", "text": [ "Molecular characterization of angiogenic properties of human oral squamous cell carcinoma cells.\n\nLittle is known about the specificity of angiogenic properties of oral cancer cells and the possible mechanisms. Stimulatory effects on proliferation and migration of human umbilical vein endothelial cells (HUVEC) characterized the angiogenic properties of oral cancer cells but not normal oral keratinocytes (NOK). ELISA found the presence of vascular endothelial growth factors (VEGF) both in the tested oral cancer cells and NOK. Attenuation of the proangiogenic effects by neutralizing VEGF antibodies suggests VEGF play a key role in the acquisition of the angiogenic phenotype in oral cancer cells. Western blotting of p53 and murine double mutant 2 (Mdm2) together with p53 DNA sequencing analysis indicate that p53 function loss by mutation or overexpression of Mdm2 occurred in all tested oral cancer cells regardless of their etiology. In summary, the angiogenic property of oral cancer cells is mediated by many factors in addition to VEGF and the functional status of p53.\n" ], "offsets": [ [ 0, 1083 ] ] } ]

[ { "id": "PMID-12167423_T2", "type": "Cell", "text": [ "oral squamous cell carcinoma cells" ], "offsets": [ [ 61, 95 ] ], "normalized": [] }, { "id": "PMID-12167423_T4", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 164, 181 ] ], "normalized": [] }, { "id": "PMID-12167423_T11", "type": "Cell", "text": [ "human umbilical vein endothelial cells" ], "offsets": [ [ 265, 303 ] ], "normalized": [] }, { "id": "PMID-12167423_T13", "type": "Cell", "text": [ "HUVEC" ], "offsets": [ [ 305, 310 ] ], "normalized": [] }, { "id": "PMID-12167423_T15", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 355, 372 ] ], "normalized": [] }, { "id": "PMID-12167423_T17", "type": "Cell", "text": [ "normal oral keratinocytes" ], "offsets": [ [ 381, 406 ] ], "normalized": [] }, { "id": "PMID-12167423_T18", "type": "Cell", "text": [ "NOK" ], "offsets": [ [ 408, 411 ] ], "normalized": [] }, { "id": "PMID-12167423_T19", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factors" ], "offsets": [ [ 442, 477 ] ], "normalized": [] }, { "id": "PMID-12167423_T20", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 479, 483 ] ], "normalized": [] }, { "id": "PMID-12167423_T21", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 504, 521 ] ], "normalized": [] }, { "id": "PMID-12167423_T23", "type": "Cell", "text": [ "NOK" ], "offsets": [ [ 526, 529 ] ], "normalized": [] }, { "id": "PMID-12167423_T27", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 588, 592 ] ], "normalized": [] }, { "id": "PMID-12167423_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "PMID-12167423_T31", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 684, 701 ] ], "normalized": [] }, { "id": "PMID-12167423_T33", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 723, 726 ] ], "normalized": [] }, { "id": "PMID-12167423_T34", "type": "Gene_or_gene_product", "text": [ "murine double mutant 2" ], "offsets": [ [ 731, 753 ] ], "normalized": [] }, { "id": "PMID-12167423_T35", "type": "Gene_or_gene_product", "text": [ "Mdm2" ], "offsets": [ [ 755, 759 ] ], "normalized": [] }, { "id": "PMID-12167423_T36", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 775, 778 ] ], "normalized": [] }, { "id": "PMID-12167423_T38", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 817, 820 ] ], "normalized": [] }, { "id": "PMID-12167423_T40", "type": "Gene_or_gene_product", "text": [ "Mdm2" ], "offsets": [ [ 868, 872 ] ], "normalized": [] }, { "id": "PMID-12167423_T41", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 896, 913 ] ], "normalized": [] }, { "id": "PMID-12167423_T45", "type": "Cell", "text": [ "oral cancer cells" ], "offsets": [ [ 983, 1000 ] ], "normalized": [] }, { "id": "PMID-12167423_T48", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1044, 1048 ] ], "normalized": [] }, { "id": "PMID-12167423_T49", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1078, 1081 ] ], "normalized": [] }, { "id": "PMID-12167423_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 55, 60 ] ], "normalized": [] }, { "id": "PMID-12167423_T26", "type": "Gene_or_gene_product", "text": [ "neutralizing VEGF antibodies" ], "offsets": [ [ 575, 603 ] ], "normalized": [] } ]

[ { "id": "PMID-12167423_E8", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 234, 247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_T11" } ] }, { "id": "PMID-12167423_E10", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 252, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_T11" } ] }, { "id": "PMID-12167423_E39", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 850, 864 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_T40" } ] }, { "id": "PMID-12167423_E1", "type": "Positive_regulation", "trigger": { "text": [ "Stimulatory effects" ], "offsets": [ [ 211, 230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_E8" } ] }, { "id": "PMID-12167423_E2", "type": "Positive_regulation", "trigger": { "text": [ "Stimulatory effects" ], "offsets": [ [ 211, 230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_E10" } ] }, { "id": "PMID-12167423_E3", "type": "Negative_regulation", "trigger": { "text": [ "Attenuation" ], "offsets": [ [ 531, 542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_E15" }, { "role": "Cause", "ref_id": "PMID-12167423_T26" } ] }, { "id": "PMID-12167423_E5", "type": "Regulation", "trigger": { "text": [ "play a key role" ], "offsets": [ [ 618, 633 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12167423_T28" }, { "role": "Theme", "ref_id": "PMID-12167423_E16" } ] }, { "id": "PMID-12167423_E6", "type": "Negative_regulation", "trigger": { "text": [ "function loss" ], "offsets": [ [ 821, 834 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12167423_E39" }, { "role": "Theme", "ref_id": "PMID-12167423_T38" } ] }, { "id": "PMID-12167423_E11", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1004, 1012 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_E17" }, { "role": "Cause", "ref_id": "PMID-12167423_T48" } ] }, { "id": "PMID-12167423_E12", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1004, 1012 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12167423_E17" }, { "role": "Cause", "ref_id": "PMID-12167423_T49" } ] }, { "id": "PMID-12167423_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 30, 40 ] ] }, "arguments": [] }, { "id": "PMID-12167423_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 330, 340 ] ] }, "arguments": [] }, { "id": "PMID-12167423_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 553, 563 ] ] }, "arguments": [] }, { "id": "PMID-12167423_E16", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 660, 670 ] ] }, "arguments": [] }, { "id": "PMID-12167423_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 960, 970 ] ] }, "arguments": [] }, { "id": "PMID-12167423_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 139, 149 ] ] }, "arguments": [] } ]

[ { "id": "PMID-12167423_1", "entity_ids": [ "PMID-12167423_T34", "PMID-12167423_T35" ] }, { "id": "PMID-12167423_2", "entity_ids": [ "PMID-12167423_T19", "PMID-12167423_T20" ] }, { "id": "PMID-12167423_3", "entity_ids": [ "PMID-12167423_T11", "PMID-12167423_T13" ] }, { "id": "PMID-12167423_4", "entity_ids": [ "PMID-12167423_T17", "PMID-12167423_T18" ] } ]

[]

[ { "id": "PMID-17306711__text", "type": "abstract", "text": [ "Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease.\n\nOBJECTIVES: This study sought to assess the cellular and histologic basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD). BACKGROUND: Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. Because failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis in subjects with PHT and CHD. METHODS: We assessed antiapoptotic and proapoptotic markers in vascular and perivascular cells in lung biopsy samples from 18 patients with CHD, 7 with reversible and 11 with irreversible PHT, and 6 control patients. Immunostaining for endothelial nitric oxide synthase, vascular endothelial growth factor, and CD34 (markers of vasoactivity and neoangiogenesis) was also performed. RESULTS: The antiapoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in control patients (p less than 0.001). Intimal proliferation was present in 10 of 11 irreversible PHT cases, but never observed in reversible PHT (p less than 0.001). Similarly, perivascular inflammatory T-cells expressed more antiapoptotic proteins in irreversible PHT (p less than 0.01). Irreversible PHT cases were also more likely to show compensatory upregulation of vascular endothelial growth factor and new small vessel formation at the sites of native vessel stenosis or occlusion (p less than 0.001). CONCLUSIONS: Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and antiapoptotic signaling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing, and thereby may contribute to clinical outcomes associated with pulmonary hypertension.\n" ], "offsets": [ [ 0, 2155 ] ] } ]

[ { "id": "PMID-17306711_T2", "type": "Cell", "text": [ "pulmonary endothelial cells" ], "offsets": [ [ 22, 49 ] ], "normalized": [] }, { "id": "PMID-17306711_T4", "type": "Organ", "text": [ "heart" ], "offsets": [ [ 151, 156 ] ], "normalized": [] }, { "id": "PMID-17306711_T5", "type": "Organ", "text": [ "heart" ], "offsets": [ [ 324, 329 ] ], "normalized": [] }, { "id": "PMID-17306711_T7", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 558, 574 ] ], "normalized": [] }, { "id": "PMID-17306711_T9", "type": "Cell", "text": [ "vascular" ], "offsets": [ [ 824, 832 ] ], "normalized": [] }, { "id": "PMID-17306711_T11", "type": "Cell", "text": [ "perivascular cells" ], "offsets": [ [ 837, 855 ] ], "normalized": [] }, { "id": "PMID-17306711_T13", "type": "Multi-tissue_structure", "text": [ "lung biopsy samples" ], "offsets": [ [ 859, 878 ] ], "normalized": [] }, { "id": "PMID-17306711_T14", "type": "Gene_or_gene_product", "text": [ "endothelial nitric oxide synthase" ], "offsets": [ [ 997, 1030 ] ], "normalized": [] }, { "id": "PMID-17306711_T15", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1032, 1066 ] ], "normalized": [] }, { "id": "PMID-17306711_T16", "type": "Gene_or_gene_product", "text": [ "CD34" ], "offsets": [ [ 1072, 1076 ] ], "normalized": [] }, { "id": "PMID-17306711_T19", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [] }, { "id": "PMID-17306711_T20", "type": "Cell", "text": [ "pulmonary endothelial cells" ], "offsets": [ [ 1208, 1235 ] ], "normalized": [] }, { "id": "PMID-17306711_T21", "type": "Cell", "text": [ "perivascular inflammatory T-cells" ], "offsets": [ [ 1492, 1525 ] ], "normalized": [] }, { "id": "PMID-17306711_T24", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1688, 1722 ] ], "normalized": [] }, { "id": "PMID-17306711_T26", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1737, 1743 ] ], "normalized": [] }, { "id": "PMID-17306711_T29", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1777, 1783 ] ], "normalized": [] }, { "id": "PMID-17306711_T31", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1896, 1912 ] ], "normalized": [] }, { "id": "PMID-17306711_T33", "type": "Cell", "text": [ "perivascular inflammatory cells" ], "offsets": [ [ 1956, 1987 ] ], "normalized": [] }, { "id": "PMID-17306711_T36", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 2049, 2055 ] ], "normalized": [] }, { "id": "PMID-17306711_T3", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 69, 76 ] ], "normalized": [] }, { "id": "PMID-17306711_T10", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 599, 606 ] ], "normalized": [] }, { "id": "PMID-17306711_T12", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 2023, 2030 ] ], "normalized": [] }, { "id": "PMID-17306711_T1000", "type": "Organism", "text": [ "children" ], "offsets": [ [ 371, 379 ] ], "normalized": [] }, { "id": "PMID-17306711_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 887, 895 ] ], "normalized": [] }, { "id": "PMID-17306711_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 968, 976 ] ], "normalized": [] }, { "id": "PMID-17306711_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1319, 1327 ] ], "normalized": [] }, { "id": "PMID-17306711_T38", "type": "Tissue", "text": [ "Intimal" ], "offsets": [ [ 1351, 1358 ] ], "normalized": [] } ]

[ { "id": "PMID-17306711_E1", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 9, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T2" } ] }, { "id": "PMID-17306711_E6", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 575, 584 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T7" } ] }, { "id": "PMID-17306711_E18", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1195, 1204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T19" } ] }, { "id": "PMID-17306711_E23", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 1672, 1684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T24" } ] }, { "id": "PMID-17306711_E30", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 1887, 1895 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_E2" } ] }, { "id": "PMID-17306711_E2", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1913, 1922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T31" } ] }, { "id": "PMID-17306711_E3", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 77, 90 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T3" } ] }, { "id": "PMID-17306711_E4", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 607, 620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T10" } ] }, { "id": "PMID-17306711_E5", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1359, 1372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T38" } ] }, { "id": "PMID-17306711_E7", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1744, 1753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T26" } ] }, { "id": "PMID-17306711_E8", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 1672, 1684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_E7" } ] }, { "id": "PMID-17306711_E9", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 1887, 1895 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_E13" } ] }, { "id": "PMID-17306711_E10", "type": "Growth", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 2031, 2044 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17306711_T12" } ] }, { "id": "PMID-17306711_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 718, 730 ] ] }, "arguments": [] }, { "id": "PMID-17306711_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 1106, 1121 ] ] }, "arguments": [] }, { "id": "PMID-17306711_E13", "type": "Pathway", "trigger": { "text": [ "antiapoptotic signaling" ], "offsets": [ [ 1927, 1950 ] ] }, "arguments": [] } ]

[]

[ { "id": "PMID-17306711_R1", "type": "frag", "arg1_id": "PMID-17306711_T9", "arg2_id": "PMID-17306711_T11", "normalized": [] } ]

[ { "id": "PMID-15510518__text", "type": "abstract", "text": [ "[Glaucoma and ocular ischemic syndrome--case report]\n\nPURPOSE: Ocular ischemic syndrome (OIS) is often poorly diagnosed and treated as primary open angle glaucoma or later on, as neovascular glaucoma. We present a 54 year old male, treated topical since 23 years for glaucoma and sent to our clinic for trabeculectomy because of rapid worsening of vision on right eye with bilateral total excavation of optic disc. MATERIAL AND METHODS: Observational case report. RESULTS: Because of typical signs of IOS (iris neovascularization, mid-peripheral dot and blot hemorrhages in both eyes, narrowed arterioles in right eye, following examinations were performed: Doppler ultrasonography of carotid arteries, digital subtractional angiography of the carotid vessels and magnetic resonance angiography. The examinations showed occlusion of the right common carotid artery and with 80% stenosis of the left common carotid artery, occlusion of abdominal aorta. After phacoemulsification with implantation of intraocular lens because of rapid intumescence cataract in the right eye, and endarterectomy of left external carotid artery, the neovascularization of the iris regressed in both eyes. CONCLUSION: In case of iris neovascularization or mid-peripheral hemorrhages the Doppler sonography of carotid arteries should be performed. Quick cooperation between ophthalmologist, radiologist and vascular surgeon following endarterectomy seems to stop progressing changes of ocular ischemic syndrome.\n" ], "offsets": [ [ 0, 1489 ] ] } ]

[ { "id": "PMID-15510518_T2", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 364, 367 ] ], "normalized": [] }, { "id": "PMID-15510518_T3", "type": "Multi-tissue_structure", "text": [ "iris" ], "offsets": [ [ 506, 510 ] ], "normalized": [] }, { "id": "PMID-15510518_T5", "type": "Organ", "text": [ "eyes" ], "offsets": [ [ 579, 583 ] ], "normalized": [] }, { "id": "PMID-15510518_T6", "type": "Multi-tissue_structure", "text": [ "arterioles" ], "offsets": [ [ 594, 604 ] ], "normalized": [] }, { "id": "PMID-15510518_T7", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 614, 617 ] ], "normalized": [] }, { "id": "PMID-15510518_T8", "type": "Multi-tissue_structure", "text": [ "carotid arteries" ], "offsets": [ [ 685, 701 ] ], "normalized": [] }, { "id": "PMID-15510518_T9", "type": "Multi-tissue_structure", "text": [ "carotid vessels" ], "offsets": [ [ 744, 759 ] ], "normalized": [] }, { "id": "PMID-15510518_T10", "type": "Multi-tissue_structure", "text": [ "right common carotid artery" ], "offsets": [ [ 837, 864 ] ], "normalized": [] }, { "id": "PMID-15510518_T11", "type": "Multi-tissue_structure", "text": [ "left common carotid artery" ], "offsets": [ [ 894, 920 ] ], "normalized": [] }, { "id": "PMID-15510518_T12", "type": "Multi-tissue_structure", "text": [ "abdominal aorta" ], "offsets": [ [ 935, 950 ] ], "normalized": [] }, { "id": "PMID-15510518_T13", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 1068, 1071 ] ], "normalized": [] }, { "id": "PMID-15510518_T14", "type": "Multi-tissue_structure", "text": [ "left external carotid artery" ], "offsets": [ [ 1095, 1123 ] ], "normalized": [] }, { "id": "PMID-15510518_T16", "type": "Multi-tissue_structure", "text": [ "iris" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "PMID-15510518_T17", "type": "Organ", "text": [ "eyes" ], "offsets": [ [ 1178, 1182 ] ], "normalized": [] }, { "id": "PMID-15510518_T18", "type": "Multi-tissue_structure", "text": [ "iris" ], "offsets": [ [ 1207, 1211 ] ], "normalized": [] }, { "id": "PMID-15510518_T20", "type": "Multi-tissue_structure", "text": [ "carotid arteries" ], "offsets": [ [ 1287, 1303 ] ], "normalized": [] }, { "id": "PMID-15510518_T22", "type": "Organ", "text": [ "Ocular" ], "offsets": [ [ 63, 69 ] ], "normalized": [] }, { "id": "PMID-15510518_T21", "type": "Organism", "text": [ "male" ], "offsets": [ [ 226, 230 ] ], "normalized": [] }, { "id": "PMID-15510518_T24", "type": "Multi-tissue_structure", "text": [ "lens" ], "offsets": [ [ 1011, 1015 ] ], "normalized": [] } ]

[ { "id": "PMID-15510518_E2", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 232, 239 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15510518_T21" } ] }, { "id": "PMID-15510518_E3", "type": "Planned_process", "trigger": { "text": [ "implantation" ], "offsets": [ [ 983, 995 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15510518_T24" } ] }, { "id": "PMID-15510518_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 511, 529 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15510518_T3" } ] }, { "id": "PMID-15510518_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 1129, 1147 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15510518_T16" } ] }, { "id": "PMID-15510518_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 1212, 1230 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15510518_T18" } ] }, { "id": "PMID-15510518_E7", "type": "Negative_regulation", "trigger": { "text": [ "regressed" ], "offsets": [ [ 1160, 1169 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15510518_E5" } ] } ]

[]

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