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BigScience Biomedical Datasets 112

[ { "id": "PMID-12484699__text", "type": "abstract", "text": [ "Regulation of transforming growth factor-beta signaling and vascular diseases.\n\nPURPOSE: Members of the transforming growth factor (TGF)-beta superfamily play critical roles in regulation of various cellular functions. Dysregulation of the signaling mechanisms of the TGF-beta superfamily proteins is associated with clinical diseases such as cancer, fibrotic diseases, and vascular disorders. Therefore, understanding these signaling mechanisms may provide us with novel ways to develop strategies for treating clinical diseases induced by these cytokines. METHODS: This review discusses our current understanding of the mechanisms of TGF-beta signaling, focusing on the roles of TGF-beta in regulation of vascular wall cells and on the regulation of TGF-beta superfamily signals by inhibitory Smads.\n" ], "offsets": [ [ 0, 802 ] ] } ]

[ { "id": "PMID-12484699_T2", "type": "Gene_or_gene_product", "text": [ "transforming growth factor-beta" ], "offsets": [ [ 14, 45 ] ], "normalized": [] }, { "id": "PMID-12484699_T5", "type": "Gene_or_gene_product", "text": [ "transforming growth factor (TGF)-beta" ], "offsets": [ [ 104, 141 ] ], "normalized": [] }, { "id": "PMID-12484699_T8", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 268, 276 ] ], "normalized": [] }, { "id": "PMID-12484699_T12", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 636, 644 ] ], "normalized": [] }, { "id": "PMID-12484699_T14", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 681, 689 ] ], "normalized": [] }, { "id": "PMID-12484699_T17", "type": "Cell", "text": [ "vascular wall cells" ], "offsets": [ [ 707, 726 ] ], "normalized": [] }, { "id": "PMID-12484699_T21", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 752, 760 ] ], "normalized": [] }, { "id": "PMID-12484699_T22", "type": "Gene_or_gene_product", "text": [ "Smads" ], "offsets": [ [ 795, 800 ] ], "normalized": [] } ]

[ { "id": "PMID-12484699_E16", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 693, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T17" } ] }, { "id": "PMID-12484699_E19", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 738, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T21" }, { "role": "Cause", "ref_id": "PMID-12484699_E4" } ] }, { "id": "PMID-12484699_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_E5" } ] }, { "id": "PMID-12484699_E2", "type": "Regulation", "trigger": { "text": [ "Dysregulation" ], "offsets": [ [ 219, 232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T8" } ] }, { "id": "PMID-12484699_E3", "type": "Regulation", "trigger": { "text": [ "roles" ], "offsets": [ [ 672, 677 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12484699_T14" }, { "role": "Theme", "ref_id": "PMID-12484699_E16" } ] }, { "id": "PMID-12484699_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 784, 794 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12484699_T22" } ] }, { "id": "PMID-12484699_E5", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 46, 55 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12484699_T2" } ] }, { "id": "PMID-12484699_E6", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 645, 654 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12484699_T12" } ] } ]

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[ { "id": "PMID-16268479__text", "type": "abstract", "text": [ "Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt.\n\nDomain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the P13-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response toVEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3alpha HKa and D5 inhibit phosphorylation of Akt and GSK-3alpha after stimulation withVEGF and S1P. Inhibitors of Akt and P13-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P. Therefore we suggest that HKa through its D5 domain alters P13-kinase-Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions.\n" ], "offsets": [ [ 0, 1759 ] ] } ]

[ { "id": "PMID-16268479_T2", "type": "Gene_or_gene_product", "text": [ "high molecular weight kininogen" ], "offsets": [ [ 20, 51 ] ], "normalized": [] }, { "id": "PMID-16268479_T6", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 61, 77 ] ], "normalized": [] }, { "id": "PMID-16268479_T7", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 96, 99 ] ], "normalized": [] }, { "id": "PMID-16268479_T11", "type": "Gene_or_gene_product", "text": [ "high molecular weight kininogen" ], "offsets": [ [ 127, 158 ] ], "normalized": [] }, { "id": "PMID-16268479_T12", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 160, 163 ] ], "normalized": [] }, { "id": "PMID-16268479_T17", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 199, 215 ] ], "normalized": [] }, { "id": "PMID-16268479_T19", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 280, 283 ] ], "normalized": [] }, { "id": "PMID-16268479_T24", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 305, 321 ] ], "normalized": [] }, { "id": "PMID-16268479_T25", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 398, 401 ] ], "normalized": [] }, { "id": "PMID-16268479_T31", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 449, 465 ] ], "normalized": [] }, { "id": "PMID-16268479_T32", "type": "Gene_or_gene_product", "text": [ "sphingosine 1-phosphate" ], "offsets": [ [ 477, 500 ] ], "normalized": [] }, { "id": "PMID-16268479_T33", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "PMID-16268479_T34", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 511, 545 ] ], "normalized": [] }, { "id": "PMID-16268479_T35", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 547, 551 ] ], "normalized": [] }, { "id": "PMID-16268479_T37", "type": "Gene_or_gene_product", "text": [ "P13-kinase" ], "offsets": [ [ 575, 585 ] ], "normalized": [] }, { "id": "PMID-16268479_T38", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 586, 589 ] ], "normalized": [] }, { "id": "PMID-16268479_T39", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 609, 612 ] ], "normalized": [] }, { "id": "PMID-16268479_T44", "type": "Cell", "text": [ "pulmonary artery endothelial cell" ], "offsets": [ [ 635, 668 ] ], "normalized": [] }, { "id": "PMID-16268479_T46", "type": "Cell", "text": [ "BPAE" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-16268479_T49", "type": "Cell", "text": [ "umbilical vein endothelial cell" ], "offsets": [ [ 685, 716 ] ], "normalized": [] }, { "id": "PMID-16268479_T51", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 773, 777 ] ], "normalized": [] }, { "id": "PMID-16268479_T52", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 781, 784 ] ], "normalized": [] }, { "id": "PMID-16268479_T53", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 817, 820 ] ], "normalized": [] }, { "id": "PMID-16268479_T56", "type": "Gene_or_gene_product", "text": [ "urokinase-type plasminogen activator receptor" ], "offsets": [ [ 850, 895 ] ], "normalized": [] }, { "id": "PMID-16268479_T57", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 902, 905 ] ], "normalized": [] }, { "id": "PMID-16268479_T62", "type": "Cell", "text": [ "BPAE cell" ], "offsets": [ [ 935, 944 ] ], "normalized": [] }, { "id": "PMID-16268479_T66", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1034, 1037 ] ], "normalized": [] }, { "id": "PMID-16268479_T67", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1041, 1045 ] ], "normalized": [] }, { "id": "PMID-16268479_T68", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1047, 1050 ] ], "normalized": [] }, { "id": "PMID-16268479_T71", "type": "Gene_or_gene_product", "text": [ "paxillin" ], "offsets": [ [ 1085, 1093 ] ], "normalized": [] }, { "id": "PMID-16268479_T73", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1123, 1126 ] ], "normalized": [] }, { "id": "PMID-16268479_T75", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1131, 1135 ] ], "normalized": [] }, { "id": "PMID-16268479_T76", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1234, 1237 ] ], "normalized": [] }, { "id": "PMID-16268479_T79", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1264, 1267 ] ], "normalized": [] }, { "id": "PMID-16268479_T80", "type": "Gene_or_gene_product", "text": [ "GSK-3alpha" ], "offsets": [ [ 1297, 1307 ] ], "normalized": [] }, { "id": "PMID-16268479_T81", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1308, 1311 ] ], "normalized": [] }, { "id": "PMID-16268479_T85", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1346, 1349 ] ], "normalized": [] }, { "id": "PMID-16268479_T86", "type": "Gene_or_gene_product", "text": [ "GSK-3alpha" ], "offsets": [ [ 1354, 1364 ] ], "normalized": [] }, { "id": "PMID-16268479_T89", "type": "Gene_or_gene_product", "text": [ "withVEGF" ], "offsets": [ [ 1383, 1391 ] ], "normalized": [] }, { "id": "PMID-16268479_T90", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1396, 1399 ] ], "normalized": [] }, { "id": "PMID-16268479_T91", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1415, 1418 ] ], "normalized": [] }, { "id": "PMID-16268479_T92", "type": "Gene_or_gene_product", "text": [ "P13-kinase" ], "offsets": [ [ 1423, 1433 ] ], "normalized": [] }, { "id": "PMID-16268479_T93", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1461, 1464 ] ], "normalized": [] }, { "id": "PMID-16268479_T97", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1472, 1488 ] ], "normalized": [] }, { "id": "PMID-16268479_T99", "type": "Gene_or_gene_product", "text": [ "paxillin" ], "offsets": [ [ 1511, 1519 ] ], "normalized": [] }, { "id": "PMID-16268479_T102", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1579, 1583 ] ], "normalized": [] }, { "id": "PMID-16268479_T103", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1588, 1591 ] ], "normalized": [] }, { "id": "PMID-16268479_T104", "type": "Gene_or_gene_product", "text": [ "HKa" ], "offsets": [ [ 1619, 1622 ] ], "normalized": [] }, { "id": "PMID-16268479_T107", "type": "Gene_or_gene_product", "text": [ "P13-kinase" ], "offsets": [ [ 1652, 1662 ] ], "normalized": [] }, { "id": "PMID-16268479_T108", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1663, 1666 ] ], "normalized": [] }, { "id": "PMID-16268479_T112", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 1688, 1704 ] ], "normalized": [] }, { "id": "PMID-16268479_T1000", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 628, 634 ] ], "normalized": [] }, { "id": "PMID-16268479_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 679, 684 ] ], "normalized": [] }, { "id": "PMID-16268479_T1", "type": "Protein_domain_or_region", "text": [ "Domain 5" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-16268479_T8", "type": "Protein_domain_or_region", "text": [ "Domain 5" ], "offsets": [ [ 102, 110 ] ], "normalized": [] }, { "id": "PMID-16268479_T9", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 112, 114 ] ], "normalized": [] }, { "id": "PMID-16268479_T21", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 288, 290 ] ], "normalized": [] }, { "id": "PMID-16268479_T27", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 406, 408 ] ], "normalized": [] }, { "id": "PMID-16268479_T40", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 617, 619 ] ], "normalized": [] }, { "id": "PMID-16268479_T55", "type": "Gene_or_gene_product", "text": [ "antibodies to urokinase-type plasminogen activator receptor" ], "offsets": [ [ 836, 895 ] ], "normalized": [] }, { "id": "PMID-16268479_T58", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 910, 912 ] ], "normalized": [] }, { "id": "PMID-16268479_T69", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 1055, 1057 ] ], "normalized": [] }, { "id": "PMID-16268479_T82", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 1316, 1318 ] ], "normalized": [] }, { "id": "PMID-16268479_T105", "type": "Protein_domain_or_region", "text": [ "D5" ], "offsets": [ [ 1635, 1637 ] ], "normalized": [] }, { "id": "PMID-16268479_T50", "type": "Cellular_component", "text": [ "focal adhesions" ], "offsets": [ [ 1101, 1116 ] ], "normalized": [] }, { "id": "PMID-16268479_T109", "type": "Cellular_component", "text": [ "focal adhesions" ], "offsets": [ [ 1540, 1555 ] ], "normalized": [] }, { "id": "PMID-16268479_T114", "type": "Cellular_component", "text": [ "focal adhesions" ], "offsets": [ [ 1742, 1757 ] ], "normalized": [] }, { "id": "PMID-16268479_T115", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 244, 248 ] ], "normalized": [] } ]

[ { "id": "PMID-16268479_E5", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 78, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T6" } ] }, { "id": "PMID-16268479_E10", "type": "Protein_processing", "trigger": { "text": [ "cleaved" ], "offsets": [ [ 119, 126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T11" } ] }, { "id": "PMID-16268479_E16", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 216, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T17" } ] }, { "id": "PMID-16268479_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 291, 301 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_E23" }, { "role": "Cause", "ref_id": "PMID-16268479_T19" }, { "role": "CSite", "ref_id": "PMID-16268479_T21" } ] }, { "id": "PMID-16268479_E23", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 322, 331 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T24" } ] }, { "id": "PMID-16268479_E30", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 466, 475 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T31" } ] }, { "id": "PMID-16268479_E43", "type": "Localization", "trigger": { "text": [ "chemotaxis" ], "offsets": [ [ 717, 727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T44" } ] }, { "id": "PMID-16268479_E48", "type": "Localization", "trigger": { "text": [ "chemotaxis" ], "offsets": [ [ 717, 727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T49" } ] }, { "id": "PMID-16268479_E61", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 945, 954 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T62" } ] }, { "id": "PMID-16268479_E64", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1017, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16268479_T67" }, { "role": "Theme", "ref_id": "PMID-16268479_T62" } ] }, { "id": "PMID-16268479_E65", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1017, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16268479_T66" }, { "role": "Theme", "ref_id": "PMID-16268479_T62" } ] }, { "id": "PMID-16268479_E70", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1069, 1081 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T71" }, { "role": "ToLoc", "ref_id": "PMID-16268479_T50" } ] }, { "id": "PMID-16268479_E72", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1136, 1147 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16268479_T73" }, { "role": "Theme", "ref_id": "PMID-16268479_T62" } ] }, { "id": "PMID-16268479_E74", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1136, 1147 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16268479_T75" }, { "role": "Theme", "ref_id": "PMID-16268479_T62" } ] }, { "id": "PMID-16268479_E77", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1245, 1260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T80" } ] }, { "id": "PMID-16268479_E78", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1245, 1260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T79" } ] }, { "id": "PMID-16268479_E83", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1327, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T86" } ] }, { "id": "PMID-16268479_E84", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1327, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T85" } ] }, { "id": "PMID-16268479_E87", "type": 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"text": [ "stimulation" ], "offsets": [ [ 1562, 1573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T62" }, { "role": "Cause", "ref_id": "PMID-16268479_T102" } ] }, { "id": "PMID-16268479_E111", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1705, 1714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T112" } ] }, { "id": "PMID-16268479_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 409, 419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_T34" }, { "role": "Cause", "ref_id": "PMID-16268479_E42" } ] }, { "id": "PMID-16268479_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 165, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16268479_E16" }, { "role": "Cause", "ref_id": "PMID-16268479_T11" }, { "role": "CSite", "ref_id": "PMID-16268479_T8" } ] }, { "id": "PMID-16268479_E3", "type": "Regulation", "trigger": { 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[ { "id": "PMID-16268479_1", "entity_ids": [ "PMID-16268479_T32", "PMID-16268479_T33" ] }, { "id": "PMID-16268479_2", "entity_ids": [ "PMID-16268479_T9", "PMID-16268479_T8" ] }, { "id": "PMID-16268479_3", "entity_ids": [ "PMID-16268479_T34", "PMID-16268479_T35" ] }, { "id": "PMID-16268479_4", "entity_ids": [ "PMID-16268479_T11", "PMID-16268479_T12" ] }, { "id": "PMID-16268479_5", "entity_ids": [ "PMID-16268479_T44", "PMID-16268479_T46" ] } ]

[]

[ { "id": "PMID-11121230__text", "type": "abstract", "text": [ "RNA damage and inhibition of neoplastic endothelial cell growth: effects of human and amphibian ribonucleases.\n\nAngiogenesis defines the many steps involved in the growth and migration of endothelial cell-derived blood vessels. This process is necessary for the growth and metastasis of tumors, and considerable effort is being expended to find inhibitors of tumor angiogenesis. This usually involves screening of potential anti-angiogenic compounds on endothelial cells. To this end, two candidate anti-angiogenic RNA-damaging agents, onconase and (-4)rhEDN, were screened for their effects on endothelial cell proliferation using three distinct types of endothelial cells in culture: HPV-16 E6/E7-immortalized human umbilical vein endothelial cells (HUVECs), a Kras-transformed HPV-16 E6/E7 HUVEC (Rhim et al., Carcinogenesis 4, 673-681, 1998), and primary HUVECs. Onconase similarly inhibited proliferation in all three cell lines (IC(50) = 0.3-1.0 microM) while (-4)rhEDN was more effective on immortalized HUVEC cell lines (IC(50) = 0.02-0.06 microM) than on primary HUVECs (IC(50) > 0.1 microM). Differential sensitivity to these agents implies that more than one endothelial cell type must be used in proliferation assays to screen for novel anti-angiogenic compounds.\n" ], "offsets": [ [ 0, 1276 ] ] } ]

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[ { "id": "PMID-11121230_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 15, 25 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_E3" } ] }, { "id": "PMID-11121230_E3", "type": "Cell_proliferation", "trigger": { "text": [ "growth" ], "offsets": [ [ 57, 63 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T4" } ] }, { "id": "PMID-11121230_E9", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 164, 170 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T12" } ] }, { "id": "PMID-11121230_E11", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 175, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T12" } ] }, { "id": "PMID-11121230_E24", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 612, 625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T25" } ] }, { "id": "PMID-11121230_E4", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 262, 268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T33" } ] }, { "id": "PMID-11121230_E5", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 273, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T33" } ] }, { "id": "PMID-11121230_E6", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 584, 591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_E24" }, { "role": "Cause", "ref_id": "PMID-11121230_T21" } ] }, { "id": "PMID-11121230_E7", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 584, 591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_E24" }, { "role": "Cause", "ref_id": "PMID-11121230_T20" } ] }, { "id": "PMID-11121230_E12", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 699, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T27" }, { "role": "Instrument", "ref_id": "PMID-11121230_T43" } ] }, { "id": "PMID-11121230_E13", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 699, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T27" }, { "role": "Instrument", "ref_id": "PMID-11121230_T42" } ] }, { "id": "PMID-11121230_E14", "type": "Planned_process", "trigger": { "text": [ "transformed" ], "offsets": [ [ 768, 779 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-11121230_T13" }, { "role": "Theme", "ref_id": "PMID-11121230_T29" } ] }, { "id": "PMID-11121230_E15", "type": "Planned_process", "trigger": { "text": [ "immortalized" ], "offsets": [ [ 998, 1010 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T35" } ] }, { "id": "PMID-11121230_E16", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1208, 1221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T37" } ] }, { "id": "PMID-11121230_E17", "type": "Development", "trigger": { "text": [ "derived" ], "offsets": [ [ 205, 212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T12" } ] }, { "id": "PMID-11121230_E18", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 896, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11121230_T48" } ] }, { "id": "PMID-11121230_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 886, 895 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T31" }, { "role": "Theme", "ref_id": "PMID-11121230_E18" } ] }, { "id": "PMID-11121230_E20", "type": "Positive_regulation", "trigger": { "text": [ "effective" ], "offsets": [ [ 985, 994 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T34" }, { "role": "Theme", "ref_id": "PMID-11121230_T35" } ] }, { "id": "PMID-11121230_E21", "type": "Positive_regulation", "trigger": { "text": [ "effective" ], "offsets": [ [ 985, 994 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11121230_T34" }, { "role": "Theme", "ref_id": "PMID-11121230_T36" } ] }, { "id": "PMID-11121230_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenesis" ], "offsets": [ [ 112, 124 ] ] }, "arguments": [] }, { "id": "PMID-11121230_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 365, 377 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-11121230_T14" } ] }, { "id": "PMID-11121230_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 429, 439 ] ] }, "arguments": [] }, { "id": "PMID-11121230_E27", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 504, 514 ] ] }, "arguments": [] }, { "id": "PMID-11121230_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1254, 1264 ] ] }, "arguments": [] } ]

[ { "id": "PMID-11121230_1", "entity_ids": [ "PMID-11121230_T27", "PMID-11121230_T28" ] } ]

[ { "id": "PMID-11121230_R1", "type": "frag", "arg1_id": "PMID-11121230_T43", "arg2_id": "PMID-11121230_T42", "normalized": [] }, { "id": "PMID-11121230_R2", "type": "frag", "arg1_id": "PMID-11121230_T45", "arg2_id": "PMID-11121230_T44", "normalized": [] } ]

[ { "id": "PMID-12610665__text", "type": "abstract", "text": [ "Arteriogenesis: the development and growth of collateral arteries.\n\nIn patients with atherosclerotic vascular diseases, collateral vessels bypassing major arterial obstructions have frequently been observed. This may explain why some patients remain without symptoms or signs of ischemia. The term \"arteriogenesis\" was introduced to differentiate the formation of collateral arteries from angiogenesis, which mainly occurs in the ischemic, collateral flow-dependent tissue. Many observations in various animal models and humans support that the remodeling of preexisting collateral vessels is the mechanism of collateral artery formation. This remodeling process seems to be mainly flow-mediated. It involves endothelial cell activation, basal membrane degradation, leukocyte invasion, proliferation of vascular cells, neointima formation (in most species studied), and changes of the extracellular matrix. The contribution of ischemia to arteriogenesis is still unclear, but arteriogenesis clearly can occur in the absence of any significant ischemia. It is questionable, whether collateral arteries also form de novo in ischemic vascular diseases. A better understanding of the mechanisms of arteriogenesis will be important for the design of more effective strategies for the treatment of patients with ischemic vascular diseases.\n" ], "offsets": [ [ 0, 1334 ] ] } ]

[ { "id": "PMID-12610665_T2", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 46, 65 ] ], "normalized": [] }, { "id": "PMID-12610665_T3", "type": "Multi-tissue_structure", "text": [ "collateral vessels" ], "offsets": [ [ 120, 138 ] ], "normalized": [] }, { "id": "PMID-12610665_T5", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 364, 383 ] ], "normalized": [] }, { "id": "PMID-12610665_T7", "type": "Multi-tissue_structure", "text": [ "collateral vessels" ], "offsets": [ [ 571, 589 ] ], "normalized": [] }, { "id": "PMID-12610665_T8", "type": "Multi-tissue_structure", "text": [ "collateral artery" ], "offsets": [ [ 610, 627 ] ], "normalized": [] }, { "id": "PMID-12610665_T11", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 709, 725 ] ], "normalized": [] }, { "id": "PMID-12610665_T12", "type": "Cellular_component", "text": [ "basal membrane" ], "offsets": [ [ 738, 752 ] ], "normalized": [] }, { "id": "PMID-12610665_T13", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 766, 775 ] ], "normalized": [] }, { "id": "PMID-12610665_T16", "type": "Cell", "text": [ "vascular cells" ], "offsets": [ [ 803, 817 ] ], "normalized": [] }, { "id": "PMID-12610665_T20", "type": "Tissue", "text": [ "neointima" ], "offsets": [ [ 819, 828 ] ], "normalized": [] }, { "id": "PMID-12610665_T21", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 885, 905 ] ], "normalized": [] }, { "id": "PMID-12610665_T25", "type": "Multi-tissue_structure", "text": [ "collateral arteries" ], "offsets": [ [ 1081, 1100 ] ], "normalized": [] }, { "id": "PMID-12610665_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 71, 79 ] ], "normalized": [] }, { "id": "PMID-12610665_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 234, 242 ] ], "normalized": [] }, { "id": "PMID-12610665_T1002", "type": "Organism", "text": [ "humans" ], "offsets": [ [ 521, 527 ] ], "normalized": [] }, { "id": "PMID-12610665_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1292, 1300 ] ], "normalized": [] }, { "id": "PMID-12610665_T35", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 466, 472 ] ], "normalized": [] }, { "id": "PMID-12610665_T9", "type": "Pathological_formation", "text": [ "arterial obstructions" ], "offsets": [ [ 155, 176 ] ], "normalized": [] } ]

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"type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 351, 360 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T5" } ] }, { "id": "PMID-12610665_E4", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 545, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T7" } ] }, { "id": "PMID-12610665_E5", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 628, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T8" } ] }, { "id": "PMID-12610665_E6", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 644, 654 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T7" } ] }, { "id": "PMID-12610665_E7", "type": "Breakdown", "trigger": { "text": [ "degradation" ], "offsets": [ [ 753, 764 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T12" } ] }, { "id": "PMID-12610665_E8", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 776, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T13" } ] }, { "id": "PMID-12610665_E11", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 870, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T21" } ] }, { "id": "PMID-12610665_E12", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E10" } ] }, { "id": "PMID-12610665_E13", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E7" } ] }, { "id": "PMID-12610665_E16", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E8" } ] }, { "id": "PMID-12610665_E17", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E15" } ] }, { "id": "PMID-12610665_E20", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E19" } ] }, { "id": "PMID-12610665_E21", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 700, 708 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12610665_E6" }, { "role": "Theme", "ref_id": "PMID-12610665_E11" } ] }, { "id": "PMID-12610665_E22", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 456, 465 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T35" } ] }, { "id": "PMID-12610665_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "Arteriogenesis" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T2" } ] }, { "id": "PMID-12610665_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 299, 313 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T5" } ] }, { "id": "PMID-12610665_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 389, 401 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 939, 953 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E27", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 976, 990 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenesis" ], "offsets": [ [ 1194, 1208 ] ] }, "arguments": [] }, { "id": "PMID-12610665_E9", "type": "Development", "trigger": { "text": [ "form" ], "offsets": [ [ 1106, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12610665_T25" } ] } ]

[]

[]

[ { "id": "PMID-17462601__text", "type": "abstract", "text": [ "An antibody directed against PDGF receptor beta enhances the antitumor and the anti-angiogenic activities of an anti-VEGF receptor 2 antibody.\n\nPlatelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment and vessel maturation. Here we produced a neutralizing antibody, 1B3, directed against mouse PDGFRbeta. 1B3 binds to PDGFRbeta with high affinity (9x10(-11)M) and blocks PDGF-BB from binding to the receptor with an IC(50) of approximately 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of 1B3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFRbeta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.\n" ], "offsets": [ [ 0, 1381 ] ] } ]

[ { "id": "PMID-17462601_T1", "type": "Gene_or_gene_product", "text": [ "PDGF receptor beta" ], "offsets": [ [ 29, 47 ] ], "normalized": [] }, { "id": "PMID-17462601_T6", "type": "Gene_or_gene_product", "text": [ "VEGF receptor 2" ], "offsets": [ [ 117, 132 ] ], "normalized": [] }, { "id": "PMID-17462601_T7", "type": "Gene_or_gene_product", "text": [ "Platelet-derived growth factor" ], "offsets": [ [ 144, 174 ] ], "normalized": [] }, { "id": "PMID-17462601_T8", "type": "Gene_or_gene_product", "text": [ "PDGF" ], "offsets": [ [ 176, 180 ] ], "normalized": [] }, { "id": "PMID-17462601_T9", "type": "Gene_or_gene_product", "text": [ "PDGFR" ], "offsets": [ [ 201, 206 ] ], "normalized": [] }, { "id": "PMID-17462601_T12", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 266, 271 ] ], "normalized": [] }, { "id": "PMID-17462601_T16", "type": "Cell", "text": [ "pericyte" ], "offsets": [ [ 320, 328 ] ], "normalized": [] }, { "id": "PMID-17462601_T18", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 345, 351 ] ], "normalized": [] }, { "id": "PMID-17462601_T19", "type": "Drug_or_compound", "text": [ "1B3" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "PMID-17462601_T20", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 434, 443 ] ], "normalized": [] }, { "id": "PMID-17462601_T22", "type": "Drug_or_compound", "text": [ "1B3" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "PMID-17462601_T23", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 458, 467 ] ], "normalized": [] }, { "id": "PMID-17462601_T24", "type": "Gene_or_gene_product", "text": [ "PDGF-BB" ], "offsets": [ [ 511, 518 ] ], "normalized": [] }, { "id": "PMID-17462601_T26", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 645, 654 ] ], "normalized": [] }, { "id": "PMID-17462601_T27", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 701, 704 ] ], "normalized": [] }, { "id": "PMID-17462601_T28", "type": "Gene_or_gene_product", "text": [ "MAPK p42/44" ], "offsets": [ [ 709, 720 ] ], "normalized": [] }, { "id": "PMID-17462601_T29", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 725, 736 ] ], "normalized": [] }, { "id": "PMID-17462601_T31", "type": "Drug_or_compound", "text": [ "1B3" ], "offsets": [ [ 757, 760 ] ], "normalized": [] }, { "id": "PMID-17462601_T34", "type": "Drug_or_compound", "text": [ "DC101" ], "offsets": [ [ 836, 841 ] ], "normalized": [] }, { "id": "PMID-17462601_T35", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptor 2" ], "offsets": [ [ 878, 923 ] ], "normalized": [] }, { "id": "PMID-17462601_T36", "type": "Pathological_formation", "text": [ "BxPC-3" ], "offsets": [ [ 942, 948 ] ], "normalized": [] }, { "id": "PMID-17462601_T39", "type": "Pathological_formation", "text": [ "non-small cell lung (NCI-H460) tumor xenograft" ], "offsets": [ [ 956, 1002 ] ], "normalized": [] }, { "id": "PMID-17462601_T40", "type": "Drug_or_compound", "text": [ "1B3" ], "offsets": [ [ 1045, 1048 ] ], "normalized": [] }, { "id": "PMID-17462601_T41", "type": "Drug_or_compound", "text": [ "DC101" ], "offsets": [ [ 1053, 1058 ] ], "normalized": [] }, { "id": "PMID-17462601_T42", "type": "Pathological_formation", "text": [ "BxPC-3 xenograft" ], "offsets": [ [ 1062, 1078 ] ], "normalized": [] }, { "id": "PMID-17462601_T44", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1104, 1109 ] ], "normalized": [] }, { "id": "PMID-17462601_T45", "type": "Drug_or_compound", "text": [ "DC101" ], "offsets": [ [ 1181, 1186 ] ], "normalized": [] }, { "id": "PMID-17462601_T47", "type": "Gene_or_gene_product", "text": [ "PDGFRbeta" ], "offsets": [ [ 1250, 1259 ] ], "normalized": [] }, { "id": "PMID-17462601_T2", "type": "Pathological_formation", "text": [ "pancreatic" ], "offsets": [ [ 930, 940 ] ], "normalized": [] }, { "id": "PMID-17462601_T3", "type": "Pathological_formation", "text": [ "cancers" ], "offsets": [ [ 1372, 1379 ] ], "normalized": [] }, { "id": "PMID-17462601_T1000", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 428, 433 ] ], "normalized": [] }, { "id": "PMID-17462601_T1001", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 872, 877 ] ], "normalized": [] }, { "id": "PMID-17462601_T1002", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1087, 1091 ] ], "normalized": [] }, { "id": "PMID-17462601_T1003", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1131, 1135 ] ], "normalized": [] }, { "id": "PMID-17462601_T1004", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1163, 1167 ] ], "normalized": [] }, { "id": "PMID-17462601_T5", "type": "Gene_or_gene_product", "text": [ "anti-VEGF receptor 2 antibody" ], "offsets": [ [ 112, 141 ] ], "normalized": [] }, { "id": "PMID-17462601_T58", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 65, 70 ] ], "normalized": [] }, { "id": "PMID-17462601_T59", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 792, 797 ] ], "normalized": [] }, { "id": "PMID-17462601_T61", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1303, 1308 ] ], "normalized": [] } ]

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"PMID-17462601_T1" }, { "role": "Theme", "ref_id": "PMID-17462601_T5" } ] }, { "id": "PMID-17462601_E3", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 254, 265 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T9" }, { "role": "Theme", "ref_id": "PMID-17462601_E11" } ] }, { "id": "PMID-17462601_E4", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 283, 292 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E31" } ] }, { "id": "PMID-17462601_E5", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 310, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E7" } ] }, { "id": "PMID-17462601_E6", "type": "Development", "trigger": { "text": [ "maturation" ], "offsets": [ [ 352, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T18" } ] }, { "id": "PMID-17462601_E7", "type": "Localization", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 329, 340 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T16" } ] }, { "id": "PMID-17462601_E2", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 254, 265 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T7" }, { "role": "Theme", "ref_id": "PMID-17462601_E11" } ] }, { "id": "PMID-17462601_E8", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 254, 265 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T9" }, { "role": "Theme", "ref_id": "PMID-17462601_E4" } ] }, { "id": "PMID-17462601_E9", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 254, 265 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T7" }, { "role": "Theme", "ref_id": "PMID-17462601_E4" } ] }, { "id": "PMID-17462601_E10", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 310, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E6" } ] }, { "id": "PMID-17462601_E12", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 310, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T9" } ] }, { "id": "PMID-17462601_E13", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 310, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T7" } ] }, { "id": "PMID-17462601_E15", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 504, 510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_E16" }, { "role": "Cause", "ref_id": "PMID-17462601_T22" } ] }, { "id": "PMID-17462601_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 524, 531 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T24" } ] }, { "id": "PMID-17462601_E18", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 606, 612 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T22" }, { "role": "Theme", "ref_id": "PMID-17462601_E25" } ] }, { "id": "PMID-17462601_E19", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T27" } ] }, { "id": "PMID-17462601_E20", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T28" } ] }, { "id": "PMID-17462601_E22", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 606, 612 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T22" }, { "role": "Theme", "ref_id": "PMID-17462601_E19" } ] }, { "id": "PMID-17462601_E23", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 606, 612 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T22" }, { "role": "Theme", "ref_id": "PMID-17462601_E20" } ] }, { "id": "PMID-17462601_E24", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 775, 783 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T31" }, { "role": "Theme", "ref_id": "PMID-17462601_E38" } ] }, { "id": "PMID-17462601_E26", "type": "Planned_process", "trigger": { "text": [ "Treatment" ], "offsets": [ [ 1011, 1020 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17462601_T40" }, { "role": "Instrument", "ref_id": "PMID-17462601_T41" }, { "role": "Theme", "ref_id": "PMID-17462601_T1002" } ] }, { "id": "PMID-17462601_E27", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1092, 1100 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_E26" }, { "role": "Theme", "ref_id": "PMID-17462601_E43" } ] }, { "id": "PMID-17462601_E28", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1168, 1175 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-17462601_T45" }, { "role": "Theme", "ref_id": "PMID-17462601_T1004" } ] }, { "id": "PMID-17462601_E29", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1346, 1355 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17462601_T3" } ] }, { "id": "PMID-17462601_E30", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 84, 94 ] ] }, "arguments": [] }, { "id": "PMID-17462601_E31", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 293, 305 ] ] }, "arguments": [] }, { "id": "PMID-17462601_E32", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 811, 821 ] ] }, "arguments": [] }, { "id": "PMID-17462601_E33", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1321, 1331 ] ] }, "arguments": [] }, { "id": "PMID-17462601_E34", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 95, 105 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T5" }, { "role": "Theme", "ref_id": "PMID-17462601_E30" } ] }, { "id": "PMID-17462601_E35", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 95, 105 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T5" }, { "role": "Theme", "ref_id": "PMID-17462601_T58" } ] }, { "id": "PMID-17462601_E36", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 48, 56 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T1" }, { "role": "Theme", "ref_id": "PMID-17462601_E34" } ] }, { "id": "PMID-17462601_E37", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 48, 56 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T1" }, { "role": "Theme", "ref_id": "PMID-17462601_E35" } ] }, { "id": "PMID-17462601_E38", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 822, 832 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T34" }, { "role": "Theme", "ref_id": "PMID-17462601_E32" } ] }, { "id": "PMID-17462601_E39", "type": "Negative_regulation", "trigger": { "text": [ "activities" ], "offsets": [ [ 822, 832 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T34" }, { "role": "Theme", "ref_id": "PMID-17462601_T59" } ] }, { "id": "PMID-17462601_E40", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 775, 783 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17462601_T31" }, { "role": "Theme", "ref_id": "PMID-17462601_E39" } ] } ]

[ { "id": "PMID-17462601_1", "entity_ids": [ "PMID-17462601_T7", "PMID-17462601_T8" ] } ]

[ { "id": "PMID-17462601_R1", "type": "frag", "arg1_id": "PMID-17462601_T2", "arg2_id": "PMID-17462601_T39", "normalized": [] } ]

[ { "id": "PMID-19369582__text", "type": "abstract", "text": [ "Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets.\n\nAngiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-(13)C(2)]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-(13)C(2)]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.\n" ], "offsets": [ [ 0, 1783 ] ] } ]

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[]

[ { "id": "PMID-10589785__text", "type": "abstract", "text": [ "The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice.\n\nThe aim of this study was to ascertain the potential usefulness of the antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for \"prevention\" experiments; and (b) 2-3-mm fragments allowed to grow to 1 cm for \"intervention\" studies. Both groups received either 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention and intervention experiments, a significant diminution of tumor size and weight was observed in the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor blood flow in linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of tumors from linomide-treated animals revealed marked avascularity. Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels. Taken together, our data indicate that in VHL disease, therapy directed at inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.\n" ], "offsets": [ [ 0, 1523 ] ] } ]

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[]

[]

[ { "id": "PMID-12140030__text", "type": "abstract", "text": [ "Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration.\n\nPURPOSE: To optimize the method of treating choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). DESIGN: Experimental study and interventional case series. METHODS: The parameters associated with locating and then photocoagulating CNV feeder vessels were identified and optimized using published data and data derived from modeling the choroidal vasculature. Based on these optimized parameters, a prototype diagnostic/treatment system was designed that captures high-speed indocyanine green (ICG) angiogram images and facilitates analysis of the images by enhancing visualization of dye movement through CNV feeder vessels (FVs). The system also permits precise aiming and delivery of 810- nm wavelength photocoagulation laser energy to target FVs on a real-time ICG angiogram image of the choroidal vasculature. Target FVs are tracked by a joy-stick controlled laser aiming beam until an intravenously-injected high-concentration ICG dye bolus is observed to enter the target vessel, at which time the laser is fired. Proof of principle of the combined diagnosis/treatment system design for performing dye-enhanced photocoagulation (DEP) in the clinical setting and determination of the minimum DEP laser energy needed to close CNV FVs was made in 11 AMD patients requiring treatment of CNV, but for whom other treatment was not appropriate. RESULTS: Using ICG-DEP, CNV feeder vessels were closed with single pulse laser energy, delivering as little as 0.6 to 1.8 J of energy to the fundus, producing no visible change in the fundus. Successful FV closure was usually indicated immediately by presence of incarcerated ICG dye in the vessel adjacent to the burn site. The prototype system proved relatively easy to operate. After acquiring and interpreting diagnostic angiograms and repositioning a patient in front of the device, feeder vessel DEP and treatment evaluation required 15 to 20 minutes. CONCLUSIONS: Indocyanine green dye-enhanced photocoagulation of CNV feeder vessels, facilitated by use of a device that permits real-time visualization of the choroidal circulation while aiming the treatment laser beam, appears to minimize the amount of energy applied to the fundus and the volume of fundus tissue affected by treatment, compared with other treatment modalities. The combination diagnosis/treatment device should be useful in optimizing FV treatment and in refining and evaluating the efficacy of DEP in future clinical trials.\n" ], "offsets": [ [ 0, 2604 ] ] } ]

[ { "id": "PMID-12140030_T3", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 53, 67 ] ], "normalized": [] }, { "id": "PMID-12140030_T8", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 392, 406 ] ], "normalized": [] }, { "id": "PMID-12140030_T9", "type": "Multi-tissue_structure", "text": [ "choroidal vasculature" ], "offsets": [ [ 493, 514 ] ], "normalized": [] }, { "id": "PMID-12140030_T10", "type": "Drug_or_compound", "text": [ "indocyanine green" ], "offsets": [ [ 631, 648 ] ], "normalized": [] }, { "id": "PMID-12140030_T11", "type": "Drug_or_compound", "text": [ "ICG" ], "offsets": [ [ 650, 653 ] ], "normalized": [] }, { "id": "PMID-12140030_T13", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 766, 780 ] ], "normalized": [] }, { "id": "PMID-12140030_T14", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 782, 785 ] ], "normalized": [] }, { "id": "PMID-12140030_T15", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 902, 905 ] ], "normalized": [] }, { "id": "PMID-12140030_T16", "type": "Drug_or_compound", "text": [ "ICG" ], "offsets": [ [ 921, 924 ] ], "normalized": [] }, { "id": "PMID-12140030_T17", "type": "Multi-tissue_structure", "text": [ "choroidal vasculature" ], "offsets": [ [ 948, 969 ] ], "normalized": [] }, { "id": "PMID-12140030_T18", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 978, 981 ] ], "normalized": [] }, { "id": "PMID-12140030_T20", "type": "Drug_or_compound", "text": [ "ICG dye" ], "offsets": [ [ 1089, 1096 ] ], "normalized": [] }, { "id": "PMID-12140030_T21", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1135, 1141 ] ], "normalized": [] }, { "id": "PMID-12140030_T23", "type": "Multi-tissue_structure", "text": [ "FVs" ], "offsets": [ [ 1391, 1394 ] ], "normalized": [] }, { "id": "PMID-12140030_T25", "type": "Drug_or_compound", "text": [ "ICG" ], "offsets": [ [ 1516, 1519 ] ], "normalized": [] }, { "id": "PMID-12140030_T27", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 1529, 1543 ] ], "normalized": [] }, { "id": "PMID-12140030_T29", "type": "Multi-tissue_structure", "text": [ "FV" ], "offsets": [ [ 1704, 1706 ] ], "normalized": [] }, { "id": "PMID-12140030_T30", "type": "Drug_or_compound", "text": [ "ICG dye" ], "offsets": [ [ 1777, 1784 ] ], "normalized": [] }, { "id": "PMID-12140030_T31", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1792, 1798 ] ], "normalized": [] }, { "id": "PMID-12140030_T32", "type": "Multi-tissue_structure", "text": [ "feeder vessel" ], "offsets": [ [ 1989, 2002 ] ], "normalized": [] }, { "id": "PMID-12140030_T33", "type": "Drug_or_compound", "text": [ "Indocyanine green dye" ], "offsets": [ [ 2072, 2093 ] ], "normalized": [] }, { "id": "PMID-12140030_T35", "type": "Multi-tissue_structure", "text": [ "feeder vessels" ], "offsets": [ [ 2127, 2141 ] ], "normalized": [] }, { "id": "PMID-12140030_T37", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 2335, 2341 ] ], "normalized": [] }, { "id": "PMID-12140030_T38", "type": "Tissue", "text": [ "fundus tissue" ], "offsets": [ [ 2360, 2373 ] ], "normalized": [] }, { "id": "PMID-12140030_T39", "type": "Multi-tissue_structure", "text": [ "FV" ], "offsets": [ [ 2513, 2515 ] ], "normalized": [] }, { "id": "PMID-12140030_T40", "type": "Tissue", "text": [ "macular" ], "offsets": [ [ 226, 233 ] ], "normalized": [] }, { "id": "PMID-12140030_T41", "type": "Tissue", "text": [ "macular" ], "offsets": [ [ 96, 103 ] ], "normalized": [] }, { "id": "PMID-12140030_T42", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 1642, 1648 ] ], "normalized": [] }, { "id": "PMID-12140030_T43", "type": "Multi-tissue_structure", "text": [ "fundus" ], "offsets": [ [ 1685, 1691 ] ], "normalized": [] }, { "id": "PMID-12140030_T1004", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1414, 1422 ] ], "normalized": [] }, { "id": "PMID-12140030_T1007", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1957, 1964 ] ], "normalized": [] } ]

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}, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T39" } ] }, { "id": "PMID-12140030_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 34, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T3" } ] }, { "id": "PMID-12140030_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 173, 191 ] ] }, "arguments": [] }, { "id": "PMID-12140030_E16", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 193, 196 ] ] }, "arguments": [] }, { "id": "PMID-12140030_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 388, 391 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T8" } ] }, { "id": "PMID-12140030_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 762, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T13" } ] }, { "id": "PMID-12140030_E20", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1387, 1390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T23" } ] }, { "id": "PMID-12140030_E21", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1446, 1449 ] ] }, "arguments": [] }, { "id": "PMID-12140030_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 1525, 1528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T27" } ] }, { "id": "PMID-12140030_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "CNV" ], "offsets": [ [ 2123, 2126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T35" } ] }, { "id": "PMID-12140030_E8", "type": "Planned_process", "trigger": { "text": [ "photocoagulation" ], "offsets": [ [ 2103, 2119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12140030_T35" } ] }, { "id": "PMID-12140030_E24", "type": 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[ { "id": "PMID-12140030_1", "entity_ids": [ "PMID-12140030_T13", "PMID-12140030_T14" ] }, { "id": "PMID-12140030_2", "entity_ids": [ "PMID-12140030_T10", "PMID-12140030_T11" ] } ]

[]

[ { "id": "PMID-11238633__text", "type": "abstract", "text": [ "IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk.\n\nIn vivo IL-12-dependent tumor inhibition rests on the ability of IL-12 to activate a CD8-mediated cytotoxicity, inhibit angiogenesis, and cause vascular injury. Although in vivo studies have shown that such inhibition stems from complex interactions of immune cells and the production of IFN-gamma and other downstream angiostatic chemokines, the mechanisms involved are still poorly defined. Here we show that IL-12 activates an anti-angiogenic program in Con A-activated mouse spleen cells (activated spc) or human PBMC (activated PBMC). The soluble factors they release in its presence arrest the cycle of endothelial cells (EC), inhibit in vitro angiogenesis, negatively modulate the production of matrix metalloproteinase-9, and the ability of EC to adhere to vitronectin and up-regulate ICAM-1 and VCAM-1 expression. These effects do not require direct cell-cell contact, yet result from continuous interaction between activated lymphoid cells and EC. We used neutralizing Abs to show that the IFN-inducible protein-10 and monokine-induced by IFN-gamma chemokines are pivotal in inducing these effects. Experiments with nu/nu mice, nonobese diabetic-SCID mice, or activated spc enriched in specific cell subpopulations demonstrated that CD4(+), CD8(+), and NK cells are all needed to mediate the full anti-angiogenetic effect of IL-12.\n" ], "offsets": [ [ 0, 1458 ] ] } ]

[ { "id": "PMID-11238633_T2", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-11238633_T4", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 20, 36 ] ], "normalized": [] }, { "id": "PMID-11238633_T8", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 75, 85 ] ], "normalized": [] }, { "id": "PMID-11238633_T9", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 86, 102 ] ], "normalized": [] }, { "id": "PMID-11238633_T11", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 124, 129 ] ], "normalized": [] }, { "id": "PMID-11238633_T12", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 140, 145 ] ], "normalized": [] }, { "id": "PMID-11238633_T13", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 181, 186 ] ], "normalized": [] }, { "id": "PMID-11238633_T14", "type": "Gene_or_gene_product", "text": [ "CD8" ], "offsets": [ [ 201, 204 ] ], "normalized": [] }, { "id": "PMID-11238633_T19", "type": "Cell", "text": [ "immune cells" ], "offsets": [ [ 369, 381 ] ], "normalized": [] }, { "id": "PMID-11238633_T21", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 404, 413 ] ], "normalized": [] }, { "id": "PMID-11238633_T23", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "PMID-11238633_T27", "type": "Drug_or_compound", "text": [ "Con A" ], "offsets": [ [ 573, 578 ] ], "normalized": [] }, { "id": "PMID-11238633_T28", "type": "Cell", "text": [ "spleen cells" ], "offsets": [ [ 595, 607 ] ], "normalized": [] }, { "id": "PMID-11238633_T30", "type": "Cell", "text": [ "spc" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-11238633_T31", "type": "Cell", "text": [ "PBMC" ], "offsets": [ [ 633, 637 ] ], "normalized": [] }, { "id": "PMID-11238633_T33", "type": "Cell", "text": [ "PBMC" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-11238633_T35", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 725, 742 ] ], "normalized": [] }, { "id": "PMID-11238633_T36", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 744, 746 ] ], "normalized": [] }, { "id": "PMID-11238633_T40", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 818, 844 ] ], "normalized": [] }, { "id": "PMID-11238633_T42", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 865, 867 ] ], "normalized": [] }, { "id": "PMID-11238633_T43", "type": "Gene_or_gene_product", "text": [ "vitronectin" ], "offsets": [ [ 881, 892 ] ], "normalized": [] }, { "id": "PMID-11238633_T46", "type": "Gene_or_gene_product", "text": [ "ICAM-1" ], "offsets": [ [ 909, 915 ] ], "normalized": [] }, { "id": "PMID-11238633_T47", "type": "Gene_or_gene_product", "text": [ "VCAM-1" ], "offsets": [ [ 920, 926 ] ], "normalized": [] }, { "id": "PMID-11238633_T48", "type": "Cell", "text": [ "lymphoid cells" ], "offsets": [ [ 1051, 1065 ] ], "normalized": [] }, { "id": "PMID-11238633_T49", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1070, 1072 ] ], "normalized": [] }, { "id": "PMID-11238633_T50", "type": "Gene_or_gene_product", "text": [ "IFN-inducible protein-10" ], "offsets": [ [ 1116, 1140 ] ], "normalized": [] }, { "id": "PMID-11238633_T53", "type": "Cell", "text": [ "spc" ], "offsets": [ [ 1296, 1299 ] ], "normalized": [] }, { "id": "PMID-11238633_T54", "type": "Gene_or_gene_product", "text": [ "CD4" ], "offsets": [ [ 1359, 1362 ] ], "normalized": [] }, { "id": "PMID-11238633_T55", "type": "Gene_or_gene_product", "text": [ "CD8" ], "offsets": [ [ 1367, 1370 ] ], "normalized": [] }, { "id": "PMID-11238633_T56", "type": "Cell", "text": [ "NK cells" ], "offsets": [ [ 1379, 1387 ] ], "normalized": [] }, { "id": "PMID-11238633_T59", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 1451, 1456 ] ], "normalized": [] }, { "id": "PMID-11238633_T1000", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 589, 594 ] ], "normalized": [] }, { "id": "PMID-11238633_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 627, 632 ] ], "normalized": [] }, { "id": "PMID-11238633_T1002", "type": "Organism", "text": [ "nu/nu mice" ], "offsets": [ [ 1242, 1252 ] ], "normalized": [] }, { "id": "PMID-11238633_T1003", "type": "Organism", "text": [ "nonobese diabetic-SCID mice" ], "offsets": [ [ 1254, 1281 ] ], "normalized": [] }, { "id": "PMID-11238633_T6", "type": "Cell", "text": [ "CD4(+)" ], "offsets": [ [ 1359, 1365 ] ], "normalized": [] }, { "id": "PMID-11238633_T15", "type": "Cell", "text": [ "CD8(+)" ], "offsets": [ [ 1367, 1373 ] ], "normalized": [] }, { "id": "PMID-11238633_T62", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 975, 979 ] ], "normalized": [] }, { "id": "PMID-11238633_T63", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 980, 984 ] ], "normalized": [] }, { "id": "PMID-11238633_T66", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1321, 1325 ] ], "normalized": [] } ]

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[ { "id": "PMID-16310808__text", "type": "abstract", "text": [ "Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells.\n\nAngiogenesis, new blood vessel formation, is a multistep process, precisely regulated by pro-angiogenic cytokines, which stimulate endothelial cells to migrate, proliferate and differentiate to form new capillary microvessels. Excessive vascular development and blood vessel remodeling appears in psoriasis, rheumatoid arthritis, diabetic retinopathy and solid tumors formation. Thalidomide [alpha-(N-phthalimido)-glutarimide] is known to be a potent inhibitor of angiogenesis, but the mechanism of its inhibitory action remains unclear. The aim of the study was to investigate the potential influence of thalidomide on the several steps of angiogenesis, using in vitro models. We have evaluated the effect of thalidomide on VEGF secretion, cell migration, adhesion as well as in capillary formation of human endothelial cell line EA.hy 926. Thalidomide at the concentrations of 0.01 microM and 10 microM inhibited VEGF secretion into supernatants, decreased the number of formed capillary tubes and increased cell adhesion to collagen. Administration of thalidomide at the concentration of 0.01 microM increased cell migration, while at 10 microM, it decreased cell migration. Thalidomide in concentrations from 0.1 microM to 10 microM did not change cell proliferation of 72-h cell cultures. We conclude that anti-angiogenic action of thalidomide is due to direct inhibitory action on VEGF secretion and capillary microvessel formation as well as immunomodulatory influence on EA.hy 926 cells migration and adhesion.\n" ], "offsets": [ [ 0, 1660 ] ] } ]

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"PMID-16310808_E55", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1398, 1411 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_T85" } ] }, { "id": "PMID-16310808_E56", "type": "Regulation", "trigger": { "text": [ "change" ], "offsets": [ [ 1386, 1392 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16310808_T62" }, { "role": "Theme", "ref_id": "PMID-16310808_E55" } ] }, { "id": "PMID-16310808_E58", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenesis" ], "offsets": [ [ 141, 153 ] ] }, "arguments": [] }, { "id": "PMID-16310808_E59", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 234, 244 ] ] }, "arguments": [] }, { "id": "PMID-16310808_E60", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 605, 617 ] ] }, "arguments": [] }, { "id": "PMID-16310808_E61", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 782, 794 ] ] }, "arguments": [] }, { "id": "PMID-16310808_E62", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1457, 1467 ] ] }, "arguments": [] }, { "id": "PMID-16310808_E63", "type": "Localization", "trigger": { "text": [ "cell migration" ], "offsets": [ [ 48, 62 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_T12" } ] }, { "id": "PMID-16310808_E1", "type": "Binding", "trigger": { "text": [ "adhesion" ], "offsets": [ [ 64, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_T12" } ] }, { "id": "PMID-16310808_E2", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1259, 1268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_T5" } ] }, { "id": "PMID-16310808_E4", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1244, 1253 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_E2" }, { "role": "Cause", "ref_id": "PMID-16310808_E46" } ] }, { "id": "PMID-16310808_E5", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1293, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_E9" }, { "role": "Cause", "ref_id": "PMID-16310808_E46" } ] }, { "id": "PMID-16310808_E9", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1308, 1317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16310808_T16" } ] } ]

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[]

[ { "id": "PMID-15725689__text", "type": "abstract", "text": [ "Role of thrombogenic factors in the development of atherosclerosis.\n\nHemostatic factors play a crucial role in generating thrombotic plugs at sites of vascular damage (atherothrombosis). However, whether hemostatic factors contribute directly or indirectly to the pathogenesis of atherosclerosis remains uncertain. Autopsy studies have revealed that intimal thickening represents the first stage of atherosclerosis and that lipid-rich plaque arises from such lesions. Several factors contribute to the start of intimal thickening. Platelets release several growth factors and bioactive agents that play a central role in development of not only thrombus but also of intimal thickening. We have been investigating which coagulation factors simultaneously, or subsequently with platelet aggregation, participate in thrombus formation. Tissue factor (TF) is an essential initiator of blood coagulation that is expressed in various stages of atherosclerotic lesions in humans and other animals. Factors including thrombin and fibrin, which are downstream of the coagulation cascade activated by TF, also contribute to atherosclerosis. TF is involved in cell migration, embryogenesis and angiogenesis. Thus TF, in addition to factors downstream of the coagulation cascade and the protease-activated receptor 2 activation system, would be a multifactorial regulator of atherogenesis.\n" ], "offsets": [ [ 0, 1378 ] ] } ]

[ { "id": "PMID-15725689_T1", "type": "Gene_or_gene_product", "text": [ "thrombogenic factors" ], "offsets": [ [ 8, 28 ] ], "normalized": [] }, { "id": "PMID-15725689_T2", "type": "Gene_or_gene_product", "text": [ "Hemostatic factors" ], "offsets": [ [ 69, 87 ] ], "normalized": [] }, { "id": "PMID-15725689_T3", "type": "Gene_or_gene_product", "text": [ "hemostatic factors" ], "offsets": [ [ 204, 222 ] ], "normalized": [] }, { "id": "PMID-15725689_T4", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 350, 357 ] ], "normalized": [] }, { "id": "PMID-15725689_T5", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 511, 518 ] ], "normalized": [] }, { "id": "PMID-15725689_T6", "type": "Cell", "text": [ "Platelets" ], "offsets": [ [ 531, 540 ] ], "normalized": [] }, { "id": "PMID-15725689_T7", "type": "Tissue", "text": [ "intimal" ], "offsets": [ [ 666, 673 ] ], "normalized": [] }, { "id": "PMID-15725689_T8", "type": "Cell", "text": [ "platelet" ], "offsets": [ [ 776, 784 ] ], "normalized": [] }, { "id": "PMID-15725689_T9", "type": "Gene_or_gene_product", "text": [ "Tissue factor" ], "offsets": [ [ 833, 846 ] ], "normalized": [] }, { "id": "PMID-15725689_T10", "type": "Gene_or_gene_product", "text": [ "TF" ], "offsets": [ [ 848, 850 ] ], "normalized": [] }, { "id": "PMID-15725689_T11", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 881, 886 ] ], "normalized": [] }, { "id": "PMID-15725689_T12", "type": "Gene_or_gene_product", "text": [ "thrombin" ], "offsets": [ [ 1009, 1017 ] ], "normalized": [] }, { "id": "PMID-15725689_T13", "type": "Gene_or_gene_product", "text": [ "fibrin" ], "offsets": [ [ 1022, 1028 ] ], "normalized": [] }, { "id": "PMID-15725689_T16", "type": "Gene_or_gene_product", "text": [ "TF" ], "offsets": [ [ 1091, 1093 ] ], "normalized": [] }, { "id": "PMID-15725689_T17", "type": "Gene_or_gene_product", "text": [ "TF" ], "offsets": [ [ 1131, 1133 ] ], "normalized": [] }, { "id": "PMID-15725689_T20", "type": "Gene_or_gene_product", "text": [ "TF" ], "offsets": [ [ 1202, 1204 ] ], "normalized": [] }, { "id": "PMID-15725689_T23", "type": "Gene_or_gene_product", "text": [ "protease-activated receptor 2" ], "offsets": [ [ 1275, 1304 ] ], "normalized": [] }, { "id": "PMID-15725689_T1000", "type": "Organism", "text": [ "humans" ], "offsets": [ [ 965, 971 ] ], "normalized": [] }, { "id": "PMID-15725689_T28", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 151, 159 ] ], "normalized": [] }, { "id": "PMID-15725689_T24", "type": "Pathological_formation", "text": [ "thrombotic plugs" ], "offsets": [ [ 122, 138 ] ], "normalized": [] }, { "id": "PMID-15725689_T33", "type": "Pathological_formation", "text": [ "lipid-rich plaque" ], "offsets": [ [ 424, 441 ] ], "normalized": [] }, { "id": "PMID-15725689_T34", "type": "Pathological_formation", "text": [ "thrombus" ], "offsets": [ [ 645, 653 ] ], "normalized": [] }, { "id": "PMID-15725689_T35", "type": "Pathological_formation", "text": [ "thrombus" ], "offsets": [ [ 813, 821 ] ], "normalized": [] }, { "id": "PMID-15725689_T38", "type": "Pathological_formation", "text": [ "atherosclerotic lesions" ], "offsets": [ [ 938, 961 ] ], "normalized": [] }, { "id": "PMID-15725689_T41", "type": "Pathological_formation", "text": [ "lesions" ], "offsets": [ [ 459, 466 ] ], "normalized": [] }, { "id": "PMID-15725689_T45", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1149, 1153 ] ], "normalized": [] } ]

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[ { "id": "PMID-15725689_1", "entity_ids": [ "PMID-15725689_T9", "PMID-15725689_T10" ] } ]

[]

[ { "id": "PMID-10771470__text", "type": "abstract", "text": [ "Active hair growth (anagen) is associated with angiogenesis.\n\nAfter the completion of skin development, angiogenesis, i.e., the growth of new capillaries from pre-existing blood vessels, is held to occur in the skin only under pathologic conditions. It has long been noted, however, that hair follicle cycling is associated with prominent changes in skin perfusion, that the epithelial hair bulbs of anagen follicles display angiogenic properties, and that the follicular dermal papilla can produce angiogenic factors. Despite these suggestive observations, no formal proof is as yet available for the concept that angiogenesis is a physiologic event that occurs all over the mature mammalian integument whenever hair follicles switch from resting (telogen) to active growth (anagen). This study uses quantitative histomorphometry and double-immunohistologic detection techniques for the demarcation of proliferating endothelial cells, to show that synchronized hair follicle cycling in adolescent C57BL/6 mice is associated with substantial angiogenesis, and that inhibiting angiogenesis in vivo by the intraperitoneal application of a fumagillin derivative retards experimentally induced anagen development in these mice. Thus, angiogenesis is a physiologic event in normal postnatal murine skin, apparently is dictated by the hair follicle, and appears to be required for normal anagen development. Anagen-associated angiogenesis offers an attractive model for identifying the physiologic controls of cutaneous angiogenesis, and an interesting system for screening the effects of potential antiangiogenic drugs in vivo.\n" ], "offsets": [ [ 0, 1623 ] ] } ]

[ { "id": "PMID-10771470_T2", "type": "Multi-tissue_structure", "text": [ "hair" ], "offsets": [ [ 7, 11 ] ], "normalized": [] }, { "id": "PMID-10771470_T3", "type": "Tissue", "text": [ "capillaries" ], "offsets": [ [ 142, 153 ] ], "normalized": [] }, { "id": "PMID-10771470_T6", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 86, 90 ] ], "normalized": [] }, { "id": "PMID-10771470_T10", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 172, 185 ] ], "normalized": [] }, { "id": "PMID-10771470_T12", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 211, 215 ] ], "normalized": [] }, { "id": "PMID-10771470_T14", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 288, 301 ] ], "normalized": [] }, { "id": "PMID-10771470_T16", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 350, 354 ] ], "normalized": [] }, { "id": "PMID-10771470_T17", "type": "Tissue", "text": [ "epithelial hair bulbs" ], "offsets": [ [ 375, 396 ] ], "normalized": [] }, { "id": "PMID-10771470_T18", "type": "Multi-tissue_structure", "text": [ "anagen follicles" ], "offsets": [ [ 400, 416 ] ], "normalized": [] }, { "id": "PMID-10771470_T20", "type": "Tissue", "text": [ "follicular dermal papilla" ], "offsets": [ [ 461, 486 ] ], "normalized": [] }, { "id": "PMID-10771470_T24", "type": "Multi-tissue_structure", "text": [ "hair follicles" ], "offsets": [ [ 713, 727 ] ], "normalized": [] }, { "id": "PMID-10771470_T27", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 917, 934 ] ], "normalized": [] }, { "id": "PMID-10771470_T29", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 962, 975 ] ], "normalized": [] }, { "id": "PMID-10771470_T33", "type": "Drug_or_compound", "text": [ "fumagillin derivative" ], "offsets": [ [ 1137, 1158 ] ], "normalized": [] }, { "id": "PMID-10771470_T36", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 1293, 1297 ] ], "normalized": [] }, { "id": "PMID-10771470_T37", "type": "Multi-tissue_structure", "text": [ "hair follicle" ], "offsets": [ [ 1329, 1342 ] ], "normalized": [] }, { "id": "PMID-10771470_T1000", "type": "Organism", "text": [ "C57BL/6 mice" ], "offsets": [ [ 998, 1010 ] ], "normalized": [] }, { "id": "PMID-10771470_T1001", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1218, 1222 ] ], "normalized": [] }, { "id": "PMID-10771470_T1002", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 1286, 1292 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-18835936__text", "type": "abstract", "text": [ "Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity.\n\nOBJECTIVE: The expansion of adipose tissue is linked to the development of its vasculature. However, the regulation of adipose tissue angiogenesis in humans has not been extensively studied. Our aim was to compare the angiogenesis associated with subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from the same obese patients in an in vivo model. RESEARCH DESIGN AND METHODS: Adipose tissue samples from visceral (VAT) and subcutaneous (SAT) sites, obtained from 36 obese patients (mean BMI 46.5 kg/m(2)) during bariatric surgery, were layered on chick chorioallantoic membrane (CAM). RESULTS: Both SAT and VAT expressed angiogenic factors without significant difference for vascular endothelial growth factor (VEGF) expression. Adipose tissue layered on CAM stimulated angiogenesis. Angiogenic stimulation was macroscopically detectable, with engulfment of the samples, in 39% and was evidenced by angiography in 59% of the samples. A connection between CAM and adipose tissue vessels was evidenced by immunohistochemistry, with recruitment of both avian and human endothelial cells. The angiogenic potency of adipose tissue was not related to its localization (with an angiogenic stimulation in 60% of SAT samples and 61% of VAT samples) or to adipocyte size or inflammatory infiltrate assessed in adipose samples before the graft on CAM. Stimulation of angiogenesis by adipose tissue was nearly abolished by bevacizumab, which specifically targets human VEGF. CONCLUSIONS: We have established a model to study the regulation of angiogenesis by human adipose tissue. This model highlighted the role of VEGF in angiogenesis in both SAT and VAT.\n" ], "offsets": [ [ 0, 1760 ] ] } ]

[ { "id": "PMID-18835936_T2", "type": "Tissue", "text": [ "visceral" ], "offsets": [ [ 29, 37 ] ], "normalized": [] }, { "id": "PMID-18835936_T3", "type": "Tissue", "text": [ "subcutaneous adipose tissue" ], "offsets": [ [ 42, 69 ] ], "normalized": [] }, { "id": "PMID-18835936_T4", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 124, 138 ] ], "normalized": [] }, { "id": "PMID-18835936_T5", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 175, 186 ] ], "normalized": [] }, { "id": "PMID-18835936_T6", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 215, 229 ] ], "normalized": [] }, { "id": "PMID-18835936_T9", "type": "Tissue", "text": [ "subcutaneous adipose tissue" ], "offsets": [ [ 343, 370 ] ], "normalized": [] }, { "id": "PMID-18835936_T10", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 372, 375 ] ], "normalized": [] }, { "id": "PMID-18835936_T11", "type": "Tissue", "text": [ "visceral adipose tissue" ], "offsets": [ [ 381, 404 ] ], "normalized": [] }, { "id": "PMID-18835936_T12", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "PMID-18835936_T13", "type": "Tissue", "text": [ "Adipose tissue samples" ], "offsets": [ [ 490, 512 ] ], "normalized": [] }, { "id": "PMID-18835936_T14", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 528, 531 ] ], "normalized": [] }, { "id": "PMID-18835936_T15", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-18835936_T16", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membrane" ], "offsets": [ [ 667, 691 ] ], "normalized": [] }, { "id": "PMID-18835936_T17", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 693, 696 ] ], "normalized": [] }, { "id": "PMID-18835936_T19", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 789, 823 ] ], "normalized": [] }, { "id": "PMID-18835936_T20", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 825, 829 ] ], "normalized": [] }, { "id": "PMID-18835936_T21", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 869, 872 ] ], "normalized": [] }, { "id": "PMID-18835936_T24", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 1069, 1072 ] ], "normalized": [] }, { "id": "PMID-18835936_T25", "type": "Tissue", "text": [ "adipose tissue vessels" ], "offsets": [ [ 1077, 1099 ] ], "normalized": [] }, { "id": "PMID-18835936_T26", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1180, 1197 ] ], "normalized": [] }, { "id": "PMID-18835936_T28", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 1225, 1239 ] ], "normalized": [] }, { "id": "PMID-18835936_T30", "type": "Tissue", "text": [ "SAT samples" ], "offsets": [ [ 1318, 1329 ] ], "normalized": [] }, { "id": "PMID-18835936_T31", "type": "Tissue", "text": [ "VAT samples" ], "offsets": [ [ 1341, 1352 ] ], "normalized": [] }, { "id": "PMID-18835936_T32", "type": "Cell", "text": [ "adipocyte" ], "offsets": [ [ 1360, 1369 ] ], "normalized": [] }, { "id": "PMID-18835936_T33", "type": "Multi-tissue_structure", "text": [ "CAM" ], "offsets": [ [ 1450, 1453 ] ], "normalized": [] }, { "id": "PMID-18835936_T35", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 1486, 1500 ] ], "normalized": [] }, { "id": "PMID-18835936_T37", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 1525, 1536 ] ], "normalized": [] }, { "id": "PMID-18835936_T38", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1571, 1575 ] ], "normalized": [] }, { "id": "PMID-18835936_T40", "type": "Tissue", "text": [ "adipose tissue" ], "offsets": [ [ 1667, 1681 ] ], "normalized": [] }, { "id": "PMID-18835936_T42", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1718, 1722 ] ], "normalized": [] }, { "id": "PMID-18835936_T44", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 1747, 1750 ] ], "normalized": [] }, { "id": "PMID-18835936_T45", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 1755, 1758 ] ], "normalized": [] }, { "id": "PMID-18835936_T41", "type": "Tissue", "text": [ "SAT" ], "offsets": [ [ 713, 716 ] ], "normalized": [] }, { "id": "PMID-18835936_T46", "type": "Tissue", "text": [ "VAT" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "PMID-18835936_T47", "type": "Tissue", "text": [ "Adipose tissue" ], "offsets": [ [ 843, 857 ] ], "normalized": [] }, { "id": "PMID-18835936_T48", "type": "Tissue", "text": [ "graft" ], "offsets": [ [ 1441, 1446 ] ], "normalized": [] }, { "id": "PMID-18835936_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 80, 85 ] ], "normalized": [] }, { "id": "PMID-18835936_T1001", "type": "Organism", "text": [ "humans" ], "offsets": [ [ 246, 252 ] ], "normalized": [] }, { "id": "PMID-18835936_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 431, 439 ] ], "normalized": [] }, { "id": "PMID-18835936_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 586, 594 ] ], "normalized": [] }, { "id": "PMID-18835936_T1004", "type": "Organism", "text": [ "chick" ], "offsets": [ [ 661, 666 ] ], "normalized": [] }, { "id": "PMID-18835936_T1005", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1174, 1179 ] ], "normalized": [] }, { "id": "PMID-18835936_T1006", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1565, 1570 ] ], "normalized": [] }, { "id": "PMID-18835936_T1007", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1661, 1666 ] ], "normalized": [] }, { "id": "PMID-18835936_T59", "type": "Organism", "text": [ "avian" ], "offsets": [ [ 1164, 1169 ] ], "normalized": [] }, { "id": "PMID-18835936_T62", "type": "Tissue", "text": [ "adipose samples" ], "offsets": [ [ 1414, 1429 ] ], "normalized": [] } ]

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[ { "id": "PMID-12823209__text", "type": "abstract", "text": [ "Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of the esophagus.\n\nThe most common genetic alterations found in a wide variety of cancers are p53 tumor suppressor gene mutations. p53 appears to be a nuclear transcription factor that plays a role in the control of cell proliferation, apoptosis, and the maintenance of genetic stability. Angiogenesis is a critical process in solid tumor growth and metastasis. Vascular endothelial growth factor (VEGF), a recently identified growth factor with significant angiogenic properties, may be a major tumor angiogenesis regulator. Few studies have investigated the association between p53 and VEGF expressions and prognosis in esophageal carcinoma. Forty-seven specimens resected from patients with stage II and III squamous cell carcinoma (SCC) of the esophagus were studied using immunohistochemical staining. VEGF and p53 expressions were observed in 40% and 53% of the tumors, respectively. The p53 and VEGF staining statuses were coincident in only 21% of the tumors, and no significant correlation was found between p53 and VEGF statuses. No clinicopathologic factors were significantly correlated with p53 or VEGF expression. No significant association between p53 and VEGF expressions and poor prognosis was found. In conclusion, p53 and VEGF were not correlated with prognosis in patients with stage II and III SCC of the esophagus.\n" ], "offsets": [ [ 0, 1466 ] ] } ]

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[]

[ { "id": "PMID-10487573__text", "type": "abstract", "text": [ "External beam radiotherapy for subretinal neovascularization in age-related macular degeneration: is this treatment efficient?\n\nPURPOSE: Control of the natural course of subretinal neovascularization (SRNV) in age-related macular degeneration (AMD) is difficult. Only a subset of patients is suitable for laser coagulation. This prospective study aimed to determine the efficacy and individual benefit of external beam radiotherapy (EBRT). METHODS AND MATERIALS: The prospective trial included 287 patients with subfoveal neovascularization due to AMD which was verified by fluorescein angiography. Patients have been treated between January 1996 and October 1997. All patients received a total dose of 16 Gy in 2-Gy daily fractions with 5-6 MeV photons based on computerized treatment planning in individual head mask fixation. This first analysis is based on 73 patients (50 women, 23 men, median age 74.3 years), with a median follow-up of 13.3 months and a minimum follow-up of 11 months. RESULTS: All patients completed therapy and tolerability was good. First clinical control with second angiography was performed 6 weeks after irradiation, then in 3-month intervals. Eighteen patients with SRNV refusing radiotherapy served as a control group and were matched with 18 irradiated patients. After 7 months median visual acuity (VA) was 20/160 for the irradiated and 20/400 for the untreated patients. One year after radiotherapy final median VA was 20/400 in both groups. CONCLUSION: These results suggest that 16 Gy of conventionally fractionated external beam irradiation slows down the visual loss in exudative AMD for only a few months. Patients' reading vision could not be saved for a long-term run.\n" ], "offsets": [ [ 0, 1712 ] ] } ]

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[]

[]

[ { "id": "PMID-10978899__text", "type": "abstract", "text": [ "Urokinase receptor: a molecular organizer in cellular communication.\n\nIn a variety of cell types, the glycolipid-anchored urokinase receptor (uPAR) is colocalized pericellularly with components of the plasminogen activation system and endocytosis receptors. uPAR is also coexpressed with caveolin and members of the integrin adhesion receptor superfamily. The formation of functional units with these various proteins allows the uPAR to mediate the focused proteolysis required for cell migration and invasion and to contribute both directly and indirectly to cell adhesive processes in a non-proteolytic fashion. This dual activity, together with the initiation of signal transduction pathways by uPAR, is believed to influence cellular behaviour in angiogenesis, inflammation, wound repair and tumor progression/metastasis and open up the way for uPAR-based therapeutic approaches.\n" ], "offsets": [ [ 0, 884 ] ] } ]

[ { "id": "PMID-10978899_T1", "type": "Gene_or_gene_product", "text": [ "Urokinase receptor" ], "offsets": [ [ 0, 18 ] ], "normalized": [] }, { "id": "PMID-10978899_T2", "type": "Gene_or_gene_product", "text": [ "glycolipid-anchored urokinase receptor" ], "offsets": [ [ 102, 140 ] ], "normalized": [] }, { "id": "PMID-10978899_T3", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 142, 146 ] ], "normalized": [] }, { "id": "PMID-10978899_T4", "type": "Gene_or_gene_product", "text": [ "plasminogen" ], "offsets": [ [ 201, 212 ] ], "normalized": [] }, { "id": "PMID-10978899_T7", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 258, 262 ] ], "normalized": [] }, { "id": "PMID-10978899_T8", "type": "Gene_or_gene_product", "text": [ "caveolin" ], "offsets": [ [ 288, 296 ] ], "normalized": [] }, { "id": "PMID-10978899_T10", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 429, 433 ] ], "normalized": [] }, { "id": "PMID-10978899_T12", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 698, 702 ] ], "normalized": [] }, { "id": "PMID-10978899_T15", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 796, 801 ] ], "normalized": [] }, { "id": "PMID-10978899_T16", "type": "Gene_or_gene_product", "text": [ "uPAR" ], "offsets": [ [ 849, 853 ] ], "normalized": [] }, { "id": "PMID-10978899_T13", "type": "Gene_or_gene_product", "text": [ "integrin adhesion receptor" ], "offsets": [ [ 316, 342 ] ], "normalized": [] }, { "id": "PMID-10978899_T20", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 86, 90 ] ], "normalized": [] }, { "id": "PMID-10978899_T21", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-10978899_T25", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-10978899_T28", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 779, 784 ] ], "normalized": [] } ]

[ { "id": "PMID-10978899_E6", "type": "Gene_expression", "trigger": { "text": [ "coexpressed" ], "offsets": [ [ 271, 282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T7" }, { "role": "Theme", "ref_id": "PMID-10978899_T8" }, { "role": "Theme", "ref_id": "PMID-10978899_T13" } ] }, { "id": "PMID-10978899_E1", "type": "Localization", "trigger": { "text": [ "colocalized" ], "offsets": [ [ 151, 162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T2" }, { "role": "Theme", "ref_id": "PMID-10978899_T4" }, { "role": "AtLoc", "ref_id": "PMID-10978899_T20" } ] }, { "id": "PMID-10978899_E2", "type": "Positive_regulation", "trigger": { "text": [ "initiation" ], "offsets": [ [ 652, 662 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_E16" }, { "role": "Cause", "ref_id": "PMID-10978899_T12" } ] }, { "id": "PMID-10978899_E3", "type": "Negative_regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 719, 728 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10978899_E2" }, { "role": "Theme", "ref_id": "PMID-10978899_E15" } ] }, { "id": "PMID-10978899_E4", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 802, 813 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T15" } ] }, { "id": "PMID-10978899_E5", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 814, 824 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T15" } ] }, { "id": "PMID-10978899_E7", "type": "Negative_regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 719, 728 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10978899_E2" }, { "role": "Theme", "ref_id": "PMID-10978899_E4" } ] }, { "id": "PMID-10978899_E8", "type": "Negative_regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 719, 728 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10978899_E2" }, { "role": "Theme", "ref_id": "PMID-10978899_E5" } ] }, { "id": "PMID-10978899_E9", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 487, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T21" } ] }, { "id": "PMID-10978899_E10", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 501, 509 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T21" } ] }, { "id": "PMID-10978899_E11", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 469, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_E9" } ] }, { "id": "PMID-10978899_E12", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 469, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_E10" } ] }, { "id": "PMID-10978899_E13", "type": "Binding", "trigger": { "text": [ "adhesive processes" ], "offsets": [ [ 565, 583 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10978899_T25" } ] }, { "id": "PMID-10978899_E14", "type": "Regulation", "trigger": { "text": [ "contribute" ], "offsets": [ [ 517, 527 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10978899_T10" }, { "role": "Theme", "ref_id": "PMID-10978899_E13" } ] }, { "id": "PMID-10978899_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 751, 763 ] ] }, "arguments": [] }, { "id": "PMID-10978899_E16", "type": "Pathway", "trigger": { "text": [ "signal transduction pathways" ], "offsets": [ [ 666, 694 ] ] }, "arguments": [] } ]

[ { "id": "PMID-10978899_1", "entity_ids": [ "PMID-10978899_T2", "PMID-10978899_T3" ] } ]

[]

[ { "id": "PMID-16398404__text", "type": "abstract", "text": [ "The differential regulation of human telomerase reverse transcriptase and vascular endothelial growth factor may contribute to the clinically more aggressive behavior of p63-positive breast carcinomas.\n\np63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.\n" ], "offsets": [ [ 0, 1702 ] ] } ]

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"PMID-16398404_T12", "type": "Organ", "text": [ "mammary gland" ], "offsets": [ [ 270, 283 ] ], "normalized": [] }, { "id": "PMID-16398404_T13", "type": "Cell", "text": [ "p63-positive neoplastic cells" ], "offsets": [ [ 288, 317 ] ], "normalized": [] }, { "id": "PMID-16398404_T14", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 288, 291 ] ], "normalized": [] }, { "id": "PMID-16398404_T15", "type": "Pathological_formation", "text": [ "invasive breast carcinomas" ], "offsets": [ [ 347, 373 ] ], "normalized": [] }, { "id": "PMID-16398404_T18", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 426, 429 ] ], "normalized": [] }, { "id": "PMID-16398404_T19", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 486, 491 ] ], "normalized": [] }, { "id": "PMID-16398404_T20", "type": "Organism_subdivision", "text": [ "breast" ], "offsets": [ [ 528, 534 ] ], "normalized": [] }, { "id": "PMID-16398404_T21", "type": "Pathological_formation", "text": [ "invasive ductal carcinomas" ], "offsets": [ [ 782, 808 ] ], "normalized": [] }, { "id": "PMID-16398404_T22", "type": "Cell", "text": [ "p63-positive cells" ], "offsets": [ [ 810, 828 ] ], "normalized": [] }, { "id": "PMID-16398404_T23", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 810, 813 ] ], "normalized": [] }, { "id": "PMID-16398404_T24", "type": "Pathological_formation", "text": [ "carcinomas" ], "offsets": [ [ 850, 860 ] ], "normalized": [] }, { "id": "PMID-16398404_T25", "type": "Cell", "text": [ "p63-positive carcinomas" ], "offsets": [ [ 862, 885 ] ], "normalized": [] }, { "id": "PMID-16398404_T26", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 862, 865 ] ], "normalized": [] }, { "id": "PMID-16398404_T27", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 982, 985 ] ], "normalized": [] }, { "id": "PMID-16398404_T28", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1036, 1041 ] ], "normalized": [] }, { "id": "PMID-16398404_T32", "type": "Gene_or_gene_product", "text": [ "telomerase reverse transcriptase" ], "offsets": [ [ 1076, 1108 ] ], "normalized": [] }, { "id": "PMID-16398404_T33", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1110, 1115 ] ], "normalized": [] }, { "id": "PMID-16398404_T34", "type": "Gene_or_gene_product", "text": [ "tissue inhibitor of matrix metalloproteinase 1" ], "offsets": [ [ 1118, 1164 ] ], "normalized": [] }, { "id": "PMID-16398404_T35", "type": "Gene_or_gene_product", "text": [ "TIMP1" ], "offsets": [ [ 1166, 1171 ] ], "normalized": [] }, { "id": "PMID-16398404_T36", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1177, 1211 ] ], "normalized": [] }, { "id": "PMID-16398404_T37", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "PMID-16398404_T39", "type": "Gene_or_gene_product", "text": [ "TIMP1" ], "offsets": [ [ 1238, 1243 ] ], "normalized": [] }, { "id": "PMID-16398404_T40", "type": "Pathological_formation", "text": [ "p63-positive carcinomas" ], "offsets": [ [ 1310, 1333 ] ], "normalized": [] }, { "id": "PMID-16398404_T41", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 1310, 1313 ] ], "normalized": [] }, { "id": "PMID-16398404_T42", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1335, 1340 ] ], "normalized": [] }, { "id": "PMID-16398404_T44", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1414, 1418 ] ], "normalized": [] }, { "id": "PMID-16398404_T48", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1495, 1500 ] ], "normalized": [] }, { "id": "PMID-16398404_T50", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1575, 1580 ] ], "normalized": [] }, { "id": "PMID-16398404_T51", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1585, 1589 ] ], "normalized": [] }, { "id": "PMID-16398404_T52", "type": "Pathological_formation", "text": [ "p63-positive breast carcinomas" ], "offsets": [ [ 1593, 1623 ] ], "normalized": [] }, { "id": "PMID-16398404_T53", "type": "Gene_or_gene_product", "text": [ "p63" ], "offsets": [ [ 1593, 1596 ] ], "normalized": [] }, { "id": "PMID-16398404_T54", "type": "Pathological_formation", "text": [ "neoplasms" ], "offsets": [ [ 1691, 1700 ] ], "normalized": [] }, { "id": "PMID-16398404_T9", "type": "Gene_or_gene_product", "text": [ "metalloproteinases" ], "offsets": [ [ 628, 646 ] ], "normalized": [] }, { "id": "PMID-16398404_T43", "type": "Pathological_formation", "text": [ "neoplasms" ], "offsets": [ [ 940, 949 ] ], "normalized": [] }, { "id": "PMID-16398404_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 31, 36 ] ], "normalized": [] }, { "id": "PMID-16398404_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1070, 1075 ] ], "normalized": [] }, { "id": "PMID-16398404_T45", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 577, 581 ] ], "normalized": [] } ]

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[ { "id": "PMID-16398404_1", "entity_ids": [ "PMID-16398404_T33", "PMID-16398404_T32" ] }, { "id": "PMID-16398404_2", "entity_ids": [ "PMID-16398404_T34", "PMID-16398404_T35" ] }, { "id": "PMID-16398404_3", "entity_ids": [ "PMID-16398404_T36", "PMID-16398404_T37" ] } ]

[]

[ { "id": "PMID-19236257__text", "type": "abstract", "text": [ "Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors.\n\nBACKGROUND: Aberrant angiogenesis is a landmark feature in cancer, which is important for proliferation, growth and metastasis, and is mediated by various pro-angiogenic factors. The VEGF pathway is one of the most important and best-studied angiogenic pathways. Inhibition of this pathway may provide clinical benefits to cancer patients. OBJECTIVES: Strategies to inhibit the VEGF pathway, including antibodies to VEGF, antibodies to the extracellular domain of VEGFR-1 or VEGFR-2, decoy receptors for VEGF and tyrosine kinase inhibitors of VEGFRs, are summarized. METHODS: This review outlines and compares the latest development of these strategies, with emphasis on aflibercept, a novel decoy fusion protein of domain 2 of VEGFR-1 and domain 3 of VEGFR-2 with the Fc fragment of IgG1. RESULTS: Aflibercept was shown to have early clinical activity. Multiple studies are ongoing to determine the clinical benefits of aflibercept in cancer patients.\n" ], "offsets": [ [ 0, 1076 ] ] } ]

[ { "id": "PMID-19236257_T1", "type": "Drug_or_compound", "text": [ "Aflibercept" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "PMID-19236257_T2", "type": "Drug_or_compound", "text": [ "AVE0005" ], "offsets": [ [ 13, 20 ] ], "normalized": [] }, { "id": "PMID-19236257_T4", "type": "Pathological_formation", "text": [ "tumour" ], "offsets": [ [ 62, 68 ] ], "normalized": [] }, { "id": "PMID-19236257_T6", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factors" ], "offsets": [ [ 85, 120 ] ], "normalized": [] }, { "id": "PMID-19236257_T10", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 306, 310 ] ], "normalized": [] }, { "id": "PMID-19236257_T16", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 501, 505 ] ], "normalized": [] }, { "id": "PMID-19236257_T18", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 539, 543 ] ], "normalized": [] }, { "id": "PMID-19236257_T21", "type": "Gene_or_gene_product", "text": [ "VEGFR-1" ], "offsets": [ [ 587, 594 ] ], "normalized": [] }, { "id": "PMID-19236257_T22", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "PMID-19236257_T24", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 627, 631 ] ], "normalized": [] }, { "id": "PMID-19236257_T25", "type": "Drug_or_compound", "text": [ "tyrosine kinase inhibitors" ], "offsets": [ [ 636, 662 ] ], "normalized": [] }, { "id": "PMID-19236257_T26", "type": "Gene_or_gene_product", "text": [ "VEGFRs" ], "offsets": [ [ 666, 672 ] ], "normalized": [] }, { "id": "PMID-19236257_T27", "type": "Drug_or_compound", "text": [ "aflibercept" ], "offsets": [ [ 794, 805 ] ], "normalized": [] }, { "id": "PMID-19236257_T28", "type": "Gene_or_gene_product", "text": [ "VEGFR-1" ], "offsets": [ [ 851, 858 ] ], "normalized": [] }, { "id": "PMID-19236257_T29", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 875, 882 ] ], "normalized": [] }, { "id": "PMID-19236257_T31", "type": "Drug_or_compound", "text": [ "Aflibercept" ], "offsets": [ [ 922, 933 ] ], "normalized": [] }, { "id": "PMID-19236257_T32", "type": "Drug_or_compound", "text": [ "aflibercept" ], "offsets": [ [ 1044, 1055 ] ], "normalized": [] }, { "id": "PMID-19236257_T3", "type": "Gene_or_gene_product", "text": [ "IgG1" ], "offsets": [ [ 907, 911 ] ], "normalized": [] }, { "id": "PMID-19236257_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 453, 461 ] ], "normalized": [] }, { "id": "PMID-19236257_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1066, 1074 ] ], "normalized": [] }, { "id": "PMID-19236257_T30", "type": "Protein_domain_or_region", "text": [ "Fc fragment" ], "offsets": [ [ 892, 903 ] ], "normalized": [] }, { "id": "PMID-19236257_T17", "type": "Gene_or_gene_product", "text": [ "antibodies to VEGF" ], "offsets": [ [ 525, 543 ] ], "normalized": [] }, { "id": "PMID-19236257_T19", "type": "Gene_or_gene_product", "text": [ "VEGFR-2" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "PMID-19236257_T20", "type": "Gene_or_gene_product", "text": [ "antibodies to the extracellular domain of VEGFR-1" ], "offsets": [ [ 545, 594 ] ], "normalized": [] }, { "id": "PMID-19236257_T33", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 182, 188 ] ], "normalized": [] }, { "id": "PMID-19236257_T36", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 446, 452 ] ], "normalized": [] }, { "id": "PMID-19236257_T37", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 1059, 1065 ] ], "normalized": [] } ]

[ { "id": "PMID-19236257_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 489, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E15" }, { "role": "Cause", "ref_id": "PMID-19236257_T17" } ] }, { "id": "PMID-19236257_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 51, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E9" }, { "role": "Cause", "ref_id": "PMID-19236257_T6" } ] }, { "id": "PMID-19236257_E2", "type": "Regulation", "trigger": { "text": [ "Aberrant" ], "offsets": [ [ 135, 143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E10" } ] }, { "id": "PMID-19236257_E3", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 258, 266 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E10" } ] }, { "id": "PMID-19236257_E4", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 386, 396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E13" } ] }, { "id": "PMID-19236257_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 489, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E15" }, { "role": "Cause", "ref_id": "PMID-19236257_T20" } ] }, { "id": "PMID-19236257_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 489, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E15" }, { "role": "Cause", "ref_id": "PMID-19236257_T19" } ] }, { "id": "PMID-19236257_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 489, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E15" } ] }, { "id": "PMID-19236257_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 489, 496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19236257_E15" }, { "role": "Cause", "ref_id": "PMID-19236257_T25" } ] }, { "id": "PMID-19236257_E9", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 69, 81 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19236257_T4" } ] }, { "id": "PMID-19236257_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 144, 156 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 282, 292 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 365, 375 ] ] }, "arguments": [] }, { "id": "PMID-19236257_E13", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 311, 318 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19236257_T10" } ] }, { "id": "PMID-19236257_E15", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 506, 513 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19236257_T16" } ] } ]

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

[ { "id": "PMID-19236257_R1", "type": "frag", "arg1_id": "PMID-19236257_T19", "arg2_id": "PMID-19236257_T20", "normalized": [] } ]

[ { "id": "PMID-17960624__text", "type": "abstract", "text": [ "Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion.\n\nThe role of the pro-inflammatory peptide, LL-37, and its pro-form, human cationic antimicrobial protein 18 (hCAP-18), in cancer development and progression is poorly understood. In damaged and inflamed tissue, LL-37 functions as a chemoattractant, mitogen and pro-angiogenic factor suggesting that the peptide may potentiate tumor progression. The aim of this study was to characterize the distribution of hCAP-18/LL-37 in normal and cancerous ovarian tissue and to examine the effects of LL-37 on ovarian cancer cells. Expression of hCAP-18/LL-37 was localized to immune and granulosa cells of normal ovarian tissue. By contrast, ovarian tumors displayed significantly higher levels of hCAP-18/LL-37 where expression was observed in tumor and stromal cells. Protein expression was statistically compared to the degree of immune cell infiltration and microvessel density in epithelial-derived ovarian tumors and a significant correlation was observed for both. It was demonstrated that ovarian tumor tissue lysates and ovarian cancer cell lines express hCAP-18/LL-37. Treatment of ovarian cancer cell lines with recombinant LL-37 stimulated proliferation, chemotaxis, invasion and matrix metalloproteinase expression. These data demonstrate for the first time that hCAP-18/LL-37 is significantly overexpressed in ovarian tumors and suggest LL-37 may contribute to ovarian tumorigenesis through direct stimulation of tumor cells, initiation of angiogenesis and recruitment of immune cells. These data provide further evidence of the existing relationship between pro-inflammatory molecules and ovarian cancer progression.\n" ], "offsets": [ [ 0, 1767 ] ] } ]

[ { "id": "PMID-17960624_T2", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 54, 61 ] ], "normalized": [] }, { "id": "PMID-17960624_T3", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 81, 86 ] ], "normalized": [] }, { "id": "PMID-17960624_T6", "type": "Cell", "text": [ "ovarian cancer cell" ], "offsets": [ [ 97, 116 ] ], "normalized": [] }, { "id": "PMID-17960624_T7", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 188, 193 ] ], "normalized": [] }, { "id": "PMID-17960624_T8", "type": "Gene_or_gene_product", "text": [ "human cationic antimicrobial protein 18" ], "offsets": [ [ 213, 252 ] ], "normalized": [] }, { "id": "PMID-17960624_T9", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 254, 261 ] ], "normalized": [] }, { "id": "PMID-17960624_T10", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "PMID-17960624_T14", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 471, 476 ] ], "normalized": [] }, { "id": "PMID-17960624_T15", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 552, 559 ] ], "normalized": [] }, { "id": "PMID-17960624_T16", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 560, 565 ] ], "normalized": [] }, { "id": "PMID-17960624_T17", "type": "Tissue", "text": [ "ovarian tissue" ], "offsets": [ [ 590, 604 ] ], "normalized": [] }, { "id": "PMID-17960624_T18", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 635, 640 ] ], "normalized": [] }, { "id": "PMID-17960624_T19", "type": "Cell", "text": [ "ovarian cancer cells" ], "offsets": [ [ 644, 664 ] ], "normalized": [] }, { "id": "PMID-17960624_T22", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 680, 687 ] ], "normalized": [] }, { "id": "PMID-17960624_T23", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 688, 693 ] ], "normalized": [] }, { "id": "PMID-17960624_T24", "type": "Cell", "text": [ "immune" ], "offsets": [ [ 711, 717 ] ], "normalized": [] }, { "id": "PMID-17960624_T25", "type": "Cell", "text": [ "granulosa cells" ], "offsets": [ [ 722, 737 ] ], "normalized": [] }, { "id": "PMID-17960624_T26", "type": "Tissue", "text": [ "normal ovarian tissue" ], "offsets": [ [ 741, 762 ] ], "normalized": [] }, { "id": "PMID-17960624_T27", "type": "Pathological_formation", "text": [ "ovarian tumors" ], "offsets": [ [ 777, 791 ] ], "normalized": [] }, { "id": "PMID-17960624_T28", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 833, 840 ] ], "normalized": [] }, { "id": "PMID-17960624_T29", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 841, 846 ] ], "normalized": [] }, { "id": "PMID-17960624_T30", "type": "Cell", "text": [ "tumor" ], "offsets": [ [ 880, 885 ] ], "normalized": [] }, { "id": "PMID-17960624_T31", "type": "Cell", "text": [ "stromal cells" ], "offsets": [ [ 890, 903 ] ], "normalized": [] }, { "id": "PMID-17960624_T33", "type": "Cell", "text": [ "immune cell" ], "offsets": [ [ 968, 979 ] ], "normalized": [] }, { "id": "PMID-17960624_T34", "type": "Tissue", "text": [ "microvessel" ], "offsets": [ [ 997, 1008 ] ], "normalized": [] }, { "id": "PMID-17960624_T35", "type": "Pathological_formation", "text": [ "epithelial-derived ovarian tumors" ], "offsets": [ [ 1020, 1053 ] ], "normalized": [] }, { "id": "PMID-17960624_T38", "type": "Organism_substance", "text": [ "ovarian tumor tissue lysates" ], "offsets": [ [ 1132, 1160 ] ], "normalized": [] }, { "id": "PMID-17960624_T41", "type": "Cell", "text": [ "ovarian cancer cell lines" ], "offsets": [ [ 1165, 1190 ] ], "normalized": [] }, { "id": "PMID-17960624_T42", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 1199, 1206 ] ], "normalized": [] }, { "id": "PMID-17960624_T43", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 1207, 1212 ] ], "normalized": [] }, { "id": "PMID-17960624_T44", "type": "Cell", "text": [ "ovarian cancer cell lines" ], "offsets": [ [ 1227, 1252 ] ], "normalized": [] }, { "id": "PMID-17960624_T45", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 1270, 1275 ] ], "normalized": [] }, { "id": "PMID-17960624_T47", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase" ], "offsets": [ [ 1327, 1351 ] ], "normalized": [] }, { "id": "PMID-17960624_T49", "type": "Gene_or_gene_product", "text": [ "hCAP-18" ], "offsets": [ [ 1411, 1418 ] ], "normalized": [] }, { "id": "PMID-17960624_T50", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 1419, 1424 ] ], "normalized": [] }, { "id": "PMID-17960624_T51", "type": "Pathological_formation", "text": [ "ovarian tumors" ], "offsets": [ [ 1459, 1473 ] ], "normalized": [] }, { "id": "PMID-17960624_T52", "type": "Gene_or_gene_product", "text": [ "LL-37" ], "offsets": [ [ 1486, 1491 ] ], "normalized": [] }, { "id": "PMID-17960624_T54", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 1562, 1573 ] ], "normalized": [] }, { "id": "PMID-17960624_T58", "type": "Cell", "text": [ "immune cells" ], "offsets": [ [ 1621, 1633 ] ], "normalized": [] }, { "id": "PMID-17960624_T60", "type": "Pathological_formation", "text": [ "ovarian cancer" ], "offsets": [ [ 1739, 1753 ] ], "normalized": [] }, { "id": "PMID-17960624_T36", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 267, 273 ] ], "normalized": [] }, { "id": "PMID-17960624_T70", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 348, 354 ] ], "normalized": [] } ]

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[ { "id": "PMID-17960624_1", "entity_ids": [ "PMID-17960624_T8", "PMID-17960624_T9" ] } ]

[ { "id": "PMID-17960624_R1", "type": "frag", "arg1_id": "PMID-17960624_T30", "arg2_id": "PMID-17960624_T31", "normalized": [] }, { "id": "PMID-17960624_R2", "type": "frag", "arg1_id": "PMID-17960624_T24", "arg2_id": "PMID-17960624_T25", "normalized": [] } ]

[ { "id": "PMID-2418866__text", "type": "abstract", "text": [ "Retinal revascularisation in diabetic retinopathy.\n\nThe case history of a 33-year-old diabetic patient who has had diabetes for 24 years is presented. When first seen in 1975 he had bilateral proliferative retinopathy with new vessels in the retinal periphery. He had large areas of capillary non-perfusion lateral to the macula in the right eye associated with the new vessels. Nine years later, after extensive repeated photocoagulation, revascularisation of large areas previously not perfused were seen. The vessels are in the plane of the retina and do not have the appearance of new vessels.\n" ], "offsets": [ [ 0, 598 ] ] } ]

[ { "id": "PMID-2418866_T2", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 227, 234 ] ], "normalized": [] }, { "id": "PMID-2418866_T3", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 283, 292 ] ], "normalized": [] }, { "id": "PMID-2418866_T4", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 342, 345 ] ], "normalized": [] }, { "id": "PMID-2418866_T5", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 370, 377 ] ], "normalized": [] }, { "id": "PMID-2418866_T7", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 512, 519 ] ], "normalized": [] }, { "id": "PMID-2418866_T8", "type": "Multi-tissue_structure", "text": [ "retina" ], "offsets": [ [ 544, 550 ] ], "normalized": [] }, { "id": "PMID-2418866_T9", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 589, 596 ] ], "normalized": [] }, { "id": "PMID-2418866_T10", "type": "Tissue", "text": [ "macula" ], "offsets": [ [ 322, 328 ] ], "normalized": [] }, { "id": "PMID-2418866_T11", "type": "Tissue", "text": [ "retinal periphery" ], "offsets": [ [ 242, 259 ] ], "normalized": [] }, { "id": "PMID-2418866_T1000", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 95, 102 ] ], "normalized": [] }, { "id": "PMID-2418866_T13", "type": "Multi-tissue_structure", "text": [ "Retinal" ], "offsets": [ [ 0, 7 ] ], "normalized": [] } ]

[ { "id": "PMID-2418866_E1", "type": "Development", "trigger": { "text": [ "appearance" ], "offsets": [ [ 571, 581 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2418866_T9" } ] }, { "id": "PMID-2418866_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "revascularisation" ], "offsets": [ [ 8, 25 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-2418866_T13" } ] }, { "id": "PMID-2418866_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "revascularisation" ], "offsets": [ [ 440, 457 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-16893130__text", "type": "abstract", "text": [ "[Autologous bone marrow stem cell or peripheral blood endothelial progenitor cell therapy in patients with peripheral limb ischaemia]\n\nNo effective medical therapies have been developed sofar to enhance blood flow in the legs of patients with peripheral arterial disease (PAD). For patients with limb threatening ischaemia the only option for relief of rest pain or gangraena is amputation. There is evidence in experimental and clinical studies that adult bone marrow-derived stem cells and endothelial progenitor cells participate in the development of new blood vessels, called neoangiogenesis or neovascularization. Clinical results induced by autologous bone marrow stem cells or angiogenic growth/differentiation factors in end-stage patients with PAD are summarized. Considering the relatively few number of patients treated by angiogenic therapy, the interpretation of clinical results needs cautiousness.\n" ], "offsets": [ [ 0, 914 ] ] } ]

[ { "id": "PMID-16893130_T1", "type": "Cell", "text": [ "bone marrow stem cell" ], "offsets": [ [ 12, 33 ] ], "normalized": [] }, { "id": "PMID-16893130_T3", "type": "Cell", "text": [ "peripheral blood endothelial progenitor cell" ], "offsets": [ [ 37, 81 ] ], "normalized": [] }, { "id": "PMID-16893130_T5", "type": "Organism_subdivision", "text": [ "limb" ], "offsets": [ [ 118, 122 ] ], "normalized": [] }, { "id": "PMID-16893130_T6", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 203, 208 ] ], "normalized": [] }, { "id": "PMID-16893130_T7", "type": "Organism_subdivision", "text": [ "legs" ], "offsets": [ [ 221, 225 ] ], "normalized": [] }, { "id": "PMID-16893130_T8", "type": "Organism_subdivision", "text": [ "limb" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "PMID-16893130_T9", "type": "Cell", "text": [ "bone marrow-derived stem cells" ], "offsets": [ [ 457, 487 ] ], "normalized": [] }, { "id": "PMID-16893130_T11", "type": "Cell", "text": [ "endothelial progenitor cells" ], "offsets": [ [ 492, 520 ] ], "normalized": [] }, { "id": "PMID-16893130_T15", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 559, 572 ] ], "normalized": [] }, { "id": "PMID-16893130_T18", "type": "Cell", "text": [ "bone marrow stem cells" ], "offsets": [ [ 659, 681 ] ], "normalized": [] }, { "id": "PMID-16893130_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 93, 101 ] ], "normalized": [] }, { "id": "PMID-16893130_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 229, 237 ] ], "normalized": [] }, { "id": "PMID-16893130_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 282, 290 ] ], "normalized": [] }, { "id": "PMID-16893130_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 740, 748 ] ], "normalized": [] }, { "id": "PMID-16893130_T1004", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 815, 823 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-19050907__text", "type": "abstract", "text": [ "Evaluation of electrical stimulation for ischemic wound therapy: a feasibility study using the lapine wound model.\n\nChronic wounds are a major secondary complication for many people with impaired mobility. Electrical stimulation (ES) has been recommended as a adjunctive therapy, however optimal treatment paradigms have not been established. Our group seeks to determine the basic mechanisms underlying ES wound therapy, an area where understanding is currently limited. A feasibility study was carried out to develop the Ahn/Mustoe lapine wound model for systematic investigation of the effects of electrical stimulation on ischemic wound therapy. A standardized surgical procedure incorporated a hybrid stimulation system comprising an implantable mini-stimulator and surface electrodes, with creation of repeatable ischemic wounds. Twenty mature male New Zealand white rabbits (3 kg weight) were employed to evaluate the effects of two empirically selected stimulation paradigms applied continuously for 7-21 days, using each animal as its own control. Outcomes measures included transcutaneous blood gas levels, histology, total RNA content and analysis of alpha2 (I) collagen (COL-I), type IV collagen (COL-IV), alpha1 (V) collagen (COL-V), and vascular endothelial growth factor (VEGF) expression using real-time quantitative PCR. All markers for stimulated wounds showed increased activity relative to non-stimulated control wounds between 7 and 14 days following injury, with peak activity at 14 days. By 21 days post-injury, all activity had returned to near baseline level. VEGF and COL-IV levels were found to be significantly higher for pattern A (110 mus pulse width) compared to pattern B (5 mus pulse width) at 14 days, implying that pattern A may be more effective at promoting angiogenesis. All wounds were fully re-epithelialized by 10 days post-injury. Both COL-I and COL-V showed statistically significant (P less than 0.05) increased activity between day 7 and day 14 for pattern A, potentially indicating a continued effect on matrix remodeling. The early closure of all wounds implies that the rabbit ear model may not be valid for chronic wound studies.\n" ], "offsets": [ [ 0, 2181 ] ] } ]

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[]

[ { "id": "PMID-12724285__text", "type": "abstract", "text": [ "Possible role of cyclooxygenase II in the acquisition of ovarian luteal function in rodents.\n\nThe development of the corpus luteum (CL), which involves angiogenesis, is essential for the establishment of early pregnancy. We investigated the roles of the prostaglandin synthases cyclooxygenase (COX) I and COX-II in angiogenesis and progesterone production in the newly formed CL, using inhibitors of the COX enzymes and the gonadotropin-induced pseudopregnant rat as a model. Injection of indomethacin, a nonselective COX inhibitor, on the day of ovulation and the following day decreased serum levels of progesterone, as did injection of the selective COX-II inhibitor NS-398. In contrast, a selective COX-I inhibitor, SC-560, had no effect on serum progesterone concentrations. None of the inhibitors had any effect on the weight of the superovulated ovaries or on the synthesis of progesterone by cultured luteal cells. To determine whether changes in angiogenesis are responsible for the decrease in progesterone synthesis, we measured hemoglobin and CD34 levels in luteinized ovaries following injection of COX inhibitors and measured the relative frequency of cells positive for platelet-endothelial cell adhesion molecule as a specific marker for endothelial cells. All of these parameters were reduced by the COX-II inhibitors, suggesting that changes in the vasculature are responsible for the decrease in serum progesterone. Histological examination of ovarian corrosion casts indicated that NS-398 inhibited the establishment of luteal capillary vessels following the injection of hCG. The results are consistent with the hypothesis that the activity of COX-II is associated with the formation of functional CL via its stimulation of angiogenesis.\n" ], "offsets": [ [ 0, 1759 ] ] } ]

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"Multi-tissue_structure", "text": [ "CL" ], "offsets": [ [ 376, 378 ] ], "normalized": [] }, { "id": "PMID-12724285_T14", "type": "Gene_or_gene_product", "text": [ "COX enzymes" ], "offsets": [ [ 404, 415 ] ], "normalized": [] }, { "id": "PMID-12724285_T15", "type": "Gene_or_gene_product", "text": [ "gonadotropin" ], "offsets": [ [ 424, 436 ] ], "normalized": [] }, { "id": "PMID-12724285_T17", "type": "Drug_or_compound", "text": [ "indomethacin" ], "offsets": [ [ 489, 501 ] ], "normalized": [] }, { "id": "PMID-12724285_T18", "type": "Gene_or_gene_product", "text": [ "COX" ], "offsets": [ [ 518, 521 ] ], "normalized": [] }, { "id": "PMID-12724285_T20", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 589, 594 ] ], "normalized": [] }, { "id": "PMID-12724285_T21", "type": "Drug_or_compound", "text": [ "progesterone" ], "offsets": [ [ 605, 617 ] ], "normalized": [] }, { "id": "PMID-12724285_T23", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 653, 659 ] ], "normalized": [] }, { "id": "PMID-12724285_T24", "type": "Drug_or_compound", "text": [ "NS-398" ], "offsets": [ [ 670, 676 ] ], "normalized": [] }, { "id": "PMID-12724285_T25", "type": "Gene_or_gene_product", "text": [ "COX-I" ], "offsets": [ [ 703, 708 ] ], "normalized": [] }, { "id": "PMID-12724285_T26", "type": "Drug_or_compound", "text": [ "SC-560" ], "offsets": [ [ 720, 726 ] ], "normalized": [] }, { "id": "PMID-12724285_T27", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 745, 750 ] ], "normalized": [] }, { "id": "PMID-12724285_T28", "type": "Drug_or_compound", "text": [ "progesterone" ], "offsets": [ [ 751, 763 ] ], "normalized": [] }, { "id": "PMID-12724285_T29", "type": "Organ", "text": [ "superovulated ovaries" ], "offsets": [ [ 839, 860 ] ], "normalized": [] }, { "id": "PMID-12724285_T32", "type": "Drug_or_compound", "text": [ "progesterone" ], "offsets": [ [ 884, 896 ] ], "normalized": [] }, { "id": "PMID-12724285_T33", "type": "Cell", "text": [ "cultured luteal cells" ], "offsets": [ [ 900, 921 ] ], "normalized": [] }, { "id": "PMID-12724285_T38", "type": "Drug_or_compound", "text": [ "progesterone" ], "offsets": [ [ 1004, 1016 ] ], "normalized": [] }, { "id": "PMID-12724285_T39", "type": "Gene_or_gene_product", "text": [ "hemoglobin" ], "offsets": [ [ 1040, 1050 ] ], "normalized": [] }, { "id": "PMID-12724285_T40", "type": "Gene_or_gene_product", "text": [ "CD34" ], "offsets": [ [ 1055, 1059 ] ], "normalized": [] }, { "id": "PMID-12724285_T42", "type": "Organ", "text": [ "ovaries" ], "offsets": [ [ 1081, 1088 ] ], "normalized": [] }, { "id": "PMID-12724285_T45", "type": "Gene_or_gene_product", "text": [ "COX" ], "offsets": [ [ 1112, 1115 ] ], "normalized": [] }, { "id": "PMID-12724285_T47", "type": "Gene_or_gene_product", "text": [ "platelet-endothelial cell adhesion molecule" ], "offsets": [ [ 1185, 1228 ] ], "normalized": [] }, { "id": "PMID-12724285_T48", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1254, 1271 ] ], "normalized": [] }, { "id": "PMID-12724285_T50", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 1317, 1323 ] ], "normalized": [] }, { "id": "PMID-12724285_T52", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 1367, 1378 ] ], "normalized": [] }, { "id": "PMID-12724285_T54", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1415, 1420 ] ], "normalized": [] }, { "id": "PMID-12724285_T55", "type": "Drug_or_compound", "text": [ "progesterone" ], "offsets": [ [ 1421, 1433 ] ], "normalized": [] }, { "id": "PMID-12724285_T56", "type": "Organ", "text": [ "ovarian" ], "offsets": [ [ 1463, 1470 ] ], "normalized": [] }, { "id": "PMID-12724285_T58", "type": "Drug_or_compound", "text": [ "NS-398" ], "offsets": [ [ 1502, 1508 ] ], "normalized": [] }, { "id": "PMID-12724285_T62", "type": "Multi-tissue_structure", "text": [ "luteal capillary vessels" ], "offsets": [ [ 1540, 1564 ] ], "normalized": [] }, { "id": "PMID-12724285_T64", "type": "Gene_or_gene_product", "text": [ "hCG" ], "offsets": [ [ 1592, 1595 ] ], "normalized": [] }, { "id": "PMID-12724285_T66", "type": "Gene_or_gene_product", "text": [ "COX-II" ], "offsets": [ [ 1665, 1671 ] ], "normalized": [] }, { "id": "PMID-12724285_T68", "type": "Multi-tissue_structure", "text": [ "CL" ], "offsets": [ [ 1719, 1721 ] ], "normalized": [] }, { "id": "PMID-12724285_T1000", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 460, 463 ] ], "normalized": [] }, { "id": "PMID-12724285_T6", "type": "Drug_or_compound", "text": [ "prostaglandin" ], "offsets": [ [ 254, 267 ] ], "normalized": [] }, { "id": "PMID-12724285_T76", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1166, 1171 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-19605361__text", "type": "abstract", "text": [ "MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover.\n\nThe formation of new blood vessels from pre-existing ones requires highly coordinated restructuring of endothelial cells (EC) and the surrounding extracellular matrix. Directed EC migration is a central step in this process and depends on cellular signaling cascades that initiate and control the structural rearrangements. On the basis of earlier findings that ERK5 deficiency in mouse EC results in massive defects in vessel architecture, we focused on the impact of the MEK5/ERK5 signaling pathway on EC migration. Using a retroviral gene transfer approach, we found that constitutive activation of MEK5/ERK5 signaling strongly inhibits EC migration and results in massive morphological changes. The area covered by spread EC was dramatically enlarged, accompanied by an increase in focal contacts and altered organization of actin filaments. Consequently, cells were more rigid and show reduced motility. This phenotype was most likely based on decreased focal contact turnover caused by reduced expression of p130Cas, a key player in directed cell migration. We demonstrate for the first time that ERK5 signaling not only is involved in EC survival and stress response but also controls migration and morphology of EC.\n" ], "offsets": [ [ 0, 1310 ] ] } ]

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[]

[ { "id": "PMID-3985123__text", "type": "abstract", "text": [ "Mast cells and tumors. The specific enhancement of tumor proliferation in vitro.\n\nMast cells were found to be unique among the peritoneal leukocytes by virtue of their capacity to enhance profoundly the proliferation of a variety of tumors in vitro. This phenomenon occurs at mast cell/tumor ratios which reflect the stoichiometry of host cell/tumor relationships in vivo. The growth factor was found to reside in mast cell granules and was identified as heparin by sequential purification and enzymatic degradation. This cellular interaction was tumor-specific, although isolated granules could enhance fibroblast proliferation. The findings are discussed in relation to previous morphologic studies, reports of in vitro mast-cell-mediated tumor cytotoxicity, and the role of mast cells in angiogenesis and connective tissue proliferation.\n" ], "offsets": [ [ 0, 841 ] ] } ]

[ { "id": "PMID-3985123_T1", "type": "Cell", "text": [ "Mast cells" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-3985123_T2", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 15, 21 ] ], "normalized": [] }, { "id": "PMID-3985123_T3", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 51, 56 ] ], "normalized": [] }, { "id": "PMID-3985123_T4", "type": "Cell", "text": [ "Mast cells" ], "offsets": [ [ 82, 92 ] ], "normalized": [] }, { "id": "PMID-3985123_T6", "type": "Cell", "text": [ "peritoneal leukocytes" ], "offsets": [ [ 127, 148 ] ], "normalized": [] }, { "id": "PMID-3985123_T7", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 233, 239 ] ], "normalized": [] }, { "id": "PMID-3985123_T8", "type": "Cell", "text": [ "mast cell" ], "offsets": [ [ 276, 285 ] ], "normalized": [] }, { "id": "PMID-3985123_T9", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 286, 291 ] ], "normalized": [] }, { "id": "PMID-3985123_T10", "type": "Cell", "text": [ "host cell" ], "offsets": [ [ 334, 343 ] ], "normalized": [] }, { "id": "PMID-3985123_T11", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 344, 349 ] ], "normalized": [] }, { "id": "PMID-3985123_T12", "type": "Cell", "text": [ "mast cell" ], "offsets": [ [ 414, 423 ] ], "normalized": [] }, { "id": "PMID-3985123_T13", "type": "Drug_or_compound", "text": [ "heparin" ], "offsets": [ [ 455, 462 ] ], "normalized": [] }, { "id": "PMID-3985123_T14", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 547, 552 ] ], "normalized": [] }, { "id": "PMID-3985123_T15", "type": "Organism_substance", "text": [ "granules" ], "offsets": [ [ 581, 589 ] ], "normalized": [] }, { "id": "PMID-3985123_T18", "type": "Cell", "text": [ "fibroblast" ], "offsets": [ [ 604, 614 ] ], "normalized": [] }, { "id": "PMID-3985123_T19", "type": "Cell", "text": [ "mast-cell" ], "offsets": [ [ 722, 731 ] ], "normalized": [] }, { "id": "PMID-3985123_T20", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 741, 746 ] ], "normalized": [] }, { "id": "PMID-3985123_T22", "type": "Cell", "text": [ "mast cells" ], "offsets": [ [ 777, 787 ] ], "normalized": [] }, { "id": "PMID-3985123_T25", "type": "Tissue", "text": [ "connective tissue" ], "offsets": [ [ 808, 825 ] ], "normalized": [] }, { "id": "PMID-3985123_T5", "type": "Organism_substance", "text": [ "granules" ], "offsets": [ [ 424, 432 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-16720995__text", "type": "abstract", "text": [ "GDP and AGE receptors: mechanisms of peritoneal damage.\n\nLong-term peritoneal dialysis (PD) is limited by morphological changes of the peritoneal membrane. Structural changes were promoted by toxicity of glucose degradation products (GDPs) which are generated during heat sterilization in peritoneal dialysis fluids (PDFs). Besides their direct toxicity GDPs promote formation of advanced glycation endproducts (AGEs). RAGE (receptor for AGE) is the best characterized signal transduction receptor for AGEs and is expressed on mesothelial cells. The effects of PDFs with different amounts of GDPs were compared on morphological changes in the peritoneal membrane in a RAGE -/- mouse model. It could be demonstrated that RAGE plays a pivotal role in structural damage (e.g. inflammation, neoangiogenesis and fibrosis) of the peritoneal membrane. Further investigations of this pathway with regard to preventing peritoneal fibrosis should be performed to maintain the integrity of the peritoneal membrane in peritoneal dialysis patients.\n" ], "offsets": [ [ 0, 1036 ] ] } ]

[ { "id": "PMID-16720995_T1", "type": "Drug_or_compound", "text": [ "GDP" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-16720995_T2", "type": "Drug_or_compound", "text": [ "AGE" ], "offsets": [ [ 8, 11 ] ], "normalized": [] }, { "id": "PMID-16720995_T3", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 37, 47 ] ], "normalized": [] }, { "id": "PMID-16720995_T5", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 135, 154 ] ], "normalized": [] }, { "id": "PMID-16720995_T6", "type": "Drug_or_compound", "text": [ "glucose degradation products" ], "offsets": [ [ 204, 232 ] ], "normalized": [] }, { "id": "PMID-16720995_T7", "type": "Drug_or_compound", "text": [ "GDPs" ], "offsets": [ [ 234, 238 ] ], "normalized": [] }, { "id": "PMID-16720995_T9", "type": "Drug_or_compound", "text": [ "GDPs" ], "offsets": [ [ 354, 358 ] ], "normalized": [] }, { "id": "PMID-16720995_T10", "type": "Drug_or_compound", "text": [ "advanced glycation endproducts" ], "offsets": [ [ 380, 410 ] ], "normalized": [] }, { "id": "PMID-16720995_T11", "type": "Drug_or_compound", "text": [ "AGEs" ], "offsets": [ [ 412, 416 ] ], "normalized": [] }, { "id": "PMID-16720995_T12", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 419, 423 ] ], "normalized": [] }, { "id": "PMID-16720995_T13", "type": "Drug_or_compound", "text": [ "AGEs" ], "offsets": [ [ 502, 506 ] ], "normalized": [] }, { "id": "PMID-16720995_T14", "type": "Cell", "text": [ "mesothelial cells" ], "offsets": [ [ 527, 544 ] ], "normalized": [] }, { "id": "PMID-16720995_T15", "type": "Drug_or_compound", "text": [ "GDPs" ], "offsets": [ [ 592, 596 ] ], "normalized": [] }, { "id": "PMID-16720995_T16", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 643, 662 ] ], "normalized": [] }, { "id": "PMID-16720995_T18", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 668, 672 ] ], "normalized": [] }, { "id": "PMID-16720995_T19", "type": "Gene_or_gene_product", "text": [ "RAGE" ], "offsets": [ [ 720, 724 ] ], "normalized": [] }, { "id": "PMID-16720995_T22", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 824, 843 ] ], "normalized": [] }, { "id": "PMID-16720995_T23", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 910, 920 ] ], "normalized": [] }, { "id": "PMID-16720995_T24", "type": "Multi-tissue_structure", "text": [ "peritoneal membrane" ], "offsets": [ [ 983, 1002 ] ], "normalized": [] }, { "id": "PMID-16720995_T25", "type": "Multi-tissue_structure", "text": [ "peritoneal" ], "offsets": [ [ 1006, 1016 ] ], "normalized": [] }, { "id": "PMID-16720995_T26", "type": "Gene_or_gene_product", "text": [ "receptor for AGE" ], "offsets": [ [ 425, 441 ] ], "normalized": [] }, { "id": "PMID-16720995_T1000", "type": "Organism", "text": [ "RAGE -/- mouse" ], "offsets": [ [ 668, 682 ] ], "normalized": [] }, { "id": "PMID-16720995_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1026, 1034 ] ], "normalized": [] } ]

[ { "id": "PMID-16720995_E1", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 48, 54 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T3" } ] }, { "id": "PMID-16720995_E2", "type": "Remodeling", "trigger": { "text": [ "morphological changes" ], "offsets": [ [ 106, 127 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T5" } ] }, { "id": "PMID-16720995_E3", "type": "Positive_regulation", "trigger": { "text": [ "promoted" ], "offsets": [ [ 180, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_E2" }, { "role": "Cause", "ref_id": "PMID-16720995_T6" } ] }, { "id": "PMID-16720995_E4", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 359, 366 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_E5" }, { "role": "Cause", "ref_id": "PMID-16720995_T9" } ] }, { "id": "PMID-16720995_E5", "type": "Synthesis", "trigger": { "text": [ "formation" ], "offsets": [ [ 367, 376 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T10" } ] }, { "id": "PMID-16720995_E6", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 514, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T12" } ] }, { "id": "PMID-16720995_E7", "type": "Remodeling", "trigger": { "text": [ "morphological changes" ], "offsets": [ [ 614, 635 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T16" } ] }, { "id": "PMID-16720995_E8", "type": "Breakdown", "trigger": { "text": [ "structural damage" ], "offsets": [ [ 749, 766 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16720995_T22" } ] }, { "id": "PMID-16720995_E9", "type": "Regulation", "trigger": { "text": [ "plays a pivotal role" ], "offsets": [ [ 725, 745 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16720995_T19" }, { "role": "Theme", "ref_id": "PMID-16720995_E8" } ] }, { "id": "PMID-16720995_E10", "type": "Regulation", "trigger": { "text": [ "plays a pivotal role" ], "offsets": [ [ 725, 745 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16720995_T19" }, { "role": "Theme", "ref_id": "PMID-16720995_E11" } ] }, { "id": "PMID-16720995_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 787, 802 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16720995_T22" } ] } ]

[ { "id": "PMID-16720995_1", "entity_ids": [ "PMID-16720995_T6", "PMID-16720995_T7" ] }, { "id": "PMID-16720995_2", "entity_ids": [ "PMID-16720995_T10", "PMID-16720995_T11" ] }, { "id": "PMID-16720995_3", "entity_ids": [ "PMID-16720995_T26", "PMID-16720995_T12" ] } ]

[]

[ { "id": "PMID-19622586__text", "type": "abstract", "text": [ "EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation.\n\nPURPOSE: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. EXPERIMENTAL DESIGN: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. RESULTS: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T(163.) Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. CONCLUSIONS: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies.\n" ], "offsets": [ [ 0, 2048 ] ] } ]

[ { "id": "PMID-19622586_T1", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19622586_T5", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 45, 50 ] ], "normalized": [] }, { "id": "PMID-19622586_T7", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 59, 62 ] ], "normalized": [] }, { "id": "PMID-19622586_T12", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 194, 200 ] ], "normalized": [] }, { "id": "PMID-19622586_T13", "type": "Drug_or_compound", "text": [ "xanthone derivatives" ], "offsets": [ [ 256, 276 ] ], "normalized": [] }, { "id": "PMID-19622586_T15", "type": "Drug_or_compound", "text": [ "3,6-di(2,3-epoxypropoxy)xanthone" ], "offsets": [ [ 446, 478 ] ], "normalized": [] }, { "id": "PMID-19622586_T16", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 480, 484 ] ], "normalized": [] }, { "id": "PMID-19622586_T17", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 495, 500 ] ], "normalized": [] }, { "id": "PMID-19622586_T19", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 581, 585 ] ], "normalized": [] }, { "id": "PMID-19622586_T20", "type": "Tissue", "text": [ "tube" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "PMID-19622586_T21", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 712, 716 ] ], "normalized": [] }, { "id": "PMID-19622586_T23", "type": "Drug_or_compound", "text": [ "glutathione" ], "offsets": [ [ 846, 857 ] ], "normalized": [] }, { "id": "PMID-19622586_T24", "type": "Drug_or_compound", "text": [ "monochlorobimane" ], "offsets": [ [ 897, 913 ] ], "normalized": [] }, { "id": "PMID-19622586_T25", "type": "Drug_or_compound", "text": [ "glutathione" ], "offsets": [ [ 917, 928 ] ], "normalized": [] }, { "id": "PMID-19622586_T26", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 954, 958 ] ], "normalized": [] }, { "id": "PMID-19622586_T30", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 967, 983 ] ], "normalized": [] }, { "id": "PMID-19622586_T32", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "PMID-19622586_T34", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1073, 1078 ] ], "normalized": [] }, { "id": "PMID-19622586_T36", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1106, 1111 ] ], "normalized": [] }, { "id": "PMID-19622586_T37", "type": "Gene_or_gene_product", "text": [ "Bim" ], "offsets": [ [ 1117, 1120 ] ], "normalized": [] }, { "id": "PMID-19622586_T39", "type": "Gene_or_gene_product", "text": [ "Bax" ], "offsets": [ [ 1136, 1139 ] ], "normalized": [] }, { "id": "PMID-19622586_T41", "type": "Drug_or_compound", "text": [ "glutathione" ], "offsets": [ [ 1210, 1221 ] ], "normalized": [] }, { "id": "PMID-19622586_T43", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase" ], "offsets": [ [ 1236, 1273 ] ], "normalized": [] }, { "id": "PMID-19622586_T44", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1275, 1278 ] ], "normalized": [] }, { "id": "PMID-19622586_T45", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 1309, 1313 ] ], "normalized": [] }, { "id": "PMID-19622586_T48", "type": "Drug_or_compound", "text": [ "Glutathione" ], "offsets": [ [ 1329, 1340 ] ], "normalized": [] }, { "id": "PMID-19622586_T50", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 1392, 1396 ] ], "normalized": [] }, { "id": "PMID-19622586_T51", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1400, 1403 ] ], "normalized": [] }, { "id": "PMID-19622586_T54", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1444, 1449 ] ], "normalized": [] }, { "id": "PMID-19622586_T57", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein/ERK kinase" ], "offsets": [ [ 1479, 1515 ] ], "normalized": [] }, { "id": "PMID-19622586_T58", "type": "Gene_or_gene_product", "text": [ "MEK" ], "offsets": [ [ 1517, 1520 ] ], "normalized": [] }, { "id": "PMID-19622586_T59", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 1555, 1559 ] ], "normalized": [] }, { "id": "PMID-19622586_T61", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1563, 1568 ] ], "normalized": [] }, { "id": "PMID-19622586_T62", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1641, 1644 ] ], "normalized": [] }, { "id": "PMID-19622586_T64", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1666, 1671 ] ], "normalized": [] }, { "id": "PMID-19622586_T65", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 1730, 1734 ] ], "normalized": [] }, { "id": "PMID-19622586_T67", "type": "Drug_or_compound", "text": [ "glutathione" ], "offsets": [ [ 1743, 1754 ] ], "normalized": [] }, { "id": "PMID-19622586_T69", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1766, 1769 ] ], "normalized": [] }, { "id": "PMID-19622586_T71", "type": "Gene_or_gene_product", "text": [ "Mcl-1" ], "offsets": [ [ 1788, 1793 ] ], "normalized": [] }, { "id": "PMID-19622586_T72", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1809, 1826 ] ], "normalized": [] }, { "id": "PMID-19622586_T76", "type": "Drug_or_compound", "text": [ "EPOX" ], "offsets": [ [ 1896, 1900 ] ], "normalized": [] }, { "id": "PMID-19622586_T86", "type": "Protein_domain_or_region", "text": [ "T(163" ], "offsets": [ [ 1453, 1458 ] ], "normalized": [] }, { "id": "PMID-19622586_T92", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 286, 292 ] ], "normalized": [] }, { "id": "PMID-19622586_T95", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 594, 598 ] ], "normalized": [] }, { "id": "PMID-19622586_T96", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 610, 614 ] ], "normalized": [] }, { "id": "PMID-19622586_T97", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1322, 1327 ] ], "normalized": [] } ]

[ { "id": "PMID-19622586_E4", "type": "Catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 30, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T5" } ] }, { "id": "PMID-19622586_E6", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 63, 75 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T7" } ] }, { "id": "PMID-19622586_E10", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 169, 175 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T12" } ] }, { "id": "PMID-19622586_E11", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 180, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T12" } ] }, { "id": "PMID-19622586_E28", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T30" } ] }, { "id": "PMID-19622586_E31", "type": "Catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1041, 1052 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T32" } ] }, { "id": "PMID-19622586_E33", "type": "Negative_regulation", "trigger": { "text": [ "Down-regulation" ], "offsets": [ [ 1054, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T34" } ] }, { "id": "PMID-19622586_E35", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1094, 1102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T37" } ] }, { "id": "PMID-19622586_E38", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1122, 1132 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T39" } ] }, { "id": "PMID-19622586_E40", "type": "Negative_regulation", "trigger": { "text": [ "depletion" ], "offsets": [ [ 1222, 1231 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T41" } ] }, { "id": "PMID-19622586_E42", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 1280, 1292 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T43" } ] }, { "id": "PMID-19622586_E46", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 1357, 1365 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19622586_E47" }, { "role": "Theme", "ref_id": "PMID-19622586_E49" } ] }, { "id": "PMID-19622586_E47", "type": "Planned_process", "trigger": { "text": [ "supplementation" ], "offsets": [ [ 1341, 1356 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19622586_T48" } ] }, { "id": "PMID-19622586_E49", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory effects" ], "offsets": [ [ 1370, 1388 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19622586_T50" }, { "role": "Theme", "ref_id": "PMID-19622586_T51" } ] }, { "id": "PMID-19622586_E52", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1411, 1420 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19622586_T51" }, { "role": "Theme", "ref_id": "PMID-19622586_E53" } ] }, { "id": "PMID-19622586_E53", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1425, 1440 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-19622586_T86" }, { "role": "Theme", "ref_id": "PMID-19622586_T54" } ] }, { "id": "PMID-19622586_E55", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 1532, 1540 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19622586_E56" }, { "role": "Theme", "ref_id": "PMID-19622586_E20" } ] }, { "id": "PMID-19622586_E56", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 1461, 1475 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T57" } ] }, { "id": "PMID-19622586_E60", "type": "Catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1608, 1619 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T61" } ] }, { "id": "PMID-19622586_E63", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1652, 1662 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T64" }, { "role": "Cause", "ref_id": "PMID-19622586_T62" } ] }, { "id": "PMID-19622586_E66", "type": "Negative_regulation", "trigger": { "text": [ "depletion" ], "offsets": [ [ 1755, 1764 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T67" } ] }, { "id": "PMID-19622586_E68", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 1770, 1782 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T69" } ] }, { "id": "PMID-19622586_E70", "type": "Catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1794, 1805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19622586_T71" } ] }, { "id": "PMID-19622586_E74", "type": "Negative_regulation", "trigger": { "text": 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[ { "id": "PMID-19622586_1", "entity_ids": [ "PMID-19622586_T15", "PMID-19622586_T16" ] }, { "id": "PMID-19622586_2", "entity_ids": [ "PMID-19622586_T43", "PMID-19622586_T44" ] }, { "id": "PMID-19622586_3", "entity_ids": [ "PMID-19622586_T57", "PMID-19622586_T58" ] } ]

[]

[ { "id": "PMID-11835401__text", "type": "abstract", "text": [ "Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors.\n\nInteractions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.\n" ], "offsets": [ [ 0, 1579 ] ] } ]

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"Gene_or_gene_product", "text": [ "secreted protein, acidic, and rich in cysteine" ], "offsets": [ [ 358, 404 ] ], "normalized": [] }, { "id": "PMID-11835401_T17", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 411, 417 ] ], "normalized": [] }, { "id": "PMID-11835401_T23", "type": "Cell", "text": [ "vascular cells" ], "offsets": [ [ 491, 505 ] ], "normalized": [] }, { "id": "PMID-11835401_T25", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "PMID-11835401_T29", "type": "Cell", "text": [ "arterial smooth muscle cell" ], "offsets": [ [ 563, 590 ] ], "normalized": [] }, { "id": "PMID-11835401_T31", "type": "Gene_or_gene_product", "text": [ "platelet-derived growth factor" ], "offsets": [ [ 619, 649 ] ], "normalized": [] }, { "id": "PMID-11835401_T33", "type": "Gene_or_gene_product", "text": [ "monomeric type I collagen" ], "offsets": [ [ 668, 693 ] ], "normalized": [] }, { "id": "PMID-11835401_T34", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 716, 721 ] ], "normalized": [] }, { "id": "PMID-11835401_T35", "type": "Gene_or_gene_product", "text": [ "SPARC peptides" ], "offsets": [ [ 726, 740 ] ], "normalized": [] }, { "id": "PMID-11835401_T36", "type": "Cell", "text": [ "smooth muscle cells" ], "offsets": [ [ 790, 809 ] ], "normalized": [] }, { "id": "PMID-11835401_T37", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 895, 900 ] ], "normalized": [] }, { "id": "PMID-11835401_T41", "type": "Cell", "text": [ "smooth muscle cell" ], "offsets": [ [ 938, 956 ] ], "normalized": [] }, { "id": "PMID-11835401_T42", "type": "Drug_or_compound", "text": [ "cyclin-dependent kinase inhibitors" ], "offsets": [ [ 1068, 1102 ] ], "normalized": [] }, { "id": "PMID-11835401_T43", "type": "Gene_or_gene_product", "text": [ "Cyclin-dependent kinase-2" ], "offsets": [ [ 1104, 1129 ] ], "normalized": [] }, { "id": "PMID-11835401_T44", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 1140, 1144 ] ], "normalized": [] }, { "id": "PMID-11835401_T45", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 1149, 1157 ] ], "normalized": [] }, { "id": "PMID-11835401_T47", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 1170, 1192 ] ], "normalized": [] }, { "id": "PMID-11835401_T49", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1271, 1276 ] ], "normalized": [] }, { "id": "PMID-11835401_T50", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1326, 1331 ] ], "normalized": [] }, { "id": "PMID-11835401_T51", "type": "Gene_or_gene_product", "text": [ "SPARC" ], "offsets": [ [ 1339, 1344 ] ], "normalized": [] }, { "id": "PMID-11835401_T52", "type": "Gene_or_gene_product", "text": [ "platelet-derived growth factor" ], "offsets": [ [ 1390, 1420 ] ], "normalized": [] }, { "id": "PMID-11835401_T57", "type": "Cell", "text": [ "smooth muscle cell" ], "offsets": [ [ 1463, 1481 ] ], "normalized": [] }, { "id": "PMID-11835401_T58", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase-2" ], "offsets": [ [ 1543, 1568 ] ], "normalized": [] }, { "id": "PMID-11835401_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 67, 72 ] ], "normalized": [] }, { "id": "PMID-11835401_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 557, 562 ] ], "normalized": [] }, { "id": "PMID-11835401_T3", "type": "Protein_domain_or_region", "text": [ "C-terminal Ca2+-binding region" ], "offsets": [ [ 828, 858 ] ], "normalized": [] }, { "id": "PMID-11835401_T64", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 1518, 1526 ] ], "normalized": [] }, { "id": "PMID-11835401_T65", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 140, 144 ] ], "normalized": [] }, { "id": "PMID-11835401_T67", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 999, 1003 ] ], "normalized": [] }, { "id": "PMID-11835401_T68", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1041, 1045 ] ], "normalized": [] }, { "id": "PMID-11835401_T69", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 226, 231 ] ], "normalized": [] }, { "id": "PMID-11835401_T19", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 919, 927 ] ], "normalized": [] } ]

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[ { "id": "PMID-15331370__text", "type": "abstract", "text": [ "Enhanced IGF-1 expression improves smooth muscle cell engraftment after cell transplantation.\n\nThe functional benefit of cell transplantation after a myocardial infarction is diminished by early cell losses. IGF-1 enhances cell proliferation and survival. We hypothesized that IGF-1-transfected smooth muscle cells (SMCs) would enhance cell survival and improve engraftment after cell transplantation. The IGF-1 gene was transfected into male SMCs and compared with SMCs transfected with a plasmid vector (vector control) and nontransfected SMCs (cell control). IGF-1 mRNA (n=10/group) and protein levels (n=6/group) were higher (P less than 0.05 for all groups) at 3, 7, and 14 days compared with controls. VEGF was also increased in parallel to enhanced IGF-1 expression. IGF-1-transfected cells demonstrated greater cell proliferation, stimulated angiogenesis, and decreased caspase-3 activity after simulated ischemia and reperfusion (P less than 0.05 for all groups compared with vector or cell controls). A uniform left ventricular injury was produced in female rats using a cryoprobe. Three weeks later, 2 x 10(6) cells from three groups were implanted into the scar. One week later, IGF-1-transfected SMCs had increased myocardial IGF-1 and VEGF levels, increased Bcl2 expression, limited cell apoptosis, and enhanced vessel formation in the myocardial scar compared with the two control groups (P less than 0.05 for all groups). The proportion of SMCs surviving in the implanted region was greater (P less than 0.05) in the IGF-1-transfected group than in the vector or cell controls. Gene enhancement with IGF-1 improved donor cell proliferation, survival, and engraftment after cell transplantation, perhaps mediated by enhanced angiogenesis and reduced apoptosis.\n" ], "offsets": [ [ 0, 1780 ] ] } ]

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"role": "Instrument", "ref_id": "PMID-15331370_T84" } ] }, { "id": "PMID-15331370_E49", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 851, 863 ] ] }, "arguments": [] }, { "id": "PMID-15331370_E50", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1744, 1756 ] ] }, "arguments": [] }, { "id": "PMID-15331370_E41", "type": "Death", "trigger": { "text": [ "losses" ], "offsets": [ [ 200, 206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15331370_T55" } ] }, { "id": "PMID-15331370_E51", "type": "Planned_process", "trigger": { "text": [ "implanted" ], "offsets": [ [ 1481, 1490 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15331370_T44" } ] } ]

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[]

[ { "id": "PMID-16374459__text", "type": "abstract", "text": [ "Regulation of skin microvasculature angiogenesis, cell migration, and permeability by a specific inhibitor of PKCalpha.\n\nActivation of protein kinase C (PKC) induces phenotypic changes in the morphology of microvascular endothelial cells that affect major functions of the microvasculature. These functions include the first stages of sprouting in angiogenesis, cell migration following wounding, and vascular permeability. The specific isoform(s) of PKC responsible for each of these changes has not been previously identified. In this study, we used two inflammatory agents, IL-1beta and phorbol myristic acetate, to activate PKC isozymes and specific inhibitors of PKCalpha (Go6976) and PKCbeta (hispidin) to distinguish how each of these isoform(s) controls angiogenesis, wound healing, and permeability. In all cases, only inhibition of PKCalpha inhibited each of these functions when compared to the inhibition of PKCbeta. Additional analysis of the mechanism of action of Go6976 (RT-PCR, Western blots, and immunohistochemistry) of the changes in the phosphorylated and nonphosphorylated forms of PKCalpha in the cell membrane and cytoplasm confirmed the specificity of PKCalpha inhibition by Go6976. These studies therefore indicate a specific and a regulatory role of the PKCalpha isoform in three major endothelial cell functions that are important in the maintenance of microvascular homeostasis.\n" ], "offsets": [ [ 0, 1408 ] ] } ]

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[]

[ { "id": "PMID-14555793__text", "type": "abstract", "text": [ "Therapeutic angiogenesis: a complex problem requiring a sophisticated approach.\n\nBlood and vascular disorders underlie a plethora of pathologic conditions and are the single most frequent cause of human disease. Ischemia, involving restricted blood flow to tissues is the most common consequence of vessel dysfunction resulting in the disruption of oxygen and nutrient delivery and the accumulation of waste metabolites. Cells cannot survive extended severe ischemia but may be able to adapt to a moderate condition where diffusion to and from bordering nonischemic regions sustains vital functions. Under this condition, the secondary functions of effected cells are likely to be impaired, and a new metabolic equilibrium is established, determined by the level of cross-diffusion and degree of hypoxia. In tissues with a normally high metabolic turnover such as skeletal and cardiac muscle, even mild ischemia causes hypoxia, acidosis, and depressed function (contractility) and eventually threatens myocyte viability and organ function. Ischemic cardiac muscle is additionally vulnerable because reperfusion is essential for survival but reperfusion itself poses additional stress principally from increased production of free radicals during reoxygenation. The latter effect is called reperfusion injury and can cause as much damage as the ischemia. The treatment possibilities for ischemia-related vascular disease are limited. Lipid/cholesterol-lowering agents, diet and antiplatelet adherence (aspirin) therapy may help slow the progression of vessel disease in some instances; but surgical reconstruction may be the only option in advanced stages, and even this is not always an option. An alternative and rather obvious strategy to treat ischemia is to activate endogenous angiogenic or arteriogenic pathways to stimulate revascularization of the tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade, and a new discipline called therapeutic angiogenesis has emerged. This review focuses on the application of therapeutic angiogenesis for treating ischemic muscle disease and includes a critical evaluation of the parameters and limitations of current procedures. The development of this technology has benefited from its application to both peripheral and coronary artery disease and results from both are reviewed here.\n" ], "offsets": [ [ 0, 2397 ] ] } ]

[ { "id": "PMID-14555793_T2", "type": "Organism_substance", "text": [ "Blood" ], "offsets": [ [ 81, 86 ] ], "normalized": [] }, { "id": "PMID-14555793_T4", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 243, 248 ] ], "normalized": [] }, { "id": "PMID-14555793_T5", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 299, 305 ] ], "normalized": [] }, { "id": "PMID-14555793_T6", "type": "Drug_or_compound", "text": [ "oxygen" ], "offsets": [ [ 349, 355 ] ], "normalized": [] }, { "id": "PMID-14555793_T7", "type": "Tissue", "text": [ "skeletal" ], "offsets": [ [ 864, 872 ] ], "normalized": [] }, { "id": "PMID-14555793_T8", "type": "Tissue", "text": [ "cardiac muscle" ], "offsets": [ [ 877, 891 ] ], "normalized": [] }, { "id": "PMID-14555793_T9", "type": "Cell", "text": [ "myocyte" ], "offsets": [ [ 1002, 1009 ] ], "normalized": [] }, { "id": "PMID-14555793_T10", "type": "Tissue", "text": [ "cardiac muscle" ], "offsets": [ [ 1049, 1063 ] ], "normalized": [] }, { "id": "PMID-14555793_T12", "type": "Drug_or_compound", "text": [ "aspirin" ], "offsets": [ [ 1501, 1508 ] ], "normalized": [] }, { "id": "PMID-14555793_T13", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1551, 1557 ] ], "normalized": [] }, { "id": "PMID-14555793_T19", "type": "Organ", "text": [ "muscle" ], "offsets": [ [ 2132, 2138 ] ], "normalized": [] }, { "id": "PMID-14555793_T20", "type": "Multi-tissue_structure", "text": [ "coronary artery" ], "offsets": [ [ 2332, 2347 ] ], "normalized": [] }, { "id": "PMID-14555793_T3", "type": "Multi-tissue_structure", "text": [ "peripheral" ], "offsets": [ [ 2317, 2327 ] ], "normalized": [] }, { "id": "PMID-14555793_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 197, 202 ] ], "normalized": [] }, { "id": "PMID-14555793_T23", "type": "Drug_or_compound", "text": [ "Lipid" ], "offsets": [ [ 1433, 1438 ] ], "normalized": [] }, { "id": "PMID-14555793_T24", "type": "Drug_or_compound", "text": [ "cholesterol" ], "offsets": [ [ 1439, 1450 ] ], "normalized": [] }, { "id": "PMID-14555793_T28", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 91, 99 ] ], "normalized": [] }, { "id": "PMID-14555793_T29", "type": "Organ", "text": [ "organ" ], "offsets": [ [ 1024, 1029 ] ], "normalized": [] }, { "id": "PMID-14555793_T30", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 1856, 1862 ] ], "normalized": [] }, { "id": "PMID-14555793_T31", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 257, 264 ] ], "normalized": [] }, { "id": "PMID-14555793_T32", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 808, 815 ] ], "normalized": [] }, { "id": "PMID-14555793_T33", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "PMID-14555793_T35", "type": "Cell", "text": [ "Cells" ], "offsets": [ [ 421, 426 ] ], "normalized": [] } ]

[ { "id": "PMID-14555793_E1", "type": "Breakdown", "trigger": { "text": [ "dysfunction" ], "offsets": [ [ 306, 317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_T5" } ] }, { "id": "PMID-14555793_E2", "type": "Catabolism", "trigger": { "text": [ "disruption" ], "offsets": [ [ 335, 345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_T6" } ] }, { "id": "PMID-14555793_E3", "type": "Planned_process", "trigger": { "text": [ "therapy" ], "offsets": [ [ 1510, 1517 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-14555793_T12" } ] }, { "id": "PMID-14555793_E4", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1762, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_E11" } ] }, { "id": "PMID-14555793_E5", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1762, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_E12" } ] }, { "id": "PMID-14555793_E6", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 1821, 1830 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_E13" }, { "role": "Cause", "ref_id": "PMID-14555793_E5" } ] }, { "id": "PMID-14555793_E7", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 1821, 1830 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_E13" }, { "role": "Cause", "ref_id": "PMID-14555793_E4" } ] }, { "id": "PMID-14555793_E8", "type": "Regulation", "trigger": { "text": [ "effected" ], "offsets": [ [ 649, 657 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_T33" } ] }, { "id": "PMID-14555793_E9", "type": "Death", "trigger": { "text": [ "survive" ], "offsets": [ [ 434, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555793_T35" } ] }, { "id": "PMID-14555793_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 12, 24 ] ] }, "arguments": [] }, { "id": "PMID-14555793_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1782, 1792 ] ] }, "arguments": [] }, { "id": "PMID-14555793_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "arteriogenic pathways" ], "offsets": [ [ 1796, 1817 ] ] }, "arguments": [] }, { "id": "PMID-14555793_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "revascularization" ], "offsets": [ [ 1831, 1848 ] ] }, "arguments": [] }, { "id": "PMID-14555793_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 2017, 2029 ] ] }, "arguments": [] }, { "id": "PMID-14555793_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 2097, 2109 ] ] }, "arguments": [] } ]

[]

[ { "id": "PMID-14555793_R1", "type": "frag", "arg1_id": "PMID-14555793_T7", "arg2_id": "PMID-14555793_T8", "normalized": [] }, { "id": "PMID-14555793_R2", "type": "frag", "arg1_id": "PMID-14555793_T3", "arg2_id": "PMID-14555793_T20", "normalized": [] } ]

[ { "id": "PMID-16907772__text", "type": "abstract", "text": [ "Formation of new bone during vertical distraction osteogenesis of the human mandible is related to the presence of blood vessels.\n\nWe examined the effect of distraction rate on blood vessel growth in intramembraneous ossification after vertical distraction osteogenesis in the human mandible. Six edentulous patients (aged 60+/-9 years) with a severely atrophic mandible underwent bone augmentation with distraction osteogenesis. Two distraction rates (0.5 and 1 mm/day) were compared and for each group three patients were analyzed. Vascular histomorphometry was carried out in two different areas in the distraction gap: (1) in the first and (2) in the second 1 mm area from the osteotomy line, representing the oldest and younger new-bone area, respectively. Correlation analysis was performed between blood vessel parameters and the amount of new bone formed during distraction. Histological analysis demonstrated the presence of blood vessels throughout the soft connective tissue in the distraction gap. The volume density of blood vessels between the two investigated areas was significantly lower in the 1 mm/day groups, suggesting a delay in angiogenesis in this group of patients. A positive correlation between blood vessel volume and bone volume density was found in the younger new-bone area but not in the oldest new-bone area. This correlation was due to a higher number of blood vessels rather than to a larger size of the blood vessels. Our data suggest that the lower blood vessel density found in the patients with 1 mm/day distraction rate may be related to disruption of angiogenesis in the soft connective tissue of the gap or to a less optimal mechanical stimulation of cells involved in angiogenesis. This probably results in the slower rate of osteogenesis seen at the 1 mm/day distraction rate compared with the 0.5 mm/day distraction rate. The data support the concept that a positive relationship exists between the density of blood vessels and the formation of bone. For distraction of the human mandible in elderly patients, a distraction rate of 0.5 mm/day seems beneficial.\n" ], "offsets": [ [ 0, 2106 ] ] } ]

[ { "id": "PMID-16907772_T1", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 17, 21 ] ], "normalized": [] }, { "id": "PMID-16907772_T2", "type": "Organ", "text": [ "mandible" ], "offsets": [ [ 76, 84 ] ], "normalized": [] }, { "id": "PMID-16907772_T3", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 115, 128 ] ], "normalized": [] }, { "id": "PMID-16907772_T6", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 177, 189 ] ], "normalized": [] }, { "id": "PMID-16907772_T7", "type": "Organ", "text": [ "mandible" ], "offsets": [ [ 283, 291 ] ], "normalized": [] }, { "id": "PMID-16907772_T8", "type": "Organ", "text": [ "mandible" ], "offsets": [ [ 362, 370 ] ], "normalized": [] }, { "id": "PMID-16907772_T9", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 381, 385 ] ], "normalized": [] }, { "id": "PMID-16907772_T10", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 737, 741 ] ], "normalized": [] }, { "id": "PMID-16907772_T11", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 805, 817 ] ], "normalized": [] }, { "id": "PMID-16907772_T12", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 851, 855 ] ], "normalized": [] }, { "id": "PMID-16907772_T13", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 934, 947 ] ], "normalized": [] }, { "id": "PMID-16907772_T14", "type": "Tissue", "text": [ "soft connective tissue" ], "offsets": [ [ 963, 985 ] ], "normalized": [] }, { "id": "PMID-16907772_T15", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 1032, 1045 ] ], "normalized": [] }, { "id": "PMID-16907772_T17", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 1222, 1234 ] ], "normalized": [] }, { "id": "PMID-16907772_T18", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 1246, 1250 ] ], "normalized": [] }, { "id": "PMID-16907772_T19", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 1295, 1299 ] ], "normalized": [] }, { "id": "PMID-16907772_T20", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 1331, 1335 ] ], "normalized": [] }, { "id": "PMID-16907772_T21", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 1389, 1402 ] ], "normalized": [] }, { "id": "PMID-16907772_T22", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 1439, 1452 ] ], "normalized": [] }, { "id": "PMID-16907772_T23", "type": "Multi-tissue_structure", "text": [ "blood vessel" ], "offsets": [ [ 1486, 1498 ] ], "normalized": [] }, { "id": "PMID-16907772_T25", "type": "Tissue", "text": [ "soft connective tissue" ], "offsets": [ [ 1612, 1634 ] ], "normalized": [] }, { "id": "PMID-16907772_T27", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 1955, 1968 ] ], "normalized": [] }, { "id": "PMID-16907772_T28", "type": "Tissue", "text": [ "bone" ], "offsets": [ [ 1990, 1994 ] ], "normalized": [] }, { "id": "PMID-16907772_T29", "type": "Organ", "text": [ "mandible" ], "offsets": [ [ 2025, 2033 ] ], "normalized": [] }, { "id": "PMID-16907772_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 70, 75 ] ], "normalized": [] }, { "id": "PMID-16907772_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 277, 282 ] ], "normalized": [] }, { "id": "PMID-16907772_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 308, 316 ] ], "normalized": [] }, { "id": "PMID-16907772_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 510, 518 ] ], "normalized": [] }, { "id": "PMID-16907772_T1004", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1181, 1189 ] ], "normalized": [] }, { "id": "PMID-16907772_T1005", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1520, 1528 ] ], "normalized": [] }, { "id": "PMID-16907772_T1006", "type": "Organism", "text": [ "human" ], "offsets": [ [ 2019, 2024 ] ], "normalized": [] }, { "id": "PMID-16907772_T1007", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 2045, 2053 ] ], "normalized": [] }, { "id": "PMID-16907772_T38", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1693, 1698 ] ], "normalized": [] } ]

[ { "id": "PMID-16907772_E5", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 190, 196 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T6" } ] }, { "id": "PMID-16907772_E1", "type": "Development", "trigger": { "text": [ "Formation" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T1" } ] }, { "id": "PMID-16907772_E2", "type": "Planned_process", "trigger": { "text": [ "vertical distraction osteogenesis" ], "offsets": [ [ 29, 62 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T2" } ] }, { "id": "PMID-16907772_E3", "type": "Planned_process", "trigger": { "text": [ "vertical distraction osteogenesis" ], "offsets": [ [ 236, 269 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T7" } ] }, { "id": "PMID-16907772_E6", "type": "Development", "trigger": { "text": [ "formed" ], "offsets": [ [ 856, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T12" } ] }, { "id": "PMID-16907772_E7", "type": "Negative_regulation", "trigger": { "text": [ "delay" ], "offsets": [ [ 1142, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_E12" } ] }, { "id": "PMID-16907772_E8", "type": "Negative_regulation", "trigger": { "text": [ "disruption" ], "offsets": [ [ 1578, 1588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_E13" } ] }, { "id": "PMID-16907772_E9", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 1977, 1986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T28" } ] }, { "id": "PMID-16907772_E10", "type": "Planned_process", "trigger": { "text": [ "distraction" ], "offsets": [ [ 2000, 2011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T29" } ] }, { "id": "PMID-16907772_E11", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1678, 1689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16907772_T38" } ] }, { "id": "PMID-16907772_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1151, 1163 ] ] }, "arguments": [] }, { "id": "PMID-16907772_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1592, 1604 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16907772_T25" } ] }, { "id": "PMID-16907772_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1711, 1723 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-19695243__text", "type": "abstract", "text": [ "Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer.\n\nMetronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.\n" ], "offsets": [ [ 0, 1998 ] ] } ]

[ { "id": "PMID-19695243_T1", "type": "Drug_or_compound", "text": [ "5-fluorouracil" ], "offsets": [ [ 11, 25 ] ], "normalized": [] }, { "id": "PMID-19695243_T2", "type": "Drug_or_compound", "text": [ "oxaliplatin" ], "offsets": [ [ 27, 38 ] ], "normalized": [] }, { "id": "PMID-19695243_T3", "type": "Drug_or_compound", "text": [ "irinotecan" ], "offsets": [ [ 43, 53 ] ], "normalized": [] }, { "id": "PMID-19695243_T7", "type": "Drug_or_compound", "text": [ "irinotecan" ], "offsets": [ [ 499, 509 ] ], "normalized": [] }, { "id": "PMID-19695243_T8", "type": "Drug_or_compound", "text": [ "CPT-11" ], "offsets": [ [ 511, 517 ] ], "normalized": [] }, { "id": "PMID-19695243_T9", "type": "Drug_or_compound", "text": [ "oxaliplatin" ], "offsets": [ [ 520, 531 ] ], "normalized": [] }, { "id": "PMID-19695243_T10", "type": "Drug_or_compound", "text": [ "L-OHP" ], "offsets": [ [ 533, 538 ] ], "normalized": [] }, { "id": "PMID-19695243_T11", "type": "Drug_or_compound", "text": [ "5-fluorouracil" ], 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[ { "id": "PMID-15015551__text", "type": "abstract", "text": [ "Morphogenesis of embryonic CNS vessels.\n\nThis chapter focuses on the morphology of blood vessel formation in and around the early central nervous system (CNS, i.e., brain and spinal cord) of avian embryos. We discuss cell lineages, proliferation and interactions of endothelial cells, pericytes and smooth muscle cells, and macrophages. Due to space limitations, we can not review the molecular control of CNS angiogenesis, but refer the reader to other chapters in this book and to recent publications on the assembly of the vasculature (1,2).\n" ], "offsets": [ [ 0, 545 ] ] } ]

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[ { "id": "PMID-15015551_1", "entity_ids": [ "PMID-15015551_T6", "PMID-15015551_T7" ] } ]

[]

[ { "id": "PMID-18565374__text", "type": "abstract", "text": [ "Contemporary perspectives on vital pulp therapy: views from the endodontists and pediatric dentists.\n\nThe purpose of this study was to determine the level of agreement between pediatric dentists and endodontists at a pulp therapy symposium conjointly sponsored by the American Association of Endodontists (AAE) and the American Academy of Pediatric Dentistry (AAPD) on November 2-3, 2007. Presymposium and postsymposium tests were administered, and respondent answers were compared between pediatric dentists and endodontists. Opinions on 3 areas were sought: pulp therapy for cariously involved primary teeth; indirect pulp treatment (IPT) for cariously involved immature permanent teeth; and innovative treatment options including pulpal revascularization and regeneration. Results were analyzed with chi2 tests. Comparisons of presymposium and postsymposium responses and between the 2 groups of attendees indicated that the pediatric dentistry and endodontic communities agree that formocresol will be replaced as a primary tooth pulpotomy agent, that mineral trioxide is the first choice to take its place, that IPT in primary teeth holds hope as a replacement for pulpotomy, and that IPT is an acceptable pulp therapy technique for cariously involved young permanent teeth. Both groups believe that pulp revascularization and regeneration will be viable treatment modalities in the future. The AAE and the AAPD are positioned to begin preparation of best practice guidelines that share common language and treatment recommendations for pulp therapies performed by both specialties.\n" ], "offsets": [ [ 0, 1588 ] ] } ]

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[]

[]

[ { "id": "PMID-18469146__text", "type": "abstract", "text": [ "Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells.\n\nPhysiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1alpha protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.\n" ], "offsets": [ [ 0, 1973 ] ] } ]

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"Drug_or_compound", "text": [ "ethanol" ], "offsets": [ [ 458, 465 ] ], "normalized": [] }, { "id": "PMID-18469146_T16", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 469, 485 ] ], "normalized": [] }, { "id": "PMID-18469146_T17", "type": "Drug_or_compound", "text": [ "ethanol" ], "offsets": [ [ 536, 543 ] ], "normalized": [] }, { "id": "PMID-18469146_T21", "type": "Drug_or_compound", "text": [ "ethanol" ], "offsets": [ [ 661, 668 ] ], "normalized": [] }, { "id": "PMID-18469146_T23", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 725, 729 ] ], "normalized": [] }, { "id": "PMID-18469146_T24", "type": "Multi-tissue_structure", "text": [ "capillary network" ], "offsets": [ [ 738, 755 ] ], "normalized": [] }, { "id": "PMID-18469146_T25", "type": "Drug_or_compound", "text": [ "Ethanol" ], "offsets": [ [ 767, 774 ] ], "normalized": [] }, { "id": "PMID-18469146_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 804, 808 ] ], "normalized": [] }, { "id": "PMID-18469146_T29", "type": "Tissue", "text": [ "cord" ], "offsets": [ [ 817, 821 ] ], "normalized": [] }, { "id": "PMID-18469146_T32", "type": "Multi-tissue_structure", "text": [ "capillary network" ], "offsets": [ [ 856, 873 ] ], "normalized": [] }, { "id": "PMID-18469146_T33", "type": "Drug_or_compound", "text": [ "ethanol" ], "offsets": [ [ 919, 926 ] ], "normalized": [] }, { "id": "PMID-18469146_T37", "type": "Gene_or_gene_product", "text": [ "VEGF receptor-2" ], "offsets": [ [ 972, 987 ] ], "normalized": [] }, { "id": "PMID-18469146_T39", "type": "Gene_or_gene_product", "text": [ "VEGF receptor-2" ], "offsets": [ [ 1000, 1015 ] ], "normalized": [] }, { "id": "PMID-18469146_T42", "type": "Drug_or_compound", "text": [ "ethanol" ], "offsets": [ [ 1056, 1063 ] ], "normalized": [] }, { "id": "PMID-18469146_T43", "type": "Drug_or_compound", "text": [ "4-methylpyrazole" ], "offsets": [ [ 1078, 1094 ] ], "normalized": [] }, { "id": "PMID-18469146_T44", 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577 ] ], "normalized": [] }, { "id": "PMID-18469146_T102", "type": "Pathological_formation", "text": [ "wounds" ], "offsets": [ [ 1562, 1568 ] ], "normalized": [] } ]

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}, "arguments": [ { "role": "Cause", "ref_id": "PMID-18469146_E42" }, { "role": "Theme", "ref_id": "PMID-18469146_E53" } ] }, { "id": "PMID-18469146_E44", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1892, 1900 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18469146_E46" }, { "role": "Theme", "ref_id": "PMID-18469146_E43" } ] }, { "id": "PMID-18469146_E46", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1904, 1911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18469146_E47" } ] }, { "id": "PMID-18469146_E47", "type": "Regulation", "trigger": { "text": [ "responsiveness" ], "offsets": [ [ 1932, 1946 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18469146_T69" }, { "role": "Cause", "ref_id": "PMID-18469146_T70" } ] }, { "id": "PMID-18469146_E48", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 98, 110 ] ] }, "arguments": [] }, { "id": "PMID-18469146_E49", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 365, 377 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18469146_T100" } ] }, { "id": "PMID-18469146_E50", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 555, 567 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18469146_T101" } ] }, { "id": "PMID-18469146_E51", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 614, 626 ] ] }, "arguments": [] }, { "id": "PMID-18469146_E52", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1524, 1536 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18469146_T102" } ] }, { "id": "PMID-18469146_E53", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1847, 1859 ] ] }, "arguments": [] }, { "id": "PMID-18469146_E55", "type": "Pathway", "trigger": { "text": [ "cell signaling" ], "offsets": [ [ 46, 60 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18469146_T4" } ] }, { "id": "PMID-18469146_E56", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 486, 495 ] ] }, "arguments": [] } ]

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[ { "id": "PMID-8874381__text", "type": "abstract", "text": [ "Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo.\n\nVascular endothelial growth factor (VEGF) is a naturally secreted endothelial cell-specific mitogen. We investigated the hypothesis that naked DNA encoding for VEGF could be used in a strategy of arterial gene therapy to stimulate collateral artery development. Plasmid DNA encoding each of the three principal human VEGF isoforms (phVEGF121, phVEGF165, or phVEGF189) was applied to the hydrogel polymer coating of an angioplasty balloon and delivered percutaneously to one iliac artery of rabbits with operatively induced hindlimb ischemia. Compared with control animals transfected with LacZ, site-specific transfection of phVEGF resulted in augmented collateral vessel development documented by serial angiography, and improvement in calf blood pressure ratio (ischemic to normal limb), resting and maximum blood flow, and capillary to myocyte ratio. Similar results were obtained with phVEGF121, phVEGF165, and phVEGF189, which suggests that these isoforms are biologically equivalent with respect to in vivo angiogenesis. The fact that viral or other adjunctive vectors were not required further suggests that secreted gene products may have potential therapeutic utility even when the number of successfully transfected cells remains low. Arterial gene transfer of naked DNA encoding for a secreted angiogenic cytokine, thus, represents a potential alternative to recombinant protein administration for stimulating collateral vessel development.\n" ], "offsets": [ [ 0, 1589 ] ] } ]

[ { "id": "PMID-8874381_T1", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 58, 92 ] ], "normalized": [] }, { "id": "PMID-8874381_T2", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 137, 171 ] ], "normalized": [] }, { "id": "PMID-8874381_T3", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 173, 177 ] ], "normalized": [] }, { "id": "PMID-8874381_T4", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 203, 219 ] ], "normalized": [] }, { "id": "PMID-8874381_T5", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 297, 301 ] ], "normalized": [] }, { "id": "PMID-8874381_T10", "type": "Multi-tissue_structure", "text": [ "collateral artery" ], "offsets": [ [ 368, 385 ] ], "normalized": [] }, { "id": "PMID-8874381_T11", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "PMID-8874381_T12", "type": "Gene_or_gene_product", "text": [ "phVEGF121" ], "offsets": [ [ 469, 478 ] ], "normalized": [] }, { "id": "PMID-8874381_T13", "type": "Gene_or_gene_product", "text": [ "phVEGF165" ], "offsets": [ [ 480, 489 ] ], "normalized": [] }, { "id": "PMID-8874381_T14", "type": "Gene_or_gene_product", "text": [ "phVEGF189" ], "offsets": [ [ 494, 503 ] ], "normalized": [] }, { "id": "PMID-8874381_T15", "type": "Multi-tissue_structure", "text": [ "iliac artery" ], "offsets": [ [ 611, 623 ] ], "normalized": [] }, { "id": "PMID-8874381_T16", "type": "Organism_subdivision", "text": [ "hindlimb" ], "offsets": [ [ 660, 668 ] ], "normalized": [] }, { "id": "PMID-8874381_T17", "type": "Gene_or_gene_product", "text": [ "LacZ" ], "offsets": [ [ 726, 730 ] ], "normalized": [] }, { "id": "PMID-8874381_T18", "type": "Gene_or_gene_product", "text": [ "phVEGF" ], "offsets": [ [ 762, 768 ] ], "normalized": [] }, { "id": "PMID-8874381_T22", "type": "Multi-tissue_structure", "text": [ "collateral vessel" ], "offsets": [ [ 791, 808 ] ], "normalized": [] }, { "id": "PMID-8874381_T23", "type": "Organism_subdivision", "text": [ "normal limb" ], "offsets": [ [ 913, 924 ] ], "normalized": [] }, { "id": "PMID-8874381_T24", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 963, 972 ] ], "normalized": [] }, { "id": "PMID-8874381_T25", "type": "Cell", "text": [ "myocyte" ], "offsets": [ [ 976, 983 ] ], "normalized": [] }, { "id": "PMID-8874381_T26", "type": "Gene_or_gene_product", "text": [ "phVEGF121" ], "offsets": [ [ 1026, 1035 ] ], "normalized": [] }, { "id": "PMID-8874381_T27", "type": "Gene_or_gene_product", "text": [ "phVEGF165" ], "offsets": [ [ 1037, 1046 ] ], "normalized": [] }, { "id": "PMID-8874381_T28", "type": "Gene_or_gene_product", "text": [ "phVEGF189" ], "offsets": [ [ 1052, 1061 ] ], "normalized": [] }, { "id": "PMID-8874381_T35", "type": "Multi-tissue_structure", "text": [ "collateral vessel" ], "offsets": [ [ 1558, 1575 ] ], "normalized": [] }, { "id": "PMID-8874381_T6", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 947, 952 ] ], "normalized": [] }, { "id": "PMID-8874381_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 448, 453 ] ], "normalized": [] }, { "id": "PMID-8874381_T1001", "type": "Organism", "text": [ "rabbits" ], "offsets": [ [ 627, 634 ] ], "normalized": [] }, { "id": "PMID-8874381_T1002", "type": "Organism", "text": [ "calf" ], "offsets": [ [ 874, 878 ] ], "normalized": [] }, { "id": "PMID-8874381_T7", "type": "Multi-tissue_structure", "text": [ "collateral" ], "offsets": [ [ 104, 114 ] ], "normalized": [] }, { "id": "PMID-8874381_T42", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 879, 884 ] ], "normalized": [] }, { "id": "PMID-8874381_T44", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1363, 1368 ] ], "normalized": [] }, { "id": "PMID-8874381_T8", "type": "Organism_subdivision", "text": [ "ischemic" ], "offsets": [ [ 901, 909 ] ], "normalized": [] } ]

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[ { "id": "PMID-8874381_1", "entity_ids": [ "PMID-8874381_T2", "PMID-8874381_T3" ] } ]

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[ { "id": "PMID-12727857__text", "type": "abstract", "text": [ "Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression.\n\nThe expression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions is suppressed in malignancies. In the present study, we investigated in vivo the regulation of leukocyte-vessel wall interactions by the presence of a tumor. By means of intravital microscopy, tumor necrosis factor alpha-stimulated leukocyte-vessel wall interactions were studied in ear skin microvessels of nude mice bearing small human LS174T colon carcinomas and in C57Bl/6 mice bearing murine B16F10 melanomas. Leukocyte-vessel wall interactions were studied both within and outside small tumors growing in the ear, and in ear microvessels of mice with a large tumor growing on their flank. Tumor-free mice were used as controls. Compared with values measured at the edge of the ear and in the contralateral ear, leukocyte adhesion was found to be diminished significantly in vessels inside the ear tumor in both mouse models. This reduction disappeared with increasing distance from the tumor. Surprisingly, the level of leukocyte adhesion in ear venules of mice with a large flank tumor was also reduced significantly. Leukocyte rolling, i.e., the step preceding adhesion, was not influenced by the presence of a tumor in nude mice, but was down-regulated in immune-competent C57Bl/6 mice. Treatment of mice bearing a small ear tumor with a humanized antivascular endothelial growth factor antibody prevented the down-regulation of leukocyte-vessel wall interactions inside the tumor vessels compared with the nontreated group. Fluorescence-activated cell sorter analysis showed that isolated tumor ECs have suppressed levels of intercellular adhesion molecule 1 as compared with ECs from normal mouse tissues. In cultured b.END5 cells the tumor necrosis factor alpha-induced up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was reduced in ECs that were preincubated with basic fibroblast growth factor or vascular endothelial growth factor. The current results may have an impact on the effectiveness of clinical immunotherapeutic treatment protocols, because immune effector cells may not be able to enter tumor tissue.\n" ], "offsets": [ [ 0, 2301 ] ] } ]

[ { "id": "PMID-12727857_T1", "type": "Pathological_formation", "text": [ "Tumor" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-12727857_T5", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 29, 38 ] ], "normalized": [] }, { "id": "PMID-12727857_T6", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 39, 50 ] ], "normalized": [] }, { "id": "PMID-12727857_T15", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 198, 207 ] ], "normalized": [] }, { "id": "PMID-12727857_T16", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 208, 219 ] ], "normalized": [] }, { "id": "PMID-12727857_T19", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 328, 337 ] ], "normalized": [] }, { "id": "PMID-12727857_T20", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 338, 349 ] ], "normalized": [] }, { "id": "PMID-12727857_T21", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 384, 389 ] ], "normalized": [] }, { "id": "PMID-12727857_T23", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 426, 453 ] ], "normalized": [] }, { "id": "PMID-12727857_T25", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 465, 474 ] ], "normalized": [] }, { "id": "PMID-12727857_T26", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 475, 486 ] ], "normalized": [] }, { "id": "PMID-12727857_T27", "type": "Tissue", "text": [ "ear skin microvessels" ], "offsets": [ [ 516, 537 ] ], "normalized": [] }, { "id": "PMID-12727857_T32", "type": "Pathological_formation", "text": [ "LS174T colon carcinomas" ], "offsets": [ [ 571, 594 ] ], "normalized": [] }, { "id": "PMID-12727857_T35", "type": "Cell", "text": [ "Leukocyte" ], "offsets": [ [ 648, 657 ] ], "normalized": [] }, { "id": "PMID-12727857_T36", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 658, 669 ] ], "normalized": [] }, { "id": "PMID-12727857_T37", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 726, 732 ] ], "normalized": [] }, { "id": "PMID-12727857_T38", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 748, 751 ] ], "normalized": [] }, { "id": "PMID-12727857_T39", "type": "Tissue", "text": [ "ear microvessels" ], "offsets": [ [ 760, 776 ] ], "normalized": [] }, { "id": "PMID-12727857_T42", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 798, 803 ] ], "normalized": [] }, { "id": "PMID-12727857_T43", "type": "Organism_subdivision", "text": [ "flank" ], "offsets": [ [ 821, 826 ] ], "normalized": [] }, { "id": "PMID-12727857_T44", "type": "Pathological_formation", "text": [ "Tumor" ], "offsets": [ [ 828, 833 ] ], "normalized": [] }, { "id": "PMID-12727857_T45", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 916, 919 ] ], "normalized": [] }, { "id": "PMID-12727857_T46", "type": "Organ", "text": [ "ear" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "PMID-12727857_T47", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 950, 959 ] ], "normalized": [] }, { "id": "PMID-12727857_T48", "type": "Tissue", "text": [ "vessels" ], "offsets": [ [ 1013, 1020 ] ], "normalized": [] }, { "id": "PMID-12727857_T50", "type": "Pathological_formation", "text": [ "ear tumor" ], "offsets": [ [ 1032, 1041 ] ], "normalized": [] }, { "id": "PMID-12727857_T51", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1125, 1130 ] ], "normalized": [] }, { "id": "PMID-12727857_T53", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 1159, 1168 ] ], "normalized": [] }, { "id": "PMID-12727857_T54", "type": "Multi-tissue_structure", "text": [ "ear venules" ], "offsets": [ [ 1181, 1192 ] ], "normalized": [] }, { "id": "PMID-12727857_T58", "type": "Pathological_formation", "text": [ "flank tumor" ], "offsets": [ [ 1214, 1225 ] ], "normalized": [] }, { "id": "PMID-12727857_T59", "type": "Cell", "text": [ "Leukocyte" ], "offsets": [ [ 1258, 1267 ] ], "normalized": [] }, { "id": "PMID-12727857_T60", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1352, 1357 ] ], "normalized": [] }, { "id": "PMID-12727857_T62", "type": "Pathological_formation", "text": [ "ear tumor" ], "offsets": [ [ 1463, 1472 ] ], "normalized": [] }, { "id": "PMID-12727857_T65", "type": "Cell", "text": [ "leukocyte" ], "offsets": [ [ 1571, 1580 ] ], "normalized": [] }, { "id": "PMID-12727857_T66", "type": "Multi-tissue_structure", "text": [ "vessel wall" ], "offsets": [ [ 1581, 1592 ] ], "normalized": [] }, { "id": "PMID-12727857_T68", "type": "Multi-tissue_structure", "text": [ "tumor vessels" ], "offsets": [ [ 1617, 1630 ] ], "normalized": [] }, { "id": "PMID-12727857_T70", "type": "Cell", "text": [ "tumor ECs" ], "offsets": [ [ 1732, 1741 ] ], "normalized": [] }, { "id": "PMID-12727857_T71", "type": "Gene_or_gene_product", "text": [ "intercellular adhesion molecule 1" ], "offsets": [ [ 1768, 1801 ] ], "normalized": [] }, { "id": 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[]

[]

[ { "id": "PMID-10978248__text", "type": "abstract", "text": [ "Vasodilator-stimulated phosphoprotein is involved in stress-fiber and membrane ruffle formation in endothelial cells.\n\nVasodilator-stimulated phosphoprotein (VASP) is highly expressed in vascular endothelial cells, where it has been implicated in cellular reorganization during angiogenesis, as well as in endothelial retraction and changes in vessel permeability. However, the cellular functions of VASP are not known. In this study, we have expressed wild-type and mutant forms of VASP in endothelial cells to determine in what aspects of cytoskeletal behavior this protein participates. Expression of wild-type VASP induces marked membrane ruffling and formation of prominent stress fibers in bovine aortic endothelial cells. Deletion of the proline-rich domain of VASP abolishes its ability to bind profilin but does not affect ruffling or stress fiber formation. Further deletions reveal a sequence within the carboxy-terminal domain that is responsible for in vivo bundle formation. Ruffling occurs only on the expression of forms of VASP that possess bundling activity and the capacity to bind zyxin/vinculin-derived peptide. The ability of distinct subdomains within VASP to bind adhesion proteins and induce F-actin bundling in vivo suggests that this protein could function in the aggregation and tethering of actin filaments during the formation of endothelial cell-substrate and cell-cell contacts. These data provide a mechanism whereby VASP can influence endothelial migration and organization during capillary formation and modulate vascular permeability via effects on endothelial cell contractility.\n" ], "offsets": [ [ 0, 1617 ] ] } ]

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[ { "id": "PMID-15623651__text", "type": "abstract", "text": [ "2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha, tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma.\n\nPURPOSE: Head and neck squamous cell carcinomas have been reported to overexpress hypoxia-inducible factor (HIF)-1alpha, a transcription factor that promotes expression of angiogenesis factors and resistance to programmed and therapy-induced cell death. 2-Methoxyestradiol (2ME2) is a natural compound with HIF-1alpha inhibitory activity that is currently being evaluated in phase 1 and 2 clinical trials for advanced solid tumors and multiple myeloma. To our knowledge, this is the first study to evaluate the effects of 2ME2 in head and neck squamous cell carcinoma. EXPERIMENTAL DESIGN: In the present study, we investigated the effects of 2ME2 alone and in combination with paclitaxel, an active agent in recurrent or advanced head and neck squamous cell carcinoma. RESULTS: 2ME2 exhibited antiproliferative and cytotoxic effects in a panel of five head and neck squamous cell carcinoma cell lines in the 0.5 to 10 micromol/L range, including induction of G2-M blockade, caspase-3/7 activation, and apoptosis at 48 hours. 2ME2 resulted in decreased nuclear HIF-1alpha-binding activity and affected the expression of downstream genes, such as bid, a proapoptotic bcl-2 family member, and vascular endothelial growth factor, a proangiogenic cytokine. The up-regulation of Bid (57.5% at 12 hours, P less than 0.0006) and inhibition of vascular endothelial growth factor secretion (57.7% at 24 hours, P less than 0.015; and 50.3% at 48 hours, P less than 0.0006) could be partially attributed to the effects on HIF-1alpha, because HIF-1alpha small interfering RNAs produced similar effects. Finally, in vivo, in a xenograft model of head and neck squamous cell carcinoma using UM-SCC-11A cells, 2ME2 exhibited antitumor and antiangiogenic activity, as measured by CD31 immunostaining. CONCLUSIONS: These results provide support for the use of 2ME2 in combination with paclitaxel for the treatment of recurrent or advanced head and neck squamous cell carcinoma.\n" ], "offsets": [ [ 0, 2135 ] ] } ]

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"offsets": [ [ 250, 287 ] ], "normalized": [] }, { "id": "PMID-15623651_T20", "type": "Drug_or_compound", "text": [ "2-Methoxyestradiol" ], "offsets": [ [ 422, 440 ] ], "normalized": [] }, { "id": "PMID-15623651_T21", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 442, 446 ] ], "normalized": [] }, { "id": "PMID-15623651_T22", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 475, 485 ] ], "normalized": [] }, { "id": "PMID-15623651_T23", "type": "Pathological_formation", "text": [ "solid tumors" ], "offsets": [ [ 586, 598 ] ], "normalized": [] }, { "id": "PMID-15623651_T24", "type": "Pathological_formation", "text": [ "myeloma" ], "offsets": [ [ 612, 619 ] ], "normalized": [] }, { "id": "PMID-15623651_T25", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 690, 694 ] ], "normalized": [] }, { "id": "PMID-15623651_T28", "type": "Pathological_formation", "text": [ "head and neck squamous cell carcinoma" ], "offsets": [ [ 698, 735 ] ], "normalized": [] }, { "id": "PMID-15623651_T29", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 811, 815 ] ], "normalized": [] }, { "id": "PMID-15623651_T30", "type": "Drug_or_compound", "text": [ "paclitaxel" ], "offsets": [ [ 846, 856 ] ], "normalized": [] }, { "id": "PMID-15623651_T33", "type": "Pathological_formation", "text": [ "head and neck squamous cell carcinoma" ], "offsets": [ [ 899, 936 ] ], "normalized": [] }, { "id": "PMID-15623651_T34", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 947, 951 ] ], "normalized": [] }, { "id": "PMID-15623651_T35", "type": "Cell", "text": [ "head and neck squamous cell carcinoma cell lines" ], "offsets": [ [ 1021, 1069 ] ], "normalized": [] }, { "id": "PMID-15623651_T40", "type": "Gene_or_gene_product", "text": [ "7" ], "offsets": [ [ 1153, 1154 ] ], "normalized": [] }, { "id": "PMID-15623651_T41", "type": "Gene_or_gene_product", "text": [ "caspase-3" ], "offsets": [ [ 1143, 1152 ] ], "normalized": [] }, { "id": "PMID-15623651_T42", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 1194, 1198 ] ], "normalized": [] }, { "id": "PMID-15623651_T45", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 1229, 1239 ] ], "normalized": [] }, { "id": "PMID-15623651_T48", "type": "Gene_or_gene_product", "text": [ "bid" ], "offsets": [ [ 1314, 1317 ] ], "normalized": [] }, { "id": "PMID-15623651_T49", "type": "Gene_or_gene_product", "text": [ "bcl-2 family" ], "offsets": [ [ 1334, 1346 ] ], "normalized": [] }, { "id": "PMID-15623651_T50", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1359, 1393 ] ], "normalized": [] }, { "id": "PMID-15623651_T54", "type": "Gene_or_gene_product", "text": [ "Bid" ], "offsets": [ [ 1442, 1445 ] ], "normalized": [] }, { "id": "PMID-15623651_T57", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1506, 1540 ] ], "normalized": [] }, { "id": "PMID-15623651_T58", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 1685, 1695 ] ], "normalized": [] }, { "id": "PMID-15623651_T59", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 1705, 1715 ] ], "normalized": [] }, { "id": "PMID-15623651_T62", "type": "Pathological_formation", "text": [ "head and neck squamous cell carcinoma" ], "offsets": [ [ 1807, 1844 ] ], "normalized": [] }, { "id": "PMID-15623651_T63", "type": "Cell", "text": [ "UM-SCC-11A cells" ], "offsets": [ [ 1851, 1867 ] ], "normalized": [] }, { "id": "PMID-15623651_T64", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 1869, 1873 ] ], "normalized": [] }, { "id": "PMID-15623651_T66", "type": "Drug_or_compound", "text": [ "2ME2" ], "offsets": [ [ 2017, 2021 ] ], "normalized": [] }, { "id": "PMID-15623651_T67", "type": "Drug_or_compound", "text": [ "paclitaxel" ], "offsets": [ [ 2042, 2052 ] ], "normalized": [] }, { "id": "PMID-15623651_T70", "type": "Pathological_formation", "text": [ "head and neck squamous cell carcinoma" ], "offsets": [ [ 2096, 2133 ] ], "normalized": [] }, { "id": "PMID-15623651_T3", "type": "Gene_or_gene_product", "text": [ "CD31" ], "offsets": [ [ 1938, 1942 ] ], "normalized": [] }, { "id": "PMID-15623651_T36", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 410, 414 ] ], "normalized": [] }, { "id": "PMID-15623651_T53", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1888, 1893 ] ], "normalized": [] } ]

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[ { "id": "PMID-19292679__text", "type": "abstract", "text": [ "The effect of perfluorocarbon-based artificial oxygen carriers on tissue-engineered trachea.\n\nThe biological effect of the perfluorocarbon-based artificial oxygen carrier (Oxygent) was investigated in tissue-engineered trachea (TET) construction. Media supplemented with and without 10% Oxygent were compared in all assessments. Partial tissue oxygen tension (PtO(2)) was measured with polarographic microprobes; epithelial metabolism was monitored by microdialysis inside the TET epithelium perfused with the medium underneath. Chondrocyte-DegraPol constructs were cultured for 1 month with the medium before glycosaminoglycan assessment and histology. Tissue reaction of TET epithelial scaffolds immersed with the medium was evaluated on the chick embryo chorioallantoic membrane. Oxygent perfusion medium increased the TET epithelial PtO(2) (51.2 +/- 0.3 mm Hg vs. 33.4 +/- 0.3 mm Hg at 200 microm thickness; 12.5 +/- 0.1 mm Hg vs. 3.1 +/- 0.1 mm Hg at 400 microm thickness, p less than 0.01) and decreased the lactate concentration (0.63 +/- 0.08 vs. 0.80 +/- 0.06 mmol/L, p less than 0.05), lactate/pyruvate (1.87 +/- 0.26 vs. 3.36 +/- 10.13, p less than 0.05), and lactate/glucose ratios (0.10 +/- 0.00 vs. 0.29 +/- 0.14, p less than 0.05). Chondrocyte-DegraPol in Oxygent group presented lower glycosaminoglycan value (0.03 +/- 0.00 vs. 0.13 +/- 0.00, p less than 0.05); histology slides showed poor acid mucopolysaccharides formation. Orthogonal polarization spectral imaging showed no difference in functional capillary density between the scaffolds cultured on chorioallantoic membranes. The foreign body reaction was similar in both groups. We conclude that Oxygent increases TET epithelial PtO(2), improves epithelial metabolism, does not impair angiogenesis, and tends to slow cartilage tissue formation.\n" ], "offsets": [ [ 0, 1828 ] ] } ]

[ { "id": "PMID-19292679_T2", "type": "Drug_or_compound", "text": [ "perfluorocarbon" ], "offsets": [ [ 14, 29 ] ], "normalized": [] }, { "id": "PMID-19292679_T3", "type": "Drug_or_compound", "text": [ "oxygen" ], "offsets": [ [ 47, 53 ] ], "normalized": [] }, { "id": "PMID-19292679_T4", "type": "Multi-tissue_structure", "text": [ "tissue-engineered trachea" ], "offsets": [ [ 66, 91 ] ], "normalized": [] }, { "id": "PMID-19292679_T6", "type": "Drug_or_compound", "text": [ "perfluorocarbon" ], "offsets": [ [ 123, 138 ] ], "normalized": [] }, { "id": "PMID-19292679_T7", "type": "Drug_or_compound", "text": [ "oxygen" ], "offsets": [ [ 156, 162 ] ], "normalized": [] }, { "id": "PMID-19292679_T8", "type": "Drug_or_compound", "text": [ "Oxygent" ], "offsets": [ [ 172, 179 ] ], "normalized": [] }, { "id": "PMID-19292679_T9", "type": "Multi-tissue_structure", "text": [ "tissue-engineered trachea" ], "offsets": [ [ 201, 226 ] ], "normalized": [] }, { "id": "PMID-19292679_T10", "type": "Multi-tissue_structure", "text": [ "TET" ], "offsets": [ [ 228, 231 ] ], "normalized": [] }, { "id": "PMID-19292679_T11", "type": "Drug_or_compound", "text": [ "Oxygent" ], "offsets": [ [ 287, 294 ] ], "normalized": [] }, { "id": "PMID-19292679_T12", "type": "Drug_or_compound", "text": [ "oxygen" ], "offsets": [ [ 344, 350 ] ], "normalized": [] }, { "id": "PMID-19292679_T14", "type": "Tissue", "text": [ "TET epithelium" ], "offsets": [ [ 477, 491 ] ], "normalized": [] }, { "id": "PMID-19292679_T17", "type": "Drug_or_compound", "text": [ "glycosaminoglycan" ], "offsets": [ [ 610, 627 ] ], "normalized": [] }, { "id": "PMID-19292679_T18", "type": "Tissue", "text": [ "TET epithelial scaffolds" ], "offsets": [ [ 673, 697 ] ], "normalized": [] }, { "id": "PMID-19292679_T19", "type": "Multi-tissue_structure", "text": [ "embryo chorioallantoic membrane" ], "offsets": [ [ 750, 781 ] ], "normalized": [] }, { "id": "PMID-19292679_T21", "type": "Drug_or_compound", "text": [ "Oxygent" ], "offsets": [ [ 783, 790 ] ], "normalized": [] }, { "id": "PMID-19292679_T22", "type": "Tissue", "text": [ "TET epithelial" ], "offsets": [ [ 822, 836 ] ], "normalized": [] }, { "id": "PMID-19292679_T23", "type": "Drug_or_compound", "text": [ "lactate" ], "offsets": [ [ 1016, 1023 ] ], "normalized": [] }, { "id": "PMID-19292679_T24", "type": "Drug_or_compound", "text": [ "lactate" ], "offsets": [ [ 1100, 1107 ] ], "normalized": [] }, { "id": "PMID-19292679_T25", "type": "Drug_or_compound", "text": [ "pyruvate" ], "offsets": [ [ 1108, 1116 ] ], "normalized": [] }, { "id": "PMID-19292679_T26", "type": "Drug_or_compound", "text": [ "lactate" ], "offsets": [ [ 1177, 1184 ] ], "normalized": [] }, { "id": "PMID-19292679_T27", "type": "Drug_or_compound", "text": [ "glucose" ], "offsets": [ [ 1185, 1192 ] ], "normalized": [] }, { "id": "PMID-19292679_T29", "type": "Drug_or_compound", "text": [ "Oxygent" ], "offsets": [ [ 1279, 1286 ] ], "normalized": [] }, { "id": "PMID-19292679_T30", "type": "Drug_or_compound", "text": [ "glycosaminoglycan" ], "offsets": [ [ 1309, 1326 ] ], "normalized": [] }, { "id": "PMID-19292679_T31", "type": "Drug_or_compound", "text": [ "mucopolysaccharides" ], "offsets": [ [ 1422, 1441 ] ], "normalized": [] }, { "id": "PMID-19292679_T32", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membranes" ], "offsets": [ [ 1581, 1606 ] ], "normalized": [] }, { "id": "PMID-19292679_T33", "type": "Drug_or_compound", "text": [ "Oxygent" ], "offsets": [ [ 1679, 1686 ] ], "normalized": [] }, { "id": "PMID-19292679_T34", "type": "Tissue", "text": [ "TET epithelial" ], "offsets": [ [ 1697, 1711 ] ], "normalized": [] }, { "id": "PMID-19292679_T40", "type": "Tissue", "text": [ "cartilage tissue" ], "offsets": [ [ 1800, 1816 ] ], "normalized": [] }, { "id": "PMID-19292679_T36", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 1529, 1538 ] ], "normalized": [] }, { "id": "PMID-19292679_T1000", "type": "Organism", "text": [ "chick" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "PMID-19292679_T44", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 337, 343 ] ], "normalized": [] }, { "id": "PMID-19292679_T45", "type": "Tissue", "text": [ "Tissue" ], "offsets": [ [ 654, 660 ] ], "normalized": [] }, { "id": "PMID-19292679_T1", "type": "Cell", "text": [ "Chondrocyte" ], "offsets": [ [ 529, 540 ] ], "normalized": [] }, { "id": "PMID-19292679_T5", "type": "Cell", "text": [ "Chondrocyte" ], "offsets": [ [ 1255, 1266 ] ], "normalized": [] } ]

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[ { "id": "PMID-19292679_1", "entity_ids": [ "PMID-19292679_T9", "PMID-19292679_T10" ] } ]

[]

[ { "id": "PMID-11425277__text", "type": "abstract", "text": [ "Current prospects for controlling cancer growth with non-cytotoxic agents--nutrients, phytochemicals, herbal extracts, and available drugs.\n\nIn animal or cell culture studies, the growth and spread of cancer can be slowed by many nutrients, food factors, herbal extracts, and well-tolerated, available drugs that are still rarely used in the clinical management of cancer, in part because they seem unlikely to constitute definitive therapies in themselves. However, it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and, when used as adjuvants, could improve the cure rates achievable with standard therapies. The therapeutic options available in this regard include measures that: down-regulate serum free IGF-I; suppress the synthesis of mevalonic acid and/or certain derivatives thereof; modulate arachidonate metabolism by inhibiting 5-lipoxygenase, 12-lipoxygenase, or COX-2; antagonize the activation of AP-1 transcription factors; promote the activation of PPAR-gamma transcription factors; and that suppress angiogenesis by additional mechanisms. Many of these measures appear suitable for use in cancer prevention.\n" ], "offsets": [ [ 0, 1217 ] ] } ]

[ { "id": "PMID-11425277_T3", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 34, 40 ] ], "normalized": [] }, { "id": "PMID-11425277_T6", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 201, 207 ] ], "normalized": [] }, { "id": "PMID-11425277_T7", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 365, 371 ] ], "normalized": [] }, { "id": "PMID-11425277_T9", "type": "Gene_or_gene_product", "text": [ "IGF-I" ], "offsets": [ [ 800, 805 ] ], "normalized": [] }, { "id": "PMID-11425277_T11", "type": "Drug_or_compound", "text": [ "mevalonic acid" ], "offsets": [ [ 833, 847 ] ], "normalized": [] }, { "id": "PMID-11425277_T17", "type": "Gene_or_gene_product", "text": [ "5-lipoxygenase" ], "offsets": [ [ 931, 945 ] ], "normalized": [] }, { "id": "PMID-11425277_T18", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 947, 962 ] ], "normalized": [] }, { "id": "PMID-11425277_T19", "type": "Gene_or_gene_product", "text": [ "COX-2" ], "offsets": [ [ 967, 972 ] ], "normalized": [] }, { "id": "PMID-11425277_T24", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 1003, 1007 ] ], "normalized": [] }, { "id": "PMID-11425277_T27", "type": "Gene_or_gene_product", "text": [ "PPAR-gamma" ], "offsets": [ [ 1057, 1067 ] ], "normalized": [] }, { "id": "PMID-11425277_T31", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 1198, 1204 ] ], "normalized": [] }, { "id": "PMID-11425277_T26", "type": "Drug_or_compound", "text": [ "arachidonate" ], "offsets": [ [ 893, 905 ] ], "normalized": [] }, { "id": "PMID-11425277_T32", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 154, 158 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-707591__text", "type": "abstract", "text": [ "Subretinal neovascularization following rubella retinopathy.\n\nA 17-year-old girl and an 11-year-old girl with rubella retinopathy had decreased vision in one eye secondary to subretinal neovascularization and hemorrhage. In both cases a disciform scar with permanent decrease in central vision resulted.\n" ], "offsets": [ [ 0, 304 ] ] } ]

[ { "id": "PMID-707591_T2", "type": "Organ", "text": [ "eye" ], "offsets": [ [ 158, 161 ] ], "normalized": [] }, { "id": "PMID-707591_T1000", "type": "Organism", "text": [ "girl" ], "offsets": [ [ 76, 80 ] ], "normalized": [] }, { "id": "PMID-707591_T1001", "type": "Organism", "text": [ "girl" ], "offsets": [ [ 100, 104 ] ], "normalized": [] }, { "id": "PMID-707591_T4", "type": "Pathological_formation", "text": [ "scar" ], "offsets": [ [ 247, 251 ] ], "normalized": [] } ]

[ { "id": "PMID-707591_E1", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 11, 29 ] ] }, "arguments": [] }, { "id": "PMID-707591_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 186, 204 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-10816661__text", "type": "abstract", "text": [ "Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts.\n\nAlpha-melanocyte-stimulating hormone (alpha-MSH) has evolved as a mediator of diverse biological activities in an ever-growing number of non-melanocytic cell types. One mechanism by which alpha-MSH exerts its effects is modulation of AP-1 and NF-kappa B. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that alpha-MSH (10(-6) to 10(-14) M) activates AP-1 in human dermal fibroblasts, whereas coincubation with interleukin-1 beta (IL-1 beta) results in suppression of its activation. alpha-MSH also induces activation of NF-kappa B but does not modulate DNA binding on costimulation with IL-1 beta. Since AP-1 and NF-kappa B are key elements in controlling interleukin-8 (IL-8) transcription, human fibroblasts were treated with alpha-MSH and IL-1 beta for 24 hours, and cytokine levels in the supernatants were measured by ELISA. alpha-MSH alone had little effect, whereas coincubation with IL-1 beta led to marked downregulation of IL-8 secretion (at most 288 +/- 152 ng/mL) when compared to treatment with IL-1 beta alone (919 +/- 157 ng/mL). Our results indicate that alpha-MSH exerts modulatory effects on the activation of NF-kappa B and AP-1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of alpha-MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.\n" ], "offsets": [ [ 0, 1651 ] ] } ]

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"PMID-10816661_T11", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 330, 339 ] ], "normalized": [] }, { "id": "PMID-10816661_T14", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 376, 380 ] ], "normalized": [] }, { "id": "PMID-10816661_T15", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 385, 395 ] ], "normalized": [] }, { "id": "PMID-10816661_T16", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 460, 471 ] ], "normalized": [] }, { "id": "PMID-10816661_T18", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 476, 496 ] ], "normalized": [] }, { "id": "PMID-10816661_T22", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 600, 609 ] ], "normalized": [] }, { "id": "PMID-10816661_T23", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 642, 646 ] ], "normalized": [] }, { "id": "PMID-10816661_T24", "type": "Cell", "text": [ "dermal fibroblasts" ], "offsets": [ [ 656, 674 ] ], "normalized": [] }, { "id": "PMID-10816661_T25", "type": "Gene_or_gene_product", "text": [ "interleukin-1 beta" ], "offsets": [ [ 702, 720 ] ], "normalized": [] }, { "id": "PMID-10816661_T26", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 722, 731 ] ], "normalized": [] }, { "id": "PMID-10816661_T28", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 775, 784 ] ], "normalized": [] }, { "id": "PMID-10816661_T30", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 812, 822 ] ], "normalized": [] }, { "id": "PMID-10816661_T31", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 879, 888 ] ], "normalized": [] }, { "id": "PMID-10816661_T32", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 896, 900 ] ], "normalized": [] }, { "id": "PMID-10816661_T33", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 905, 915 ] ], "normalized": [] }, { "id": "PMID-10816661_T35", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 948, 961 ] ], "normalized": [] }, { "id": "PMID-10816661_T36", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 963, 967 ] ], "normalized": [] }, { "id": "PMID-10816661_T37", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 990, 1001 ] ], "normalized": [] }, { "id": "PMID-10816661_T38", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1020, 1029 ] ], "normalized": [] }, { "id": "PMID-10816661_T39", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1034, 1043 ] ], "normalized": [] }, { "id": "PMID-10816661_T42", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1122, 1131 ] ], "normalized": [] }, { "id": "PMID-10816661_T43", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1183, 1192 ] ], "normalized": [] }, { "id": "PMID-10816661_T46", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1225, 1229 ] ], "normalized": [] }, { "id": "PMID-10816661_T47", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1300, 1309 ] ], "normalized": [] }, { "id": "PMID-10816661_T48", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1363, 1372 ] ], "normalized": [] }, { "id": "PMID-10816661_T51", "type": "Gene_or_gene_product", "text": [ "NF-kappa B" ], "offsets": [ [ 1420, 1430 ] ], "normalized": [] }, { "id": "PMID-10816661_T52", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 1435, 1439 ] ], "normalized": [] }, { "id": "PMID-10816661_T56", "type": "Cell", "text": [ "dermal fibroblasts" ], "offsets": [ [ 1495, 1513 ] ], "normalized": [] }, { "id": "PMID-10816661_T57", "type": "Gene_or_gene_product", "text": [ "alpha-MSH" ], "offsets": [ [ 1532, 1541 ] ], "normalized": [] }, { "id": "PMID-10816661_T60", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 1585, 1605 ] ], "normalized": [] }, { "id": "PMID-10816661_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 115, 120 ] ], "normalized": [] }, { "id": "PMID-10816661_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 650, 655 ] ], "normalized": [] }, { "id": "PMID-10816661_T1002", "type": "Organism", "text": [ "human" ], "offsets": [ [ 984, 989 ] ], "normalized": [] }, { "id": "PMID-10816661_T1003", "type": "Organism", "text": [ "human" ], "offsets": [ [ 1489, 1494 ] ], "normalized": [] }, { "id": "PMID-10816661_T2", "type": "Cell", "text": [ "non-melanocytic cell" ], "offsets": [ [ 279, 299 ] ], "normalized": [] }, { "id": "PMID-10816661_T49", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1619, 1624 ] ], "normalized": [] } ]

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"Instrument", "ref_id": "PMID-10816661_T22" } ] }, { "id": "PMID-10816661_E14", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 744, 755 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_E12" }, { "role": "Theme", "ref_id": "PMID-10816661_E21" } ] }, { "id": "PMID-10816661_E15", "type": "Regulation", "trigger": { "text": [ "modulate" ], "offsets": [ [ 836, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_E16" }, { "role": "Cause", "ref_id": "PMID-10816661_T28" } ] }, { "id": "PMID-10816661_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 849, 856 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T30" } ] }, { "id": "PMID-10816661_E17", "type": "Regulation", "trigger": { "text": [ "controlling" ], "offsets": [ [ 936, 947 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_E34" }, { "role": "Cause", "ref_id": "PMID-10816661_T33" } ] }, { "id": "PMID-10816661_E18", "type": "Regulation", "trigger": { "text": [ "controlling" ], "offsets": [ [ 936, 947 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_E34" }, { "role": "Cause", "ref_id": "PMID-10816661_T32" } ] }, { "id": "PMID-10816661_E19", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T37" }, { "role": "Instrument", "ref_id": "PMID-10816661_T38" }, { "role": "Instrument", "ref_id": "PMID-10816661_T39" } ] }, { "id": "PMID-10816661_E20", "type": "Positive_regulation", "trigger": { "text": [ "costimulation" ], "offsets": [ [ 860, 873 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T31" }, { "role": "Theme", "ref_id": "PMID-10816661_T30" } ] }, { "id": "PMID-10816661_E22", "type": "Positive_regulation", "trigger": { "text": [ "led" ], "offsets": [ [ 1193, 1196 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_E41" }, { "role": "Theme", "ref_id": "PMID-10816661_E44" } ] }, { "id": "PMID-10816661_E23", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1285, 1294 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-10816661_T47" } ] }, { "id": "PMID-10816661_E24", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1391, 1398 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_T48" }, { "role": "Theme", "ref_id": "PMID-10816661_E50" } ] }, { "id": "PMID-10816661_E25", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1406, 1416 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10816661_T52" } ] }, { "id": "PMID-10816661_E26", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1391, 1398 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10816661_T48" }, { "role": "Theme", "ref_id": "PMID-10816661_E25" } ] }, { "id": "PMID-10816661_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1637, 1649 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-11381168__text", "type": "abstract", "text": [ "Effects of morphological patterning on endothelial cell migration.\n\nThe migration of vascular endothelial cells (ECs) plays an important role in vascular remodeling. Here we studied the effects of cell morphology on the migration of bovine aortic ECs by culturing cells on micropatterned strips of collagen matrix (60-, 30-, and 15-microm wide). The spreading areas of the cells on 15- and 30-microm wide strips were 30% lower than those on 60-microm wide strips and unpatterned collagen. The cells on 15-microm wide strips completely aligned in the direction of the strip, and had significantly lower shape index than those in all other groups. On strips of all widths, ECs tended to migrate in the direction of strips. ECs on 15-microm wide strips had highest speed, particularly in the direction of the strip. Vinculin staining showed that the leading edge of ECs on 15-microm wide strips had focal adhesions that were oriented with their lamellipodial protrusion and the direction of cell migration; this arrangement of the focal adhesions may promote EC migration. The present study provides direct evidence on the role of cell morphology in EC migration, and will help us to understand the mechanisms of EC migration during angiogenesis and wound healing.\n" ], "offsets": [ [ 0, 1262 ] ] } ]

[ { "id": "PMID-11381168_T3", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 39, 55 ] ], "normalized": [] }, { "id": "PMID-11381168_T6", "type": "Cell", "text": [ "vascular endothelial cells" ], "offsets": [ [ 85, 111 ] ], "normalized": [] }, { "id": "PMID-11381168_T8", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 113, 116 ] ], "normalized": [] }, { "id": "PMID-11381168_T12", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 145, 153 ] ], "normalized": [] }, { "id": "PMID-11381168_T15", "type": "Cell", "text": [ "aortic ECs" ], "offsets": [ [ 240, 250 ] ], "normalized": [] }, { "id": "PMID-11381168_T17", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 307, 313 ] ], "normalized": [] }, { "id": "PMID-11381168_T18", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 298, 306 ] ], "normalized": [] }, { "id": "PMID-11381168_T19", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 479, 487 ] ], "normalized": [] }, { "id": "PMID-11381168_T20", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 671, 674 ] ], "normalized": [] }, { "id": "PMID-11381168_T21", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "PMID-11381168_T22", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 863, 866 ] ], "normalized": [] }, { "id": "PMID-11381168_T25", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1056, 1058 ] ], "normalized": [] }, { "id": "PMID-11381168_T28", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1147, 1149 ] ], "normalized": [] }, { "id": "PMID-11381168_T31", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1210, 1212 ] ], "normalized": [] }, { "id": "PMID-11381168_T1000", "type": "Organism", "text": [ "bovine" ], "offsets": [ [ 233, 239 ] ], "normalized": [] }, { "id": "PMID-11381168_T33", "type": "Gene_or_gene_product", "text": [ "Vinculin" ], "offsets": [ [ 813, 821 ] ], "normalized": [] }, { "id": "PMID-11381168_T37", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 197, 201 ] ], "normalized": [] }, { "id": "PMID-11381168_T38", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 988, 992 ] ], "normalized": [] }, { "id": "PMID-11381168_T40", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1128, 1132 ] ], "normalized": [] }, { "id": "PMID-11381168_T41", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 264, 269 ] ], "normalized": [] }, { "id": "PMID-11381168_T42", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 373, 378 ] ], "normalized": [] }, { "id": "PMID-11381168_T43", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "PMID-11381168_T44", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1247, 1252 ] ], "normalized": [] } ]

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[ { "id": "PMID-11381168_1", "entity_ids": [ "PMID-11381168_T6", "PMID-11381168_T8" ] } ]

[]

[ { "id": "PMID-12920663__text", "type": "abstract", "text": [ "Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.\n\nRetinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.\n" ], "offsets": [ [ 0, 1948 ] ] } ]

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[]

[ { "id": "PMID-18319331__text", "type": "abstract", "text": [ "Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma.\n\nWe hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid ( less than 24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions.\n" ], "offsets": [ [ 0, 1889 ] ] } ]

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"normalized": [] }, { "id": "PMID-18319331_T22", "type": "Drug_or_compound", "text": [ "lethal toxin" ], "offsets": [ [ 436, 448 ] ], "normalized": [] }, { "id": "PMID-18319331_T23", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "PMID-18319331_T25", "type": "Gene_or_gene_product", "text": [ "MKKs" ], "offsets": [ [ 492, 496 ] ], "normalized": [] }, { "id": "PMID-18319331_T26", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 527, 531 ] ], "normalized": [] }, { "id": "PMID-18319331_T31", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase" ], "offsets": [ [ 579, 616 ] ], "normalized": [] }, { "id": "PMID-18319331_T32", "type": "Gene_or_gene_product", "text": [ "p38 MAPK" ], "offsets": [ [ 621, 629 ] ], "normalized": [] }, { "id": "PMID-18319331_T33", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 671, 675 ] ], "normalized": [] }, { "id": "PMID-18319331_T34", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 770, 774 ] ], "normalized": [] }, { "id": "PMID-18319331_T40", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 870, 904 ] ], "normalized": [] }, { "id": "PMID-18319331_T41", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 906, 919 ] ], "normalized": [] }, { "id": "PMID-18319331_T42", "type": "Gene_or_gene_product", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 925, 955 ] ], "normalized": [] }, { "id": "PMID-18319331_T43", "type": "Pathological_formation", "text": [ "malignant fibrous histiocytomas" ], "offsets": [ [ 1016, 1047 ] ], "normalized": [] }, { "id": "PMID-18319331_T44", "type": "Pathological_formation", "text": [ "leiomyosarcomas" ], "offsets": [ [ 1049, 1064 ] ], "normalized": [] }, { "id": "PMID-18319331_T45", "type": "Pathological_formation", "text": [ "liposarcomas" ], "offsets": [ [ 1070, 1082 ] ], "normalized": [] }, { "id": "PMID-18319331_T46", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 1093, 1097 ] ], "normalized": [] }, { "id": "PMID-18319331_T48", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1108, 1112 ] ], "normalized": [] }, { "id": "PMID-18319331_T51", "type": "Pathological_formation", "text": [ "fibrosarcoma" ], "offsets": [ [ 1134, 1146 ] ], "normalized": [] }, { "id": "PMID-18319331_T54", "type": "Multi-tissue_structure", "text": [ "vessel" ], "offsets": [ [ 1297, 1303 ] ], "normalized": [] }, { "id": "PMID-18319331_T56", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "PMID-18319331_T62", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 1500, 1504 ] ], "normalized": [] }, { "id": "PMID-18319331_T64", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1508, 1513 ] ], "normalized": [] }, { "id": "PMID-18319331_T68", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1623, 1628 ] ], "normalized": [] }, { "id": "PMID-18319331_T69", "type": "Tissue", "text": [ "nontumor tissues" ], "offsets": [ [ 1640, 1656 ] ], "normalized": [] }, { "id": "PMID-18319331_T71", "type": "Gene_or_gene_product", "text": [ "MKK" ], "offsets": [ [ 1743, 1746 ] ], "normalized": [] }, { "id": "PMID-18319331_T72", "type": "Drug_or_compound", "text": [ "LeTx" ], "offsets": [ [ 1761, 1765 ] ], "normalized": [] }, { "id": "PMID-18319331_T75", "type": "Pathological_formation", "text": [ "fibrosarcomas" ], "offsets": [ [ 1834, 1847 ] ], "normalized": [] }, { "id": "PMID-18319331_T1000", "type": "Organism", "text": [ "anthrax" ], "offsets": [ [ 428, 435 ] ], "normalized": [] }, { "id": "PMID-18319331_T3", "type": "Cell", "text": [ "Shac fibrosarcoma-derived cell lines" ], "offsets": [ [ 387, 423 ] ], "normalized": [] }, { "id": "PMID-18319331_T9", "type": "Cell", "text": [ "NCI" ], "offsets": [ [ 378, 381 ] ], "normalized": [] }, { "id": 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[ { "id": "PMID-18319331_1", "entity_ids": [ "PMID-18319331_T8", "PMID-18319331_T11" ] }, { "id": "PMID-18319331_2", "entity_ids": [ "PMID-18319331_T22", "PMID-18319331_T23" ] } ]

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[ { "id": "PMID-19080335__text", "type": "abstract", "text": [ "Effect of transplanted mesenchymal stem cells from rats of different ages on the improvement of heart function after acute myocardial infarction.\n\nBACKGROUND: Mesenchymal stem cells (MSCs) transplantation is of therapeutic potential after ischemic injury in both experimental and clinical studies. Clinically, elderly patients are more vulnerable to acute myocardial infarction (AMI). But little is known about the characteristics of young donor-derived MSCs transplanted to old patients with AMI. The present study was designed to investigate the effect of transplanted MSCs from rats of different ages on the improvement of heart function after AMI. METHODS: MSCs from Sprague-Dawley (SD) rats were isolated and cultured in vitro. The apoptosis characteristics of MSCs were observed under conditions of ischemia and anoxia. SD rats underwent MI received intramyocardial injection of MSCs from young donor rats (n = 8), old donor rats (n = 8), respectively. AMI control group received equal volume physiological saline. Immunofluorescence was used to observe the differentiation of the grafted cells into cardiomyocytes. Four weeks after cell transplantation, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry for vascular endothelial growth factor (VEGF), VIII-factor immunohistochemistry for vessel density, TUNEL, caspase-3 for cardiomyocyte apoptosis, echocardiography and hemodynamic detection for heart function were performed. RESULTS: The apoptosis rate of the old donor-derived MSCs group was significantly higher than that of the young donor-derived MSCs group under conditions of ischemia and anoxia (P less than 0.05). Engrafted MSCs survived, proliferated and differentiated into myocardium-like cells. VEGF gene expression and capillary density in the old donor-derived group were lower than those in the young donor-derived group but higher than those in the control group (P less than 0.05). The transplantation of old donor-derived MSCs attenuated apoptosis of cardiomyocytes in the peri-infarct region compared with the control group and the effect was elevated in young donor-derived MSCs (P less than 0.05). The heart functions (left ventricle ejection fraction (LVEF), left ventricle fractional shortening (LVFS)) were improved more significantly in the old donor-derived MSCs group than in the control group and the heart function in the young donor-derived MSCs group further improved (P less than 0.05). CONCLUSIONS: Young donor-derived MSCs can improve heart function significantly through angiogenesis and decreasing cardiomyocyte apoptosis when transplanted to the infarcted area.\n" ], "offsets": [ [ 0, 2649 ] ] } ]

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"PMID-19080335_E12", "type": "Development", "trigger": { "text": [ "differentiated" ], "offsets": [ [ 1708, 1722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T28" } ] }, { "id": "PMID-19080335_E13", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 1991, 2001 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_E35" }, { "role": "Cause", "ref_id": "PMID-19080335_E33" } ] }, { "id": "PMID-19080335_E15", "type": "Death", "trigger": { "text": [ "survived" ], "offsets": [ [ 1681, 1689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T28" } ] }, { "id": "PMID-19080335_E16", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 2097, 2103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T37" } ] }, { "id": "PMID-19080335_E17", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 2108, 2116 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_E16" } ] }, { "id": "PMID-19080335_E19", "type": "Positive_regulation", "trigger": { "text": [ "improved" ], "offsets": [ [ 2438, 2446 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T42" } ] }, { "id": "PMID-19080335_E20", "type": "Positive_regulation", "trigger": { "text": [ "improve" ], "offsets": [ [ 2511, 2518 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19080335_T45" }, { "role": "Cause", "ref_id": "PMID-19080335_E21" } ] }, { "id": "PMID-19080335_E21", "type": "Regulation", "trigger": { "text": [ "improve" ], "offsets": [ [ 2511, 2518 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19080335_T44" }, { "role": "Theme", "ref_id": "PMID-19080335_E26" } ] }, { "id": "PMID-19080335_E23", "type": "Planned_process", "trigger": { "text": [ "transplanted" ], "offsets": [ [ 2613, 2625 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19080335_T44" } ] }, { "id": "PMID-19080335_E24", "type": "Planned_process", "trigger": { "text": [ "transplantation" ], "offsets": [ [ 1144, 1159 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19080335_T66" } ] }, { "id": "PMID-19080335_E25", "type": "Planned_process", "trigger": { "text": [ "grafted" ], "offsets": [ [ 1087, 1094 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-19080335_T68" } ] }, { "id": "PMID-19080335_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 2556, 2568 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-19509166__text", "type": "abstract", "text": [ "Fibroblast growth factor receptor 2-positive fibroblasts provide a suitable microenvironment for tumor development and progression in esophageal carcinoma.\n\nPURPOSE: Tumor fibroblasts (TF) have been suggested to play an essential role in the complex process of tumor-stroma interactions and tumorigenesis. The aim of the present study was to investigate the specific role of TF in the esophageal cancer microenvironment. EXPERIMENTAL DESIGN: An Affymetrix expression microarray was used to compare gene expression profiles between six pairs of TFs and normal fibroblasts from esophageal squamous cell carcinoma (ESCC). Differentially expressed genes were identified, and a subset was evaluated by quantitative real-time PCR and immunohistochemistry. RESULTS: About 43% (126 of 292) of known deregulated genes in TFs were associated with cell proliferation, extracellular matrix remodeling, and immune response. Up-regulation of fibroblast growth factor receptor 2 (FGFR2), which showed the most significant change, was detected in all six tested TFs compared with their paired normal fibroblasts. A further study found that FGFR2-positive fibroblasts were only observed inside the tumor tissues and not in tumor-surrounding stromal tissues, suggesting that FGFR2 could be used as a TF-specific marker in ESCC. Moreover, the conditioned medium from TFs was found to be able to promote ESCC tumor cell growth, migration, and invasion in vitro. CONCLUSIONS: Our study provides new candidate genes for the esophageal cancer microenvironment. Based on our results, we hypothesize that FGFR2(+)-TFs might provide cancer cells with a suitable microenvironment via secretion of proteins that could promote cancer development and progression through stimulation of cancer cell proliferation, induction of angiogenesis, inhibition of cell adhesion, enhancement of cell mobility, and promotion of the epithelial-mesenchymal transition.\n" ], "offsets": [ [ 0, 1925 ] ] } ]

[ { "id": "PMID-19509166_T1", "type": "Cell", "text": [ "Fibroblast growth factor receptor 2-positive fibroblasts" ], "offsets": [ [ 0, 56 ] ], "normalized": [] }, { "id": "PMID-19509166_T2", "type": "Gene_or_gene_product", "text": [ "Fibroblast growth factor receptor 2" ], "offsets": [ [ 0, 35 ] ], "normalized": [] }, { "id": "PMID-19509166_T5", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 97, 102 ] ], "normalized": [] }, { "id": "PMID-19509166_T6", "type": "Pathological_formation", "text": [ "esophageal carcinoma" ], "offsets": [ [ 134, 154 ] ], "normalized": [] }, { "id": "PMID-19509166_T7", "type": "Cell", "text": [ "Tumor fibroblasts" ], "offsets": [ [ 166, 183 ] ], "normalized": [] }, { "id": "PMID-19509166_T9", "type": "Cell", "text": [ "TF" ], "offsets": [ [ 185, 187 ] ], "normalized": [] }, { "id": "PMID-19509166_T10", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 261, 266 ] ], "normalized": [] }, { "id": "PMID-19509166_T11", "type": "Tissue", "text": [ "stroma" ], "offsets": [ [ 267, 273 ] ], "normalized": [] }, { "id": "PMID-19509166_T12", "type": "Cell", "text": [ "TF" ], "offsets": [ [ 375, 377 ] ], "normalized": [] }, { "id": "PMID-19509166_T13", "type": "Cell", "text": [ "TFs" ], "offsets": [ [ 544, 547 ] ], "normalized": [] }, { "id": "PMID-19509166_T14", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 559, 570 ] ], "normalized": [] }, { "id": "PMID-19509166_T15", "type": "Pathological_formation", "text": [ "esophageal squamous cell carcinoma" ], "offsets": [ [ 576, 610 ] ], "normalized": [] }, { "id": "PMID-19509166_T16", "type": "Pathological_formation", "text": [ "ESCC" ], "offsets": [ [ 612, 616 ] ], "normalized": [] }, { "id": "PMID-19509166_T17", "type": "Cell", "text": [ "TFs" ], "offsets": [ [ 812, 815 ] ], "normalized": [] }, { "id": "PMID-19509166_T18", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 857, 877 ] ], "normalized": [] }, { "id": "PMID-19509166_T20", "type": "Gene_or_gene_product", "text": [ "fibroblast growth factor receptor 2" ], "offsets": [ [ 928, 963 ] ], "normalized": [] }, { "id": "PMID-19509166_T21", "type": "Gene_or_gene_product", "text": [ "FGFR2" ], "offsets": [ [ 965, 970 ] ], "normalized": [] }, { "id": "PMID-19509166_T22", "type": "Cell", "text": [ "TFs" ], "offsets": [ [ 1046, 1049 ] ], "normalized": [] }, { "id": "PMID-19509166_T23", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1084, 1095 ] ], "normalized": [] }, { "id": "PMID-19509166_T24", "type": "Cell", "text": [ "FGFR2-positive fibroblasts" ], "offsets": [ [ 1124, 1150 ] ], "normalized": [] }, { "id": "PMID-19509166_T25", "type": "Gene_or_gene_product", "text": [ "FGFR2" ], "offsets": [ [ 1124, 1129 ] ], "normalized": [] }, { "id": "PMID-19509166_T26", "type": "Tissue", "text": [ "tumor tissues" ], "offsets": [ [ 1181, 1194 ] ], "normalized": [] }, { "id": "PMID-19509166_T27", "type": "Tissue", "text": [ "tumor-surrounding stromal tissues" ], "offsets": [ [ 1206, 1239 ] ], "normalized": [] }, { "id": "PMID-19509166_T28", "type": "Gene_or_gene_product", "text": [ "FGFR2" ], "offsets": [ [ 1257, 1262 ] ], "normalized": [] }, { "id": "PMID-19509166_T29", "type": "Cell", "text": [ "TF" ], "offsets": [ [ 1282, 1284 ] ], "normalized": [] }, { "id": "PMID-19509166_T30", "type": "Pathological_formation", "text": [ "ESCC" ], "offsets": [ [ 1304, 1308 ] ], "normalized": [] }, { "id": "PMID-19509166_T31", "type": "Cell", "text": [ "TFs" ], "offsets": [ [ 1348, 1351 ] ], "normalized": [] }, { "id": "PMID-19509166_T36", "type": "Cell", "text": [ "ESCC tumor cell" ], "offsets": [ [ 1384, 1399 ] ], "normalized": [] }, { "id": "PMID-19509166_T38", "type": "Pathological_formation", "text": [ "esophageal cancer" ], "offsets": [ [ 1502, 1519 ] ], "normalized": [] }, { "id": "PMID-19509166_T39", "type": "Cell", "text": [ "FGFR2(+)-TFs" ], "offsets": [ [ 1580, 1592 ] ], "normalized": [] }, { "id": "PMID-19509166_T40", "type": "Gene_or_gene_product", "text": [ "FGFR2" ], "offsets": [ [ 1580, 1585 ] ], "normalized": [] }, { "id": "PMID-19509166_T41", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 1607, 1619 ] ], "normalized": [] }, { "id": "PMID-19509166_T44", "type": "Cell", "text": [ "cancer cell" ], "offsets": [ [ 1756, 1767 ] ], "normalized": [] }, { "id": "PMID-19509166_T47", "type": "Cell", "text": [ "epithelial" ], "offsets": [ [ 1890, 1900 ] ], "normalized": [] }, { "id": "PMID-19509166_T48", "type": "Cell", "text": [ "mesenchymal" ], "offsets": [ [ 1901, 1912 ] ], "normalized": [] }, { "id": "PMID-19509166_T49", "type": "Pathological_formation", "text": [ "esophageal cancer" ], "offsets": [ [ 385, 402 ] ], "normalized": [] }, { "id": "PMID-19509166_T56", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 837, 841 ] ], "normalized": [] }, { "id": "PMID-19509166_T58", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1824, 1828 ] ], "normalized": [] }, { "id": "PMID-19509166_T59", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1854, 1858 ] ], "normalized": [] } ]

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[ { "id": "PMID-19509166_1", "entity_ids": [ "PMID-19509166_T20", "PMID-19509166_T21" ] }, { "id": "PMID-19509166_2", "entity_ids": [ "PMID-19509166_T7", "PMID-19509166_T9" ] }, { "id": "PMID-19509166_3", "entity_ids": [ "PMID-19509166_T15", "PMID-19509166_T16" ] } ]

[]

[ { "id": "PMID-12154044__text", "type": "abstract", "text": [ "Inhibition of angiogenesis by the cancer chemopreventive agent conjugated linoleic acid.\n\nDietary conjugated linoleic acid (CLA) has been shown previously to inhibit rat mammary carcinogenesis. In addition to direct effects on mammary epithelial cells,including decreased proliferation and induction of apoptosis, CLA may exert its effects indirectly by inhibiting the differentiation of mammary stromal cells to an endothelial cell type. Specifically, CLA was found to decrease the ability of mammary stromal cells to form complex anastomosing microcapillary networks in vitro on Engelbreth-Holm-Swarm-derived reconstituted basement membrane. This suggested that CLA might inhibit angiogenesis in vivo. To test this possibility, CD2/F(1) mice were placed on synthetic diets containing 0, 1, or 2% CLA for 6 weeks, before angiogenic challenge by s.c. injection with an angiogenic gel substrate (Matrigel pellet assay). After 7 days, the pellets from animals fed the control diet were infiltrated by abundant branching networks of blood vessels with patent lumen-containing RBCs. In contrast, pellets from the CLA-fed animals contained fewer infiltrating cells, which formed limited branching cellular networks, the majority of which had collapsed lumen and no RBCs. Both levels of dietary CLA showed similar effects, with the number of RBC-containing vessels per 20x field decreased to a third of that seen in control. Dietary CLA decreased serum levels of vascular endothelial growth factor (VEGF) and whole mammary gland levels of VEGF and its receptor Flk-1. Both cis-9, trans-11 and trans-10, cis-12 CLA isomers were effective in inhibiting angiogenesis in vitro in a dose-dependent fashion. The ability of CLA to inhibit angiogenesis may contribute to its efficacy as a chemopreventive agent.\n" ], "offsets": [ [ 0, 1798 ] ] } ]

[ { "id": "PMID-12154044_T3", "type": "Drug_or_compound", "text": [ "conjugated linoleic acid" ], "offsets": [ [ 63, 87 ] ], "normalized": [] }, { "id": "PMID-12154044_T4", "type": "Drug_or_compound", "text": [ "conjugated linoleic acid" ], "offsets": [ [ 98, 122 ] ], "normalized": [] }, { "id": "PMID-12154044_T5", "type": "Drug_or_compound", "text": [ "CLA" ], "offsets": [ [ 124, 127 ] ], "normalized": [] }, { "id": "PMID-12154044_T6", "type": "Organ", "text": [ "mammary" ], "offsets": [ [ 170, 177 ] ], "normalized": [] }, { "id": "PMID-12154044_T7", "type": "Cell", "text": [ "mammary epithelial cells" ], "offsets": [ [ 227, 251 ] ], "normalized": [] }, { "id": "PMID-12154044_T8", "type": "Drug_or_compound", "text": [ "CLA" ], "offsets": [ [ 314, 317 ] ], "normalized": [] }, { "id": "PMID-12154044_T11", "type": "Cell", "text": [ "mammary stromal cells" ], "offsets": [ [ 388, 409 ] ], "normalized": [] }, { "id": "PMID-12154044_T12", "type": "Cell", "text": [ "endothelial cell" ], 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[ { "id": "PMID-19082449__text", "type": "abstract", "text": [ "Clinical significance of chicken ovalbumin upstream promoter-transcription factor II expression in human colorectal cancer.\n\nChicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an essential role in angiogenesis and development. A previous study showed that the expression of COUP-TFII enhanced invasiveness of human lung carcinoma cells. However, no published data are available concerning the biological and clinical significance of COUP-TFII expression in colorectal cancer. Thus, our objective was to explore the expression of COUP-TFII in colorectal cancer as well as its association with clinicopathological features, and to evaluate the role of COUP-TFII as a prognostic indicator in colorectal cancer. We investigated the presence of COUP-TFII in human colorectal cancer tissues and adjacent normal tissues from 95 primary colorectal cancer patients by immunohistochemistry. The correlation between the expression of COUP-TFII and clinicopathologic features was investigated. The 3-year disease-free survival (DFS) and overall survival (OS) of patients with tumors expressing different levels of COUP-TFII were evaluated by the Kaplan-Meier method. No significant correlation was found between COUP-TFII expression and age at surgery, gender, histopathologic differentiation, vessel invasion, carcinoembryonic antigen (CEA), or nodal involvement. However, survival analysis showed that the COUP-TFII-positive group had a significantly better OS compared to COUP-TFII-negative group (80.4% vs. 57.7%, P=0.0491). Based on our results, COUP-TFII may represent a biomarker for good prognosis in colorectal cancer.\n" ], "offsets": [ [ 0, 1643 ] ] } ]

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[ { "id": "PMID-19082449_1", "entity_ids": [ "PMID-19082449_T4", "PMID-19082449_T5" ] }, { "id": "PMID-19082449_2", "entity_ids": [ "PMID-19082449_T36", "PMID-19082449_T37" ] } ]

[]

[ { "id": "PMID-10543260__text", "type": "abstract", "text": [ "Increased serum levels of vascular endothelial growth factor in patients with renal cell carcinoma.\n\nNeovascularization, an essential event for the growth of solid tumors, is regulated by a number of angiogenic factors. One such factor, vascular endothelial growth factor (VEGF), is considered to exert a potent angiogenic activity, as indicated by immunohistochemical and molecular evidence. In this study we investigated the serum VEGF level (s-VEGF) in patients with renal cell carcinoma (RCC). s-VEGF in peripheral blood samples was analyzed in 40 RCC patients and 40 patients without cancer (controls) using a sandwich enzyme-linked immunoassay. In 20 RCC patients, serum samples were obtained separately from the bilateral renal veins. s-VEGF was also measured before, 4 and 8 weeks after nephrectomy in 11 patients. There were significant differences in s-VEGF between the RCC patients and the controls (207.3+/-32.9 vs. 71.5+/-9.1 pg/ml, mean+/-SE) (P less than 0.005), between the tumor-bearing renal veins and the contralateral ones (P less than 0.01), between the pre- and post-nephrectomy situations (P less than 0.01) and among the various parameters of tumor status such as tumor extent (P less than 0.001) and existence of metastasis (P less than 0.001). s-VEGF significantly correlated with the tumor volume obtained by a three-dimensional measurement (r=0.802, P less than 0.0001). The sensitivity and specificity of s-VEGF at the cut-off level of 100 pg/ml, as determined by the receiver-operating-characteristics curve, were 80.0% and 72.5%, respectively. The results indicate that tumor tissue of RCC liberates VEGF into the systemic blood flow and that s-VEGF is a possible marker for RCC.\n" ], "offsets": [ [ 0, 1711 ] ] } ]

[ { "id": "PMID-10543260_T1", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 10, 15 ] ], "normalized": [] }, { "id": "PMID-10543260_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 26, 60 ] ], "normalized": [] }, { "id": "PMID-10543260_T3", "type": "Pathological_formation", "text": [ "renal cell carcinoma" ], "offsets": [ [ 78, 98 ] ], "normalized": [] }, { "id": "PMID-10543260_T8", "type": "Pathological_formation", "text": [ "solid tumors" ], "offsets": [ [ 158, 170 ] ], "normalized": [] }, { "id": "PMID-10543260_T10", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 237, 271 ] ], "normalized": [] }, { "id": "PMID-10543260_T11", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 273, 277 ] ], "normalized": [] }, { "id": "PMID-10543260_T14", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 427, 432 ] ], "normalized": [] }, { "id": "PMID-10543260_T15", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 433, 437 ] ], "normalized": [] }, { "id": "PMID-10543260_T16", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 447, 451 ] ], "normalized": [] }, { "id": "PMID-10543260_T17", "type": "Pathological_formation", "text": [ "renal cell carcinoma" ], "offsets": [ [ 470, 490 ] ], "normalized": [] }, { "id": "PMID-10543260_T19", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 500, 504 ] ], "normalized": [] }, { "id": "PMID-10543260_T20", "type": "Organism_substance", "text": [ "peripheral blood samples" ], "offsets": [ [ 508, 532 ] ], "normalized": [] }, { "id": "PMID-10543260_T21", "type": "Organism_substance", "text": [ "serum samples" ], "offsets": [ [ 671, 684 ] ], "normalized": [] }, { "id": "PMID-10543260_T22", "type": "Multi-tissue_structure", "text": [ "bilateral renal veins" ], "offsets": [ [ 719, 740 ] ], "normalized": [] }, { "id": "PMID-10543260_T23", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "PMID-10543260_T24", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 863, 867 ] ], "normalized": [] }, { "id": "PMID-10543260_T25", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 990, 995 ] ], "normalized": [] }, { "id": "PMID-10543260_T26", "type": "Multi-tissue_structure", "text": [ "renal veins" ], "offsets": [ [ 1004, 1015 ] ], "normalized": [] }, { "id": "PMID-10543260_T27", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1167, 1172 ] ], "normalized": [] }, { "id": "PMID-10543260_T28", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1188, 1193 ] ], "normalized": [] }, { "id": "PMID-10543260_T29", "type": "Pathological_formation", "text": [ "metastasis" ], "offsets": [ [ 1238, 1248 ] ], "normalized": [] }, { "id": "PMID-10543260_T30", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1272, 1276 ] ], "normalized": [] }, { "id": "PMID-10543260_T31", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1311, 1316 ] ], "normalized": [] }, { "id": "PMID-10543260_T32", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1436, 1440 ] ], "normalized": [] }, { "id": "PMID-10543260_T33", "type": "Tissue", "text": [ "tumor tissue" ], "offsets": [ [ 1601, 1613 ] ], "normalized": [] }, { "id": "PMID-10543260_T35", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1631, 1635 ] ], "normalized": [] }, { "id": "PMID-10543260_T36", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 1654, 1659 ] ], "normalized": [] }, { "id": "PMID-10543260_T37", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1676, 1680 ] ], "normalized": [] }, { "id": "PMID-10543260_T4", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 492, 495 ] ], "normalized": [] }, { "id": "PMID-10543260_T6", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 552, 555 ] ], "normalized": [] }, { "id": "PMID-10543260_T12", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 657, 660 ] ], "normalized": [] }, { "id": "PMID-10543260_T18", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 880, 883 ] ], "normalized": [] }, { "id": "PMID-10543260_T38", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 1706, 1709 ] ], "normalized": [] }, { "id": "PMID-10543260_T39", "type": "Pathological_formation", "text": [ "RCC" ], "offsets": [ [ 1617, 1620 ] ], "normalized": [] }, { "id": "PMID-10543260_T40", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 589, 595 ] ], "normalized": [] }, { "id": "PMID-10543260_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 64, 72 ] ], "normalized": [] }, { "id": "PMID-10543260_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 456, 464 ] ], "normalized": [] }, { "id": "PMID-10543260_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 556, 564 ] ], "normalized": [] }, { "id": "PMID-10543260_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 572, 580 ] ], "normalized": [] }, { "id": "PMID-10543260_T1004", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 661, 669 ] ], "normalized": [] }, { "id": "PMID-10543260_T1005", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 813, 821 ] ], "normalized": [] }, { "id": "PMID-10543260_T1006", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 884, 892 ] ], "normalized": [] } ]

[ { "id": "PMID-10543260_E7", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 148, 154 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10543260_T8" } ] }, { "id": "PMID-10543260_E34", "type": "Localization", "trigger": { "text": [ "liberates" ], "offsets": [ [ 1621, 1630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10543260_T35" }, { "role": "ToLoc", "ref_id": "PMID-10543260_T36" }, { "role": "FromLoc", "ref_id": "PMID-10543260_T33" } ] }, { "id": "PMID-10543260_E1", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10543260_T2" } ] }, { "id": "PMID-10543260_E2", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 175, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10543260_E4" } ] }, { "id": "PMID-10543260_E3", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 124, 133 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10543260_E4" }, { "role": "Theme", "ref_id": "PMID-10543260_E7" } ] }, { "id": "PMID-10543260_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "Neovascularization" ], "offsets": [ [ 101, 119 ] ] }, "arguments": [] }, { "id": "PMID-10543260_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 200, 210 ] ] }, "arguments": [] }, { "id": "PMID-10543260_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 312, 322 ] ] }, "arguments": [] } ]

[ { "id": "PMID-10543260_1", "entity_ids": [ "PMID-10543260_T10", "PMID-10543260_T11" ] }, { "id": "PMID-10543260_2", "entity_ids": [ "PMID-10543260_T17", "PMID-10543260_T4" ] } ]

[]

[ { "id": "PMID-15034798__text", "type": "abstract", "text": [ "Role of thrombin in angiogenesis and tumor progression.\n\nClinical, laboratory, histopathological, and pharmacological evidence support the notion that the coagulation system, which is activated in most cancer patients, plays an important role in tumor biology. Our laboratory has provided evidence that thrombin activates angiogenesis, a process which is essential in tumor growth and metastasis. This event is independent of fibrin formation. At the cellular level many actions of thrombin can contribute to activation of angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach to basement membrane proteins. (2). Thrombin greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This potentiation is accompanied by up-regulation of the expression of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt-1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3) integrin and serves as a ligand to this receptor. Furthermore, thrombin increases the secretion of VEGF and enhances the expression and protein synthesis of matrix metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic and tumor-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.\n" ], "offsets": [ [ 0, 1443 ] ] } ]

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[]

[ { "id": "PMID-19075960__text", "type": "abstract", "text": [ "VEGF, angiopoietin-1 and -2 in bronchial asthma: new molecular targets in airway angiogenesis and microvascular remodeling.\n\nAirway angiogenesis and microvascular remodeling are known features of bronchial asthma, but the mechanisms of these structural alterations are just beginning to be elucidated. Vascular endothelial growth factor (VEGF), one of the most potent angiogenic factors, stimulates endothelial cell proliferation and induces the angiogenesis. Recently, considerable attentions have been devoted to the physiological roles of angiopoietin (Ang)-1 and -2 as regulatory factors of VEGF. Ang-1 has been shown to induce the migration and sprouting of endothelial cells, and coexpression of Ang-1 and VEGF enhanced angiogenesis. In the presence of high levels of VEGF, Ang-2 also promotes rapid increase in capillary diameter, remodeling of the basal lamina, proliferation and migration of endothelial cells, and stimulates sprouting of new blood vessels. Thus, VEGF, Ang-1 and -2 may play complementary and coordinated roles in airway angiogenesis and microvascular remodeling, and these structural changes are potentially reversible by therapeutic intervention. The scope of the present review is to discuss from a clinical point of view the potential interactions between VEGF and angiopoietins in the asthmatic airways, and focus on the therapeutic implications targeting for these angiogenic factors. Recently, there is an increasing number of patents which have been focused on the inhibitors of VEGF action. These inhibitors are directed towards the receptors of VEGF or intracellular substrates for the receptors. We will also discuss several patents regarding inhibitors of VEGF action in the present review.\n" ], "offsets": [ [ 0, 1729 ] ] } ]

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[ { "id": "PMID-16407289__text", "type": "abstract", "text": [ "Regulation of the composition of the extracellular matrix by low density lipoprotein receptor-related protein-1: activities based on regulation of mRNA expression.\n\nLow density lipoprotein receptor-related protein-1 (LRP-1) is a catabolic receptor for extracellular matrix (ECM) structural proteins and for proteins that bind to ECM. LRP-1 also is implicated in integrin maturation. In this study, we applied a proteomics strategy to identify novel proteins involved in ECM modeling that are regulated by LRP-1. We show that LRP-1 deficiency in murine embryonic fibroblasts (MEFs) is associated with increased levels of type III collagen and pigment epithelium-derived factor, which accumulate in the substratum surrounding cells. The collagen receptor, uPAR-AP/Endo-180, is also increased in LRP-1-deficient MEFs. Human LRP-1 reversed the changes in protein expression associated with LRP-1 deficiency; however, the endocytic activity of LRP-1 was not involved. Instead, regulation occurred at the mRNA level. Inhibition of c-Jun amino-terminal kinase (JNK) blocked type III collagen expression in LRP-1-deficient MEFs, suggesting regulation of JNK activity as a mechanism by which LRP-1 controls mRNA expression. The ability of LRP-1 to regulate expression of the factors identified here suggests a role for LRP-1 in determining blood vessel structure and in angiogenesis.\n" ], "offsets": [ [ 0, 1375 ] ] } ]

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"normalized": [] }, { "id": "PMID-16407289_T8", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 334, 339 ] ], "normalized": [] }, { "id": "PMID-16407289_T10", "type": "Gene_or_gene_product", "text": [ "integrin" ], "offsets": [ [ 362, 370 ] ], "normalized": [] }, { "id": "PMID-16407289_T13", "type": "Cellular_component", "text": [ "ECM" ], "offsets": [ [ 470, 473 ] ], "normalized": [] }, { "id": "PMID-16407289_T14", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 505, 510 ] ], "normalized": [] }, { "id": "PMID-16407289_T16", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 525, 530 ] ], "normalized": [] }, { "id": "PMID-16407289_T17", "type": "Cell", "text": [ "embryonic fibroblasts" ], "offsets": [ [ 552, 573 ] ], "normalized": [] }, { "id": "PMID-16407289_T18", "type": "Cell", "text": [ "MEFs" ], "offsets": [ [ 575, 579 ] ], "normalized": [] }, { "id": "PMID-16407289_T22", "type": "Gene_or_gene_product", "text": [ "pigment epithelium-derived factor" ], "offsets": [ [ 642, 675 ] ], "normalized": [] }, { "id": "PMID-16407289_T23", "type": "Cellular_component", "text": [ "substratum" ], "offsets": [ [ 701, 711 ] ], "normalized": [] }, { "id": "PMID-16407289_T25", "type": "Gene_or_gene_product", "text": [ "uPAR-AP" ], "offsets": [ [ 754, 761 ] ], "normalized": [] }, { "id": "PMID-16407289_T26", "type": "Gene_or_gene_product", "text": [ "Endo-180" ], "offsets": [ [ 762, 770 ] ], "normalized": [] }, { "id": "PMID-16407289_T28", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 793, 798 ] ], "normalized": [] }, { "id": "PMID-16407289_T29", "type": "Cell", "text": [ "MEFs" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "PMID-16407289_T30", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 821, 826 ] ], "normalized": [] }, { "id": "PMID-16407289_T32", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 886, 891 ] ], "normalized": [] }, { "id": "PMID-16407289_T33", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 939, 944 ] ], "normalized": [] }, { "id": "PMID-16407289_T35", "type": "Gene_or_gene_product", "text": [ "c-Jun amino-terminal kinase" ], "offsets": [ [ 1025, 1052 ] ], "normalized": [] }, { "id": "PMID-16407289_T36", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1054, 1057 ] ], "normalized": [] }, { "id": "PMID-16407289_T38", "type": "Gene_or_gene_product", "text": [ "type III collagen" ], "offsets": [ [ 1067, 1084 ] ], "normalized": [] }, { "id": "PMID-16407289_T40", "type": "Gene_or_gene_product", "text": [ "LRP-1" ], "offsets": [ [ 1099, 1104 ] ], "normalized": [] }, { "id": "PMID-16407289_T41", "type": "Cell", "text": [ "MEFs" ], "offsets": [ [ 1115, 1119 ] ], "normalized": [] }, { "id": "PMID-16407289_T43", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1146, 1149 ] ], "normalized": [] }, { "id": "PMID-16407289_T44", "type": "Gene_or_gene_product", 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[]

[ { "id": "PMID-12384438__text", "type": "abstract", "text": [ "Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model.\n\nHomeostasis of the extracellular matrix is a delicate balance between degradation and remodeling, the balance being maintained by the interaction of activated matrix metalloproteinases (MMPs) and specific tissue inhibitors of matrix metalloproteinases (TIMPs). Up-regulation of MMP activity, favoring proteolytic degradation of the basement membrane and extracellular matrix, has been linked to tumor growth and metastasis, as well as tumor-associated angiogenesis, whereas inhibition of MMP activity appears to restrict these processes. We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit angiogenesis in vivo. Growth of both histologic types of gene-modified tumor cells in severe combined immunodeficiency (SCID) mice was significantly restricted when compared with controls. Grossly, these tumors were small and had few feeding vessels. Histologic evaluation revealed that although tumors overexpressing TIMP-3 had an increased number of CD31(+) endothelial cells, these endothelial cells had not formed functional tubules, as evidenced by decreased vessel continuity and minimal pericyte recruitment. This effect appears to be mediated, in part, by decreased expression of vascular endothelial (VE)-cadherin by endothelial cells in the presence of TIMP-3 as seen both in an in vitro assay and in TIMP-3-overexpressing tumors. Taken together, these results demonstrate that overexpression of TIMP-3 can inhibit angiogenesis and associated tumor growth, and that the antiangiogenic effects of TIMP-3 appear to be mediated through the inhibition of functional capillary morphogenesis.\n" ], "offsets": [ [ 0, 1907 ] ] } ]

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"PMID-12384438_T56", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1536, 1553 ] ], "normalized": [] }, { "id": "PMID-12384438_T57", "type": "Gene_or_gene_product", "text": [ "TIMP-3" ], "offsets": [ [ 1573, 1579 ] ], "normalized": [] }, { "id": "PMID-12384438_T59", "type": "Gene_or_gene_product", "text": [ "TIMP-3" ], "offsets": [ [ 1621, 1627 ] ], "normalized": [] }, { "id": "PMID-12384438_T60", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 1643, 1649 ] ], "normalized": [] }, { "id": "PMID-12384438_T62", "type": "Gene_or_gene_product", "text": [ "TIMP-3" ], "offsets": [ [ 1716, 1722 ] ], "normalized": [] }, { "id": "PMID-12384438_T66", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1763, 1768 ] ], "normalized": [] }, { "id": "PMID-12384438_T68", "type": "Gene_or_gene_product", "text": [ "TIMP-3" ], "offsets": [ [ 1816, 1822 ] ], "normalized": [] }, { "id": "PMID-12384438_T71", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 1882, 1891 ] ], "normalized": [] }, { "id": "PMID-12384438_T3", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 151, 156 ] ], "normalized": [] }, { "id": "PMID-12384438_T1000", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 144, 150 ] ], "normalized": [] }, { "id": "PMID-12384438_T1001", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 804, 810 ] ], "normalized": [] }, { "id": "PMID-12384438_T1002", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 1036, 1040 ] ], "normalized": [] }, { "id": "PMID-12384438_T12", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinases" ], "offsets": [ [ 324, 349 ] ], "normalized": [] }, { "id": "PMID-12384438_T14", "type": "Gene_or_gene_product", "text": [ "MMPs" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-12384438_T15", "type": "Gene_or_gene_product", "text": [ "tissue inhibitors of matrix metalloproteinases" ], "offsets": [ [ 370, 416 ] ], "normalized": [] 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"Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 1794, 1804 ] ] }, "arguments": [] }, { "id": "PMID-12384438_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1727, 1734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12384438_E65" }, { "role": "Cause", "ref_id": "PMID-12384438_E61" } ] }, { "id": "PMID-12384438_E4", "type": "Positive_regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 753, 759 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12384438_E28" } ] } ]

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[ { "id": "PMID-18043872__text", "type": "abstract", "text": [ "Tumor microenvironment, a dangerous society leading to cancer metastasis. From mechanisms to therapy and prevention.\n\nCancer is no longer considered by scientists just a jumble of mutated cells. To grow, invade and metastasize, a treacherous society between cancer and host cells must be formed, and this association provides novel and effective clinical targets for cancer control and prevention. This collection of reviews at the front-edge of scientific knowledge focuses on host-tumor cell interactions, the disastrous consequences they can produce and approaches the ways to break up these cellular conspiracies, to leave the tumor cells unattended and vulnerable.\n" ], "offsets": [ [ 0, 670 ] ] } ]

[ { "id": "PMID-18043872_T1", "type": "Pathological_formation", "text": [ "Tumor" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18043872_T2", "type": "Cell", "text": [ "host cells" ], "offsets": [ [ 269, 279 ] ], "normalized": [] }, { "id": "PMID-18043872_T4", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 483, 493 ] ], "normalized": [] }, { "id": "PMID-18043872_T6", "type": "Cell", "text": [ "tumor cells" ], "offsets": [ [ 631, 642 ] ], "normalized": [] }, { "id": "PMID-18043872_T1000", "type": "Pathological_formation", "text": [ "Cancer" ], "offsets": [ [ 118, 124 ] ], "normalized": [] }, { "id": "PMID-18043872_T5", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 55, 61 ] ], "normalized": [] }, { "id": "PMID-18043872_T7", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 258, 264 ] ], "normalized": [] }, { "id": "PMID-18043872_T11", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 367, 373 ] ], "normalized": [] }, { "id": "PMID-18043872_T16", "type": "Cell", "text": [ "host" ], "offsets": [ [ 478, 482 ] ], "normalized": [] }, { "id": "PMID-18043872_T18", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 188, 193 ] ], "normalized": [] } ]

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[]

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[ { "id": "PMID-19654314__text", "type": "abstract", "text": [ "Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity.\n\nRecruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growth-arrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1alpha-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.\n" ], "offsets": [ [ 0, 1456 ] ] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_T43" } ] }, { "id": "PMID-19654314_E44", "type": "Negative_regulation", "trigger": { "text": [ "disrupting" ], "offsets": [ [ 1106, 1116 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_T45" } ] }, { "id": "PMID-19654314_E48", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1277, 1287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_T49" } ] }, { "id": "PMID-19654314_E51", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1295, 1305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_T52" } ] }, { "id": "PMID-19654314_E3", "type": "Development", "trigger": { "text": [ "transformed" ], "offsets": [ [ 287, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_T13" } ] }, { "id": "PMID-19654314_E5", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 537, 545 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19654314_E16" }, { "role": "Theme", "ref_id": "PMID-19654314_E22" } ] }, { "id": "PMID-19654314_E6", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 812, 823 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19654314_T32" }, { "role": "Theme", "ref_id": "PMID-19654314_E29" } ] }, { "id": "PMID-19654314_E9", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 836, 843 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_E35" }, { "role": "Cause", "ref_id": "PMID-19654314_E25" } ] }, { "id": "PMID-19654314_E11", "type": "Positive_regulation", "trigger": { "text": [ "forced" ], "offsets": [ [ 904, 910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19654314_E37" } ] }, { "id": "PMID-19654314_E12", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 966, 972 ] ] }, "arguments": [ { "role": "Cause", "ref_id": 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[]

[ { "id": "PMID-19372461__text", "type": "abstract", "text": [ "Rab GTPase regulation of VEGFR2 trafficking and signaling in endothelial cells.\n\nOBJECTIVE: Vascular endothelial growth factor receptor 2 (VEGFR2) is a receptor tyrosine kinase that regulates vascular physiology. However, mechanism(s) by which VEGFR2 signaling and trafficking is coordinated are not clear. Here, we have tested endocytic Rab GTPases for regulation of VEGFR2 trafficking and signaling linked to endothelial cell migration. METHODS AND RESULTS: Quiescent VEGFR2 displays endosomal localization and colocalization with the Rab5a GTPase, an early endosome fusion regulator. Expression of GTP or GDP-bound Rab5a mutants block activated VEGFR2 trafficking and degradation. Manipulation of Rab7a GTPase activity associated with late endosomes using overexpression of wild-type or mutant proteins blocks activated VEGFR2 trafficking and degradation. Depletion of Rab7a decreased VEGFR2 Y1175 phosphorylation but increased p42/44 (pERK1/2) MAPK phosphorylation. Endothelial cell migration was increased by Rab5a depletion but decreased by Rab7a depletion. CONCLUSIONS: Rab5a and Rab7a regulate VEGFR2 trafficking toward early and late endosomes. Our data suggest that VEGFR2-mediated regulation of endothelial function is dependent on different but specific Rab-mediated GTP hydrolysis activity required for endosomal trafficking.\n" ], "offsets": [ [ 0, 1339 ] ] } ]

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[ { "id": "PMID-19372461_1", "entity_ids": [ "PMID-19372461_T7", "PMID-19372461_T8" ] }, { "id": "PMID-19372461_2", "entity_ids": [ "PMID-19372461_T44", "PMID-19372461_T45", "PMID-19372461_T46" ] } ]

[]

[ { "id": "PMID-19446450__text", "type": "abstract", "text": [ "AngiomiRs--key regulators of angiogenesis.\n\nThe formation of new blood vessels through the process of angiogenesis is critical in vascular development and homeostasis. Aberrant angiogenesis leads to a variety of diseases, such as ischemia and cancer. Recent studies have revealed important roles for miRNAs in regulating endothelial cell (EC) function, especially angiogenesis. Mice with EC-specific deletion of Dicer, a key enzyme for generating miRNAs, display defective postnatal angiogenesis. Specific miRNAs (angiomiRs) have recently been shown to regulate angiogenesis in vivo. miRNA-126, an EC-restricted miRNA, regulates vascular integrity and developmental angiogenesis. miR-378, miR-296, and the miR-17-92 cluster contribute to tumor angiogenesis. Manipulating angiomiRs in the settings of pathological vascularization represents a new therapeutic approach.\n" ], "offsets": [ [ 0, 868 ] ] } ]

[ { "id": "PMID-19446450_T1", "type": "Gene_or_gene_product", "text": [ "AngiomiRs" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "PMID-19446450_T4", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 65, 78 ] ], "normalized": [] }, { "id": "PMID-19446450_T10", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 130, 138 ] ], "normalized": [] }, { "id": "PMID-19446450_T14", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 321, 337 ] ], "normalized": [] }, { "id": "PMID-19446450_T15", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 339, 341 ] ], "normalized": [] }, { "id": "PMID-19446450_T17", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 388, 390 ] ], "normalized": [] }, { "id": "PMID-19446450_T18", "type": "Gene_or_gene_product", "text": [ "Dicer" ], "offsets": [ [ 412, 417 ] ], "normalized": [] }, { "id": "PMID-19446450_T22", "type": "Gene_or_gene_product", "text": [ "angiomiRs" ], "offsets": [ [ 514, 523 ] ], "normalized": [] }, { "id": "PMID-19446450_T25", "type": "Gene_or_gene_product", "text": [ "miRNA-126" ], "offsets": [ [ 584, 593 ] ], "normalized": [] }, { "id": "PMID-19446450_T26", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 598, 600 ] ], "normalized": [] }, { "id": "PMID-19446450_T33", "type": "Gene_or_gene_product", "text": [ "miR-378" ], "offsets": [ [ 680, 687 ] ], "normalized": [] }, { "id": "PMID-19446450_T34", "type": "Gene_or_gene_product", "text": [ "miR-296" ], "offsets": [ [ 689, 696 ] ], "normalized": [] }, { "id": "PMID-19446450_T35", "type": "Gene_or_gene_product", "text": [ "miR-17-" ], "offsets": [ [ 706, 713 ] ], "normalized": [] }, { "id": "PMID-19446450_T39", "type": "Gene_or_gene_product", "text": [ "angiomiRs" ], "offsets": [ [ 771, 780 ] ], "normalized": [] }, { "id": "PMID-19446450_T13", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "PMID-19446450_T1000", "type": "Organism", "text": [ "Mice" ], "offsets": [ [ 378, 382 ] ], "normalized": [] }, { "id": "PMID-19446450_T31", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 243, 249 ] ], "normalized": [] }, { "id": "PMID-19446450_T3", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 629, 637 ] ], "normalized": [] }, { "id": "PMID-19446450_T6", "type": "Gene_or_gene_product", "text": [ "92" ], "offsets": [ [ 713, 715 ] ], "normalized": [] } ]

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[ { "id": "PMID-15586242__text", "type": "abstract", "text": [ "Hypoxia-responsive element-mediated soluble Tie2 vector exhibits an anti-angiogenic activity in vitro under hypoxic condition.\n\nHypoxia-inducible factor-1 (HIF-1) is one of the key mammalian transcription factors and shows increased levels in both protein stability and intrinsic transcriptional activity during low oxygen tension. Hypoxia-activated functional HIF-1 protein binds to hypoxia-responsive elements (HRE) in the enhancers of several genes including VEGF, the major player in angiogenesis, and initiates their mRNA expression. The molecular mechanisms regulating the gene expression under hypoxic conditions could increase the therapeutic window of tumor-specific delivery systems. In this study, to examine hypoxia-specific production of anti-angiogenic therapeutic gene, we constructed 5 copies of HRE (5xHRE) of human VEGF linked to soluble Tie2 (sTie2) driven by minimal SV40 promoter (5xHRE/SV40/sTie2). Our data showed that under hypoxia the secreted sTie2 selectively inhibited tube formation and migration capacities of endothelial cells in vitro. Hence, we propose that the vector system, 5xHRE/SV40/sTie2, might be a useful tool for down-regulating tumor angiogenesis under hypoxic condition.\n" ], "offsets": [ [ 0, 1215 ] ] } ]

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[]

[ { "id": "PMID-15225208__text", "type": "abstract", "text": [ "Matrix metalloproteinase activity and immunohistochemical profile of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 during human dermal wound healing.\n\nProteolytic activity is required for the turnover of the extracellular matrix during wound healing. Matrix metalloproteinases can collectively cleave all components of the extracellular matrix, with the endogenous tissue inhibitor of metalloproteinase-1 regulating their activity. Breast tissue taken at varying postoperative times (n= 92) or during surgery (controls, n= 17), was used to investigate the temporal and spatial activity of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 during human wound healing. Matrix metalloproteinase activity, determined using a quenched fluorescence substrate assay, increased during early healing (3-8 weeks) compared to controls, and then decreased between 24 and 36 weeks after surgery (p less than 0.05 until 24 weeks, Mann-Whitney U-test). Immunohistochemistry scores for matrix metalloproteinase-9 expression were significantly elevated compared to controls in scar endothelial cells and fibroblasts from 2 until 12 and 20 weeks, respectively. Matrix metalloproteinase-2 staining was observed exclusively in fibroblasts, reaching maximum levels 8-12 weeks after surgery, decreasing by 1.5 years but remaining significantly increased. Tissue inhibitor of metalloproteinase-1 staining was relatively sparse but was significantly increased until 8 weeks after surgery. These results show that matrix metalloproteinases are present at elevated levels during early wound healing, when angiogenesis occurs, and suggest that matrix metalloproteinase-9 may play a significant role. The later expression of matrix metalloproteinase-2 and -9 in fibroblasts suggests a role in extracellular matrix remodeling.\n" ], "offsets": [ [ 0, 1860 ] ] } ]

[ { "id": "PMID-15225208_T1", "type": "Gene_or_gene_product", "text": [ "Matrix metalloproteinase" ], "offsets": [ [ 0, 24 ] ], "normalized": [] }, { "id": "PMID-15225208_T2", "type": "Gene_or_gene_product", "text": [ "-9" ], "offsets": [ [ 100, 102 ] ], "normalized": [] }, { "id": "PMID-15225208_T3", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-2" ], "offsets": [ [ 69, 95 ] ], "normalized": [] }, { "id": "PMID-15225208_T4", "type": "Gene_or_gene_product", "text": [ "tissue inhibitor of metalloproteinase-1" ], "offsets": [ [ 107, 146 ] ], "normalized": [] }, { "id": "PMID-15225208_T5", "type": "Multi-tissue_structure", "text": [ "dermal" ], "offsets": [ [ 160, 166 ] ], "normalized": [] }, { "id": "PMID-15225208_T6", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 240, 260 ] ], "normalized": [] }, { "id": "PMID-15225208_T7", "type": "Gene_or_gene_product", "text": [ "Matrix metalloproteinases" ], "offsets": [ [ 283, 308 ] ], "normalized": [] }, { "id": "PMID-15225208_T8", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 355, 375 ] ], "normalized": [] }, { "id": "PMID-15225208_T9", "type": "Gene_or_gene_product", "text": [ "tissue inhibitor of metalloproteinase-1" ], "offsets": [ [ 397, 436 ] ], "normalized": [] }, { "id": "PMID-15225208_T10", "type": "Tissue", "text": [ "Breast tissue" ], "offsets": [ [ 464, 477 ] ], "normalized": [] }, { "id": "PMID-15225208_T11", "type": "Gene_or_gene_product", "text": [ "-9" ], "offsets": [ [ 652, 654 ] ], "normalized": [] }, { "id": "PMID-15225208_T12", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-2" ], "offsets": [ [ 621, 647 ] ], "normalized": [] }, { "id": "PMID-15225208_T13", "type": "Gene_or_gene_product", "text": [ "tissue inhibitor of metalloproteinase-1" ], "offsets": [ [ 659, 698 ] ], "normalized": [] }, { "id": "PMID-15225208_T14", "type": "Gene_or_gene_product", "text": [ "Matrix metalloproteinase" ], "offsets": [ [ 727, 751 ] ], "normalized": [] }, { "id": "PMID-15225208_T17", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 1032, 1058 ] ], "normalized": [] }, { "id": "PMID-15225208_T18", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1127, 1144 ] ], "normalized": [] }, { "id": "PMID-15225208_T19", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1149, 1160 ] ], "normalized": [] }, { "id": "PMID-15225208_T20", "type": "Gene_or_gene_product", "text": [ "Matrix metalloproteinase-2" ], "offsets": [ [ 1205, 1231 ] ], "normalized": [] }, { "id": "PMID-15225208_T21", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1269, 1280 ] ], "normalized": [] }, { "id": "PMID-15225208_T22", "type": "Gene_or_gene_product", "text": [ "Tissue inhibitor of metalloproteinase-1" ], "offsets": [ [ 1395, 1434 ] ], "normalized": [] }, { "id": "PMID-15225208_T27", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 1679, 1705 ] ], "normalized": [] }, { "id": "PMID-15225208_T29", "type": "Gene_or_gene_product", "text": [ "-9" ], "offsets": [ [ 1790, 1792 ] ], "normalized": [] }, { "id": "PMID-15225208_T30", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase-2" ], "offsets": [ [ 1759, 1785 ] ], "normalized": [] }, { "id": "PMID-15225208_T31", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1796, 1807 ] ], "normalized": [] }, { "id": "PMID-15225208_T34", "type": "Cellular_component", "text": [ "extracellular matrix" ], "offsets": [ [ 1827, 1847 ] ], "normalized": [] }, { "id": "PMID-15225208_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 154, 159 ] ], "normalized": [] }, { "id": "PMID-15225208_T1001", "type": "Organism", "text": [ "human" ], "offsets": [ [ 706, 711 ] ], "normalized": [] }, { "id": "PMID-15225208_T24", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinases" ], "offsets": [ [ 1551, 1576 ] ], "normalized": [] }, { "id": "PMID-15225208_T46", "type": "Pathological_formation", "text": [ "wound" ], "offsets": [ [ 1621, 1626 ] ], "normalized": [] } ]

[ { "id": "PMID-15225208_E15", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 1089, 1097 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_E16" } ] }, { "id": "PMID-15225208_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1059, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T17" } ] }, { "id": "PMID-15225208_E23", "type": "Gene_expression", "trigger": { "text": [ "present" ], "offsets": [ [ 1581, 1588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T24" } ] }, { "id": "PMID-15225208_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1745, 1755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T30" } ] }, { "id": "PMID-15225208_E32", "type": "Remodeling", "trigger": { "text": [ "remodeling" ], "offsets": [ [ 1848, 1858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T34" } ] }, { "id": "PMID-15225208_E1", "type": "Remodeling", "trigger": { "text": [ "turnover" ], "offsets": [ [ 224, 232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T6" } ] }, { "id": "PMID-15225208_E2", "type": "Breakdown", "trigger": { "text": [ "cleave" ], "offsets": [ [ 326, 332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T8" } ] }, { "id": "PMID-15225208_E3", "type": "Positive_regulation", "trigger": { "text": [ "cleave" ], "offsets": [ [ 326, 332 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15225208_T7" }, { "role": "Theme", "ref_id": "PMID-15225208_E2" } ] }, { "id": "PMID-15225208_E4", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 437, 447 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15225208_T9" }, { "role": "Theme", "ref_id": "PMID-15225208_T7" } ] }, { "id": "PMID-15225208_E5", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 820, 829 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T14" } ] }, { "id": "PMID-15225208_E6", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 894, 903 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T14" } ] }, { "id": "PMID-15225208_E7", "type": "Negative_regulation", "trigger": { "text": [ "decreasing" ], "offsets": [ [ 1332, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T20" } ] }, { "id": "PMID-15225208_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1384, 1393 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T20" } ] }, { "id": "PMID-15225208_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1488, 1497 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T22" } ] }, { "id": "PMID-15225208_E10", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 1592, 1600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_E23" } ] }, { "id": "PMID-15225208_E11", "type": "Regulation", "trigger": { "text": [ "play a significant role" ], "offsets": [ [ 1710, 1733 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15225208_T27" }, { "role": "Theme", "ref_id": "PMID-15225208_E17" } ] }, { "id": "PMID-15225208_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1745, 1755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_T29" } ] }, { "id": "PMID-15225208_E13", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1819, 1823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_E32" }, { "role": "Cause", "ref_id": "PMID-15225208_T29" } ] }, { "id": "PMID-15225208_E14", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1819, 1823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15225208_E32" }, { "role": "Cause", "ref_id": "PMID-15225208_T30" } ] }, { "id": "PMID-15225208_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1641, 1653 ] ] }, "arguments": [] } ]

[]

[ { "id": "PMID-15225208_R1", "type": "frag", "arg1_id": "PMID-15225208_T11", "arg2_id": "PMID-15225208_T12", "normalized": [] }, { "id": "PMID-15225208_R2", "type": "frag", "arg1_id": "PMID-15225208_T29", "arg2_id": "PMID-15225208_T30", "normalized": [] }, { "id": "PMID-15225208_R3", "type": "frag", "arg1_id": "PMID-15225208_T2", "arg2_id": "PMID-15225208_T3", "normalized": [] } ]

[ { "id": "PMID-19489226__text", "type": "abstract", "text": [ "[Activation of sterol regulatory element binding protein and its involvement in endothelial cell migration]\n\nOBJECTIVE: To study the activation of sterol regulatory element binding protein (SREBP) and its critical role in endothelial cell migration. METHODS: Bovine aortic endothelial cells (ECs) were cultured. The expression of SREBP and Cdc42 were determined by Western blot and quantitative real-time PCR. Moreover, outward growth migration model and transwell chamber assay were used to detect ECs migration. RESULTS: (1) SREBP was activated during ECs migration. Western blot analysis demonstrated increased active form SREBP in migrating as compared to non-migrating ECs population. SREBP activation decreased as ECs migration slowed;(2) Coincidental with SREBP activation, mRNA expression of its target genes such as low density lipoprotein receptor, HMG-CoA reductase, and fatty acid synthase also increased in migrating ECs population as detected by real-time PCR; (3) Migration induced SREBP activation in ECs was inhibited by SREBP-acting protein RNAi and pharmacologically by 25-hydroxycholesterol; (4) Inhibition of SREBP led to decreased ECs migration in various models; (5) Cells genetically deficient in SREBP-acting protein, S1P, or S2P, phenotypically exhibited impaired migration; (6) SREBP inhibition in ECs suppressed the activity of small GTPase Cdc42, a key molecule for ECs motility. CONCLUSIONS: SREBP is activated during and plays a critical role in ECs migration. Targeting SREBP could become a novel approach in fighting diseases involving abnormal ECs migration.\n" ], "offsets": [ [ 0, 1593 ] ] } ]

[ { "id": "PMID-19489226_T2", "type": "Gene_or_gene_product", "text": [ "sterol regulatory element binding protein" ], "offsets": [ [ 15, 56 ] ], "normalized": [] }, { "id": "PMID-19489226_T6", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 80, 96 ] ], "normalized": [] }, { "id": "PMID-19489226_T8", "type": "Gene_or_gene_product", "text": [ "sterol regulatory element binding protein" ], "offsets": [ [ 147, 188 ] ], "normalized": [] }, { "id": "PMID-19489226_T9", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 190, 195 ] ], "normalized": [] }, { "id": "PMID-19489226_T13", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 222, 238 ] ], "normalized": [] }, { "id": "PMID-19489226_T15", "type": "Cell", "text": [ "aortic endothelial cells" ], "offsets": [ [ 266, 290 ] ], "normalized": [] }, { "id": "PMID-19489226_T16", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 292, 295 ] ], "normalized": [] }, { "id": "PMID-19489226_T19", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 330, 335 ] ], "normalized": [] }, { "id": "PMID-19489226_T20", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 340, 345 ] ], "normalized": [] }, { "id": "PMID-19489226_T23", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 499, 502 ] ], "normalized": [] }, { "id": "PMID-19489226_T25", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "PMID-19489226_T29", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 554, 557 ] ], "normalized": [] }, { "id": "PMID-19489226_T31", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 626, 631 ] ], "normalized": [] }, { "id": "PMID-19489226_T32", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "PMID-19489226_T35", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "PMID-19489226_T39", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 720, 723 ] ], "normalized": [] }, { "id": "PMID-19489226_T42", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 763, 768 ] ], "normalized": [] }, { "id": "PMID-19489226_T46", "type": "Gene_or_gene_product", "text": [ "low density lipoprotein receptor" ], "offsets": [ [ 825, 857 ] ], "normalized": [] }, { "id": "PMID-19489226_T47", "type": "Gene_or_gene_product", "text": [ "HMG-CoA reductase" ], "offsets": [ [ 859, 876 ] ], "normalized": [] }, { "id": "PMID-19489226_T48", "type": "Gene_or_gene_product", "text": [ "fatty acid synthase" ], "offsets": [ [ 882, 901 ] ], "normalized": [] }, { "id": "PMID-19489226_T52", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 930, 933 ] ], "normalized": [] }, { "id": "PMID-19489226_T54", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 997, 1002 ] ], "normalized": [] }, { "id": "PMID-19489226_T55", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1017, 1020 ] ], "normalized": [] }, { "id": "PMID-19489226_T57", "type": "Drug_or_compound", "text": [ "25-hydroxycholesterol" ], "offsets": [ [ 1089, 1110 ] ], "normalized": [] }, { "id": "PMID-19489226_T59", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 1130, 1135 ] ], "normalized": [] }, { "id": "PMID-19489226_T63", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1153, 1156 ] ], "normalized": [] }, { "id": "PMID-19489226_T64", "type": "Gene_or_gene_product", "text": [ "SREBP-acting protein" ], "offsets": [ [ 1221, 1241 ] ], "normalized": [] }, { "id": "PMID-19489226_T65", "type": "Gene_or_gene_product", "text": [ "S1P" ], "offsets": [ [ 1243, 1246 ] ], "normalized": [] }, { "id": "PMID-19489226_T66", "type": "Gene_or_gene_product", "text": [ "S2P" ], "offsets": [ [ 1251, 1254 ] ], "normalized": [] }, { "id": "PMID-19489226_T70", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 1305, 1310 ] ], "normalized": [] }, { "id": "PMID-19489226_T71", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1325, 1328 ] ], "normalized": [] }, { "id": "PMID-19489226_T73", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1369, 1374 ] ], "normalized": [] }, { "id": "PMID-19489226_T76", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1395, 1398 ] ], "normalized": [] }, { "id": "PMID-19489226_T78", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 1422, 1427 ] ], "normalized": [] }, { "id": "PMID-19489226_T83", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1477, 1480 ] ], "normalized": [] }, { "id": "PMID-19489226_T85", "type": "Gene_or_gene_product", "text": [ "SREBP" ], "offsets": [ [ 1502, 1507 ] ], "normalized": [] }, { "id": "PMID-19489226_T89", "type": "Cell", "text": [ "ECs" ], "offsets": [ [ 1578, 1581 ] ], "normalized": [] }, { "id": "PMID-19489226_T3", "type": "Gene_or_gene_product", "text": [ "SREBP-acting protein" ], "offsets": [ [ 1038, 1058 ] ], "normalized": [] }, { "id": "PMID-19489226_T1000", "type": "Organism", "text": [ "Bovine" ], "offsets": [ [ 259, 265 ] ], "normalized": [] }, { "id": "PMID-19489226_T90", "type": "Cell", "text": [ "Cells" ], "offsets": [ [ 1190, 1195 ] ], "normalized": [] } ]

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"PMID-19489226_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 316, 326 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19489226_T20" } ] }, { "id": "PMID-19489226_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 316, 326 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19489226_T19" } ] }, { "id": "PMID-19489226_E22", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 503, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19489226_T23" } ] }, { "id": "PMID-19489226_E24", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 537, 546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19489226_T25" } ] }, { "id": "PMID-19489226_E28", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 558, 567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19489226_T29" } ] }, { "id": "PMID-19489226_E30", 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[]

[ { "id": "PMID-11912515__text", "type": "abstract", "text": [ "Upregulation of vascular endothelial growth factor receptors is associated with advanced neuroblastoma.\n\nBACKGROUND: Angiogenesis is essential for tumor growth and relies on the production of angiogenic factors. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis that binds to tyrosine kinase receptors Flt-1 and KDR. The interaction of VEGF and its receptors at gene and protein levels in neuroblastoma remains widely unknown. METHODS: Tumor biopsy specimens and serum were obtained from 37 neuroblastoma patients; adrenal biopsy sections and sera of 7 normal children served as controls. Biopsy specimens were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting; serum was analyzed by enzyme-linked immunosorbent assay (ELISA). VEGF-A(165), B, C, Flt-1, and KDR were analyzed. RESULTS: VEGF isoforms and its receptors' mRNA were expressed in neuroblastoma and control tissues. Whereas the ligands were increased in stages III and IV, the receptors were upregulated in stage III only. At protein level, VEGF-B and C, Flt-1, and KDR were not detectable in tissue lysates, whereas VEGF-A was increased in stages III and IV. Serum VEGF protein levels were upregulated in stage III. CONCLUSIONS: VEGF-A(165) is one of the major angiogenesis regulators among the ligands' family of VEGF, whereas its receptors KDR, and most probably Flt-1, may contribute to a poor prognosis (angiogenic) phenotype, as indicated by their upregulated MRNA levels in stage III neuroblastoma. VEGF-A(165) mainly contributes to increased serum VEGF levels and may serve as a diagnostic tool in advanced-stage neuroblastoma.\n" ], "offsets": [ [ 0, 1675 ] ] } ]

[ { "id": "PMID-11912515_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptors" ], "offsets": [ [ 16, 60 ] ], "normalized": [] }, { "id": "PMID-11912515_T5", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 147, 152 ] ], "normalized": [] }, { "id": "PMID-11912515_T8", "type": "Gene_or_gene_product", "text": [ "Vascular endothelial growth factor" ], "offsets": [ [ 212, 246 ] ], "normalized": [] }, { "id": "PMID-11912515_T9", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "PMID-11912515_T12", "type": "Gene_or_gene_product", "text": [ "Flt-1" ], "offsets": [ [ 331, 336 ] ], "normalized": [] }, { "id": "PMID-11912515_T13", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 341, 344 ] ], "normalized": [] }, { "id": "PMID-11912515_T15", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 365, 369 ] ], "normalized": [] }, { "id": "PMID-11912515_T17", "type": "Multi-tissue_structure", "text": [ "Tumor biopsy specimens" ], "offsets": [ [ 465, 487 ] ], "normalized": [] }, { "id": "PMID-11912515_T18", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "PMID-11912515_T19", "type": "Multi-tissue_structure", "text": [ "adrenal biopsy sections" ], "offsets": [ [ 544, 567 ] ], "normalized": [] }, { "id": "PMID-11912515_T20", "type": "Organism_substance", "text": [ "sera" ], "offsets": [ [ 572, 576 ] ], "normalized": [] }, { "id": "PMID-11912515_T21", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 741, 746 ] ], "normalized": [] }, { "id": "PMID-11912515_T22", "type": "Gene_or_gene_product", "text": [ "C" ], "offsets": [ [ 822, 823 ] ], "normalized": [] }, { "id": "PMID-11912515_T23", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 819, 820 ] ], "normalized": [] }, { "id": "PMID-11912515_T24", "type": "Gene_or_gene_product", "text": [ "VEGF-A(165)" ], "offsets": [ [ 806, 817 ] ], "normalized": [] }, { "id": "PMID-11912515_T25", "type": "Gene_or_gene_product", "text": [ "Flt-1" ], "offsets": [ [ 825, 830 ] ], "normalized": [] }, { "id": "PMID-11912515_T26", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 836, 839 ] ], "normalized": [] }, { "id": "PMID-11912515_T28", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "PMID-11912515_T29", "type": "Gene_or_gene_product", "text": [ "C" ], "offsets": [ [ 1091, 1092 ] ], "normalized": [] }, { "id": "PMID-11912515_T30", "type": "Gene_or_gene_product", "text": [ "VEGF-B" ], "offsets": [ [ 1080, 1086 ] ], "normalized": [] }, { "id": "PMID-11912515_T31", "type": "Gene_or_gene_product", "text": [ "Flt-1" ], "offsets": [ [ 1094, 1099 ] ], "normalized": [] }, { "id": "PMID-11912515_T32", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 1105, 1108 ] ], "normalized": [] }, { "id": "PMID-11912515_T33", "type": "Gene_or_gene_product", "text": [ "VEGF-A" ], "offsets": [ [ 1156, 1162 ] ], "normalized": [] }, { "id": "PMID-11912515_T35", "type": "Organism_substance", "text": [ "Serum" ], "offsets": [ [ 1199, 1204 ] ], "normalized": [] }, { "id": "PMID-11912515_T36", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1205, 1209 ] ], "normalized": [] }, { "id": "PMID-11912515_T37", "type": "Gene_or_gene_product", "text": [ "VEGF-A(165)" ], "offsets": [ [ 1269, 1280 ] ], "normalized": [] }, { "id": "PMID-11912515_T39", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1354, 1358 ] ], "normalized": [] }, { "id": "PMID-11912515_T40", "type": "Gene_or_gene_product", "text": [ "KDR" ], "offsets": [ [ 1382, 1385 ] ], "normalized": [] }, { "id": "PMID-11912515_T41", "type": "Gene_or_gene_product", "text": [ "Flt-1" ], "offsets": [ [ 1405, 1410 ] ], "normalized": [] }, { "id": "PMID-11912515_T43", "type": "Gene_or_gene_product", "text": [ "VEGF-A(165)" ], "offsets": [ [ 1545, 1556 ] ], "normalized": [] }, { "id": "PMID-11912515_T44", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1589, 1594 ] ], "normalized": [] }, { "id": "PMID-11912515_T45", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1595, 1599 ] ], "normalized": [] }, { "id": "PMID-11912515_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 534, 542 ] ], "normalized": [] }, { "id": "PMID-11912515_T1001", "type": "Organism", "text": [ "children" ], "offsets": [ [ 589, 597 ] ], "normalized": [] }, { "id": "PMID-11912515_T16", "type": "Pathological_formation", "text": [ "neuroblastoma" ], "offsets": [ [ 418, 431 ] ], "normalized": [] }, { "id": "PMID-11912515_T42", "type": "Pathological_formation", "text": [ "neuroblastoma" ], "offsets": [ [ 520, 533 ] ], "normalized": [] }, { "id": "PMID-11912515_T53", "type": "Pathological_formation", "text": [ "stage III neuroblastoma" ], "offsets": [ [ 1520, 1543 ] ], "normalized": [] }, { "id": "PMID-11912515_T38", "type": "Multi-tissue_structure", "text": [ "Biopsy specimens" ], "offsets": [ [ 618, 634 ] ], "normalized": [] }, { "id": "PMID-11912515_T46", "type": "Organism_substance", "text": [ "tissue lysates" ], "offsets": [ [ 1132, 1146 ] ], "normalized": [] }, { "id": "PMID-11912515_T57", "type": "Pathological_formation", "text": [ "neuroblastoma" ], "offsets": [ [ 920, 933 ] ], "normalized": [] }, { "id": "PMID-11912515_T58", "type": "Tissue", "text": [ "tissues" ], "offsets": [ [ 946, 953 ] ], "normalized": [] } ]

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[ { "id": "PMID-11912515_R1", "type": "frag", "arg1_id": "PMID-11912515_T29", "arg2_id": "PMID-11912515_T30", "normalized": [] }, { "id": "PMID-11912515_R2", "type": "frag", "arg1_id": "PMID-11912515_T23", "arg2_id": "PMID-11912515_T24", "normalized": [] }, { "id": "PMID-11912515_R3", "type": "frag", "arg1_id": "PMID-11912515_T22", "arg2_id": "PMID-11912515_T24", "normalized": [] } ]

[ { "id": "PMID-18313522__text", "type": "abstract", "text": [ "Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin).\n\nPURPOSE: To report on bevacizumab treatment for radiation retinopathy affecting the macula. PATIENTS AND METHODS: Twenty-one patients with radiation retinopathy (edema, hemorrhages, capillary dropout, and neovascularization) and a subjective or objective loss of vision were treated. Treatment involved intravitreal injection of bevacizumab (1.25 mg in 0.05 mL) every 6-12 weeks. Treatment was discontinued at patient request or if there was no measurable response to therapy. Main outcome measures included best corrected visual acuity, ophthalmic examination, retinal photography, and angiography. RESULTS: Bevacizumab treatment was followed by reductions in retinal hemorrhage, exudation, and edema. Visual acuities were stable or improved in 86% (n=18). Three patients discontinued therapy. Each was legally blind before treatment (n=1), experienced little to no subjective improvement (n=2), or was poorly compliant (n=2). Three patients (14%) regained 2 or more lines of visual acuity. No ocular or systemic bevacizumab-related side effects were observed. CONCLUSIONS: Intravitreal bevacizumab can be used to treat radiation retinopathy. In most cases treatment was associated with decreased vascular leakage, stabilization, or improved vision. An anti-vascular endothelial growth factor strategy may reduce tissue damage associated with radiation vasculopathy and neuropathy.\n" ], "offsets": [ [ 0, 1487 ] ] } ]

[ { "id": "PMID-18313522_T2", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 45, 79 ] ], "normalized": [] }, { "id": "PMID-18313522_T3", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 80, 91 ] ], "normalized": [] }, { "id": "PMID-18313522_T4", "type": "Drug_or_compound", "text": [ "Avastin" ], "offsets": [ [ 93, 100 ] ], "normalized": [] }, { "id": "PMID-18313522_T5", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 126, 137 ] ], "normalized": [] }, { "id": "PMID-18313522_T6", "type": "Tissue", "text": [ "macula" ], "offsets": [ [ 188, 194 ] ], "normalized": [] }, { "id": "PMID-18313522_T8", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 286, 295 ] ], "normalized": [] }, { "id": "PMID-18313522_T10", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 433, 444 ] ], "normalized": [] }, { "id": "PMID-18313522_T12", "type": "Drug_or_compound", "text": [ "Bevacizumab" ], "offsets": [ [ 713, 724 ] ], "normalized": [] }, { "id": "PMID-18313522_T15", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 1118, 1129 ] ], "normalized": [] }, { "id": "PMID-18313522_T16", "type": "Drug_or_compound", "text": [ "bevacizumab" ], "offsets": [ [ 1192, 1203 ] ], "normalized": [] }, { "id": "PMID-18313522_T17", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 1302, 1310 ] ], "normalized": [] }, { "id": "PMID-18313522_T18", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 1363, 1397 ] ], "normalized": [] }, { "id": "PMID-18313522_T1000", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 229, 237 ] ], "normalized": [] }, { "id": "PMID-18313522_T1001", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 514, 521 ] ], "normalized": [] }, { "id": "PMID-18313522_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 868, 876 ] ], "normalized": [] }, { "id": "PMID-18313522_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1038, 1046 ] ], "normalized": [] }, { "id": "PMID-18313522_T1", "type": "Gene_or_gene_product", "text": [ "anti-vascular endothelial growth factor" ], "offsets": [ [ 40, 79 ] ], "normalized": [] }, { "id": "PMID-18313522_T19", "type": "Gene_or_gene_product", "text": [ "anti-vascular endothelial growth factor" ], "offsets": [ [ 1358, 1397 ] ], "normalized": [] }, { "id": "PMID-18313522_T14", "type": "Pathological_formation", "text": [ "edema" ], "offsets": [ [ 266, 271 ] ], "normalized": [] }, { "id": "PMID-18313522_T22", "type": "Pathological_formation", "text": [ "edema" ], "offsets": [ [ 800, 805 ] ], "normalized": [] }, { "id": "PMID-18313522_T23", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 1418, 1424 ] ], "normalized": [] } ]

[ { "id": "PMID-18313522_E1", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 138, 147 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18313522_T5" } ] }, { "id": "PMID-18313522_E2", "type": "Regulation", "trigger": { "text": [ "affecting" ], "offsets": [ [ 174, 183 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18313522_E1" }, { "role": "Theme", "ref_id": "PMID-18313522_T6" } ] }, { "id": "PMID-18313522_E3", "type": "Planned_process", "trigger": { "text": [ "intravitreal injection" ], "offsets": [ [ 407, 429 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18313522_T10" } ] }, { "id": "PMID-18313522_E4", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 725, 734 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-18313522_T12" } ] }, { "id": "PMID-18313522_E5", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 1425, 1431 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18313522_T23" } ] }, { "id": "PMID-18313522_E6", "type": "Negative_regulation", "trigger": { "text": [ "reduce" ], "offsets": [ [ 1411, 1417 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18313522_E5" } ] }, { "id": "PMID-18313522_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 309, 327 ] ] }, "arguments": [] } ]

[ { "id": "PMID-18313522_1", "entity_ids": [ "PMID-18313522_T3", "PMID-18313522_T4" ] } ]

[]

[ { "id": "PMID-12869564__text", "type": "abstract", "text": [ "The role of organ vascularization and lipoplex-serum initial contact in intravenous murine lipofection.\n\nFollowing intravenous administration of cationic lipid-DNA complexes (lipoplexes) into mice, transfection (lipofection) occurs predominantly in the lungs. This was attributed to high entrapment of lipoplexes in the extended lung vascular tree. To determine whether lipofection in other organs could be enhanced by increasing the degree of vascularization, we used a transgenic mouse model with tissue-specific angiogenesis in liver. Tail vein injection of N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP)/cholesterol lipoplexes resulted in increased lipoplex entrapment in hypervascularized liver but did not boost luciferase expression, suggesting that lipoplex delivery is not a sufficient condition for efficient organ lipofection. Because the intravenously injected lipoplexes migrated within seconds to lungs, we checked whether the effects of immediate contact with serum correlate with lung lipofection efficiency of different DOTAP-based formulations. Under conditions mimicking the injection environment, the lipoplex-serum interaction was strongly dependent on helper lipid and ionic strength: lipoplexes prepared in 150 mM NaCl or lipoplexes with high ( greater than 33 mol%) cholesterol were found to aggregate immediately. This aggregation process was irreversible and was inversely correlated with the percentage of lung cells that took up lipoplexes and with the efficiency of lipofection. No other structural changes in serum were observed for cholesterol-based lipoplexes. Dioleoyl phosphatidylethanolamine-based lipoplexes were found to give low expression, apparently because of an immediate loss of integrity in serum, without lipid-DNA dissociation. Our study suggests that efficient in vivo lipofection is the result of cross-talk between lipoplex composition, interaction with serum, hemodynamics, and target tissue \"susceptibility\" to transfection.\n" ], "offsets": [ [ 0, 2000 ] ] } ]

[ { "id": "PMID-12869564_T2", "type": "Drug_or_compound", "text": [ "lipoplex" ], "offsets": [ [ 38, 46 ] ], "normalized": [] }, { "id": "PMID-12869564_T3", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 47, 52 ] ], "normalized": [] }, { "id": "PMID-12869564_T4", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 175, 185 ] ], "normalized": [] }, { "id": "PMID-12869564_T5", "type": "Organ", "text": [ "lungs" ], "offsets": [ [ 253, 258 ] ], "normalized": [] }, { "id": "PMID-12869564_T7", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 302, 312 ] ], "normalized": [] }, { "id": "PMID-12869564_T8", "type": "Multi-tissue_structure", "text": [ "lung vascular tree" ], "offsets": [ [ 329, 347 ] ], "normalized": [] }, { "id": "PMID-12869564_T13", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 531, 536 ] ], "normalized": [] }, { "id": "PMID-12869564_T14", "type": "Multi-tissue_structure", "text": [ "Tail vein" ], "offsets": [ [ 538, 547 ] ], "normalized": [] }, { "id": "PMID-12869564_T16", "type": "Drug_or_compound", "text": [ "N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP)/cholesterol lipoplexes" ], "offsets": [ [ 561, 654 ] ], "normalized": [] }, { "id": "PMID-12869564_T19", "type": "Drug_or_compound", "text": [ "lipoplex" ], "offsets": [ [ 677, 685 ] ], "normalized": [] }, { "id": "PMID-12869564_T20", "type": "Organ", "text": [ "liver" ], "offsets": [ [ 718, 723 ] ], "normalized": [] }, { "id": "PMID-12869564_T21", "type": "Drug_or_compound", "text": [ "lipoplex" ], "offsets": [ [ 781, 789 ] ], "normalized": [] }, { "id": "PMID-12869564_T22", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 897, 907 ] ], "normalized": [] }, { "id": "PMID-12869564_T23", "type": "Organ", "text": [ "lungs" ], "offsets": [ [ 935, 940 ] ], "normalized": [] }, { "id": "PMID-12869564_T24", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 999, 1004 ] ], "normalized": [] }, { "id": "PMID-12869564_T25", "type": "Organ", "text": [ "lung" ], "offsets": [ [ 1020, 1024 ] ], "normalized": [] }, { "id": "PMID-12869564_T26", "type": "Drug_or_compound", "text": [ "DOTAP" ], "offsets": [ [ 1061, 1066 ] ], "normalized": [] }, { "id": "PMID-12869564_T28", "type": "Drug_or_compound", "text": [ "lipoplex" ], "offsets": [ [ 1145, 1153 ] ], "normalized": [] }, { "id": "PMID-12869564_T29", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "PMID-12869564_T30", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 1231, 1241 ] ], "normalized": [] }, { "id": "PMID-12869564_T31", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 1269, 1279 ] ], "normalized": [] }, { "id": "PMID-12869564_T32", "type": "Drug_or_compound", "text": [ "cholesterol" ], "offsets": [ [ 1314, 1325 ] ], "normalized": [] }, { "id": "PMID-12869564_T33", "type": "Cell", "text": [ "lung cells" ], "offsets": [ [ 1457, 1467 ] ], "normalized": [] }, { "id": "PMID-12869564_T35", "type": "Drug_or_compound", "text": [ "lipoplexes" ], "offsets": [ [ 1481, 1491 ] ], "normalized": [] }, { "id": "PMID-12869564_T36", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1563, 1568 ] ], "normalized": [] }, { "id": "PMID-12869564_T37", "type": "Drug_or_compound", "text": [ "cholesterol-based lipoplexes" ], "offsets": [ [ 1587, 1615 ] ], "normalized": [] }, { "id": "PMID-12869564_T38", "type": "Drug_or_compound", "text": [ "Dioleoyl phosphatidylethanolamine-based lipoplexes" ], "offsets": [ [ 1617, 1667 ] ], "normalized": [] }, { "id": "PMID-12869564_T39", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1759, 1764 ] ], "normalized": [] }, { "id": "PMID-12869564_T40", "type": "Drug_or_compound", "text": [ "lipoplex" ], "offsets": [ [ 1888, 1896 ] ], "normalized": [] }, { "id": "PMID-12869564_T41", "type": "Organism_substance", "text": [ "serum" ], "offsets": [ [ 1927, 1932 ] ], "normalized": [] }, { "id": "PMID-12869564_T9", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 742, 752 ] ], "normalized": [] }, { "id": "PMID-12869564_T10", "type": "Drug_or_compound", "text": [ "lipid" ], "offsets": [ [ 1205, 1210 ] ], "normalized": [] }, { "id": "PMID-12869564_T1000", "type": "Organism", "text": [ "murine" ], "offsets": [ [ 84, 90 ] ], "normalized": [] }, { "id": "PMID-12869564_T1001", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "PMID-12869564_T1002", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 482, 487 ] ], "normalized": [] }, { "id": "PMID-12869564_T27", "type": "Organ", "text": [ "organs" ], "offsets": [ [ 391, 397 ] ], "normalized": [] }, { "id": "PMID-12869564_T56", "type": "Organ", "text": [ "organ" ], "offsets": [ [ 12, 17 ] ], "normalized": [] }, { "id": "PMID-12869564_T57", "type": "Organ", "text": [ "organ" ], "offsets": [ [ 843, 848 ] ], "normalized": [] }, { "id": "PMID-12869564_T60", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 499, 505 ] ], "normalized": [] }, { "id": "PMID-12869564_T61", "type": "Tissue", "text": [ "tissue" ], "offsets": [ [ 1959, 1965 ] ], "normalized": [] } ]

[ { "id": "PMID-12869564_E6", "type": "Localization", "trigger": { "text": [ "entrapment" ], "offsets": [ [ 288, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T7" }, { "role": "AtLoc", "ref_id": "PMID-12869564_T8" } ] }, { "id": "PMID-12869564_E15", "type": "Planned_process", "trigger": { "text": [ "injection" ], "offsets": [ [ 548, 557 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12869564_T16" }, { "role": "Theme", "ref_id": "PMID-12869564_T14" } ] }, { "id": "PMID-12869564_E18", "type": "Localization", "trigger": { "text": [ "entrapment" ], "offsets": [ [ 686, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T19" }, { "role": "AtLoc", "ref_id": "PMID-12869564_T20" } ] }, { "id": "PMID-12869564_E1", "type": "Planned_process", "trigger": { "text": [ "lipofection" ], "offsets": [ [ 91, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T1000" }, { "role": "Instrument", "ref_id": "PMID-12869564_T2" } ] }, { "id": "PMID-12869564_E2", "type": "Planned_process", "trigger": { "text": [ "administration" ], "offsets": [ [ 127, 141 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12869564_T4" }, { "role": "Theme", "ref_id": "PMID-12869564_T1001" } ] }, { "id": "PMID-12869564_E3", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 419, 429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_E23" } ] }, { "id": "PMID-12869564_E4", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 655, 663 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12869564_E15" }, { "role": "Theme", "ref_id": "PMID-12869564_E5" } ] }, { "id": "PMID-12869564_E5", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 667, 676 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_E18" } ] }, { "id": "PMID-12869564_E7", "type": "Positive_regulation", "trigger": { "text": [ "boost" ], "offsets": [ [ 736, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_E8" }, { "role": "Cause", "ref_id": "PMID-12869564_E15" } ] }, { "id": "PMID-12869564_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 753, 763 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T9" } ] }, { "id": "PMID-12869564_E9", "type": "Localization", "trigger": { "text": [ "delivery" ], "offsets": [ [ 790, 798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T21" } ] }, { "id": "PMID-12869564_E10", "type": "Planned_process", "trigger": { "text": [ "injected" ], "offsets": [ [ 888, 896 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12869564_T22" } ] }, { "id": "PMID-12869564_E11", "type": "Localization", "trigger": { "text": [ "migrated" ], "offsets": [ [ 908, 916 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T22" }, { "role": "ToLoc", "ref_id": "PMID-12869564_T23" } ] }, { "id": "PMID-12869564_E12", "type": "Planned_process", "trigger": { "text": [ "lipofection" ], "offsets": [ [ 1025, 1036 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T25" }, { "role": "Instrument", "ref_id": "PMID-12869564_T26" } ] }, { "id": "PMID-12869564_E14", "type": "Binding", "trigger": { "text": [ "aggregate" ], "offsets": [ [ 1340, 1349 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T32" }, { "role": "Theme", "ref_id": "PMID-12869564_T31" } ] }, { "id": "PMID-12869564_E16", "type": "Binding", "trigger": { "text": [ "aggregation" ], "offsets": [ [ 1368, 1379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T31" }, { "role": "Theme", "ref_id": "PMID-12869564_T32" } ] }, { "id": "PMID-12869564_E17", "type": "Planned_process", "trigger": { "text": [ "lipofection" ], "offsets": [ [ 1519, 1530 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12869564_T35" }, { "role": "Theme", "ref_id": "PMID-12869564_T33" } ] }, { "id": "PMID-12869564_E13", "type": "Planned_process", "trigger": { "text": [ "lipofection" ], "offsets": [ [ 370, 381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T27" } ] }, { "id": "PMID-12869564_E19", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 407, 415 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_E13" }, { "role": "Cause", "ref_id": "PMID-12869564_E3" } ] }, { "id": "PMID-12869564_E20", "type": "Planned_process", "trigger": { "text": [ "lipofection" ], "offsets": [ [ 849, 860 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12869564_T57" } ] }, { "id": "PMID-12869564_E21", "type": "Positive_regulation", "trigger": { "text": [ "sufficient" ], "offsets": [ [ 808, 818 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12869564_E9" }, { "role": "Theme", "ref_id": "PMID-12869564_E20" } ] }, { "id": "PMID-12869564_E22", "type": "Blood_vessel_development", "trigger": { "text": [ "vascularization" ], "offsets": [ [ 18, 33 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12869564_T56" } ] }, { "id": "PMID-12869564_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "vascularization" ], "offsets": [ [ 444, 459 ] ] }, "arguments": [] }, { "id": "PMID-12869564_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 515, 527 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12869564_T13" } ] } ]

[]

[]

[ { "id": "PMID-14500555__text", "type": "abstract", "text": [ "Transcriptional and post-translation regulation of the Tie1 receptor by fluid shear stress changes in vascular endothelial cells.\n\nThe interaction between the vascular endothelium and hemodynamic forces (and more specifically, fluid shear stress), induced by the flow of blood, plays a major role in vascular remodeling and in new blood vessels formation via a process termed arteriogenesis. Tie1 is an orphan tyrosine kinase receptor expressed almost exclusively in endothelial cells and is required for normal vascular development and maintenance. The present study demonstrates that Tie1 expression is rapidly down-regulated in endothelial cells exposed to shear stress, and more so to shear stress changes. This down-regulation is accompanied by a rapid cleavage of Tie1 and binding of the cleaved Tie1 45 kDa endodomain to Tie2. The rapid cleavage of Tie1 is followed by a transcriptional down-regulation in response to shear stress. The activity of the Tie1 promoter is suppressed by shear stress and by tumor necrosis factor alpha. Shear stress-induced transcriptional suppression of Tie1 is mediated by a negative shear stress response element, localized in a region of 250 bp within the promoter. The rapid down-regulation of Tie1 by shear stress changes and its rapid binding to Tie2 may be required for destabilization of endothelial cells in order to initiate the process of vascular restructuring.\n" ], "offsets": [ [ 0, 1411 ] ] } ]

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[]

[]

[ { "id": "PMID-18600526__text", "type": "abstract", "text": [ "The role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in tumor behavior.\n\nPlatelet-derived endothelial cell growth-factor (PD-ECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP). A high TP expression at tumor sites is correlated with tumor growth, induction of angiogenesis, and metastasis. Therefore, high TP is most likely associated with a poor prognosis. TP is not only expressed in tumor cells but also in tumor surrounding tissues, such as tumor infiltrating macrophages. TP catalyzes the conversion of thymidine to thymine and doxyribose-1-phosphate (dR-1-P). The latter in its parent form or in its sugar form, deoxyribose (dR) may play a role in the induction of angiogenesis. It may modulate cellular energy metabolism or be a substrate in a chemical reaction generating reactive oxygen species. L-deoxyribose (L-dR) and thymidine phosphorylase inhibitor (TPI) can reverse these effects. The mechanism of TP induction is not yet completely clear, but TNF, IL10 and other cytokines have been clearly shown to induce its expression. The various complex interactions of TP give it an essential role in cellular functioning and, hence, it is an ideal target in cancer therapy.\n" ], "offsets": [ [ 0, 1232 ] ] } ]

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[]

[ { "id": "PMID-16470244__text", "type": "abstract", "text": [ "Pericytes limit tumor cell metastasis.\n\nPreviously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role for pericytes in limiting tumor cell metastasis. These data support a new model for how tumor cells trigger metastasis by perturbing pericyte-endothelial cell-cell interactions.\n" ], "offsets": [ [ 0, 1136 ] ] } ]

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"PMID-16470244_T52" } ] }, { "id": "PMID-16470244_E1", "type": "Negative_regulation", "trigger": { "text": [ "limit" ], "offsets": [ [ 10, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_E2" }, { "role": "Cause", "ref_id": "PMID-16470244_T1" } ] }, { "id": "PMID-16470244_E3", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 148, 158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T7" }, { "role": "ToLoc", "ref_id": "PMID-16470244_T8" } ] }, { "id": "PMID-16470244_E4", "type": "Gene_expression", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 105, 115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T5" } ] }, { "id": "PMID-16470244_E5", "type": "Positive_regulation", "trigger": { "text": [ "facilitates" ], "offsets": [ [ 136, 147 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16470244_E4" }, { "role": "Theme", "ref_id": "PMID-16470244_E3" } ] }, { "id": "PMID-16470244_E6", "type": 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[ [ 617, 627 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T35" } ] }, { "id": "PMID-16470244_E11", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 714, 723 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_E13" }, { "role": "Cause", "ref_id": "PMID-16470244_E39" } ] }, { "id": "PMID-16470244_E13", "type": "Localization", "trigger": { "text": [ "metastatic" ], "offsets": [ [ 728, 738 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T41" } ] }, { "id": "PMID-16470244_E16", "type": "Localization", "trigger": { "text": [ "metastases" ], "offsets": [ [ 885, 895 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T44" }, { "role": "ToLoc", "ref_id": "PMID-16470244_T45" } ] }, { "id": "PMID-16470244_E17", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 995, 1005 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T47" } ] }, { "id": "PMID-16470244_E20", "type": "Negative_regulation", "trigger": { "text": [ "limiting" ], "offsets": [ [ 975, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_E17" } ] }, { "id": "PMID-16470244_E21", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 953, 957 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16470244_T46" }, { "role": "Theme", "ref_id": "PMID-16470244_E20" } ] }, { "id": "PMID-16470244_E23", "type": "Positive_regulation", "trigger": { "text": [ "trigger" ], "offsets": [ [ 1058, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_E24" }, { "role": "Cause", "ref_id": "PMID-16470244_E25" } ] }, { "id": "PMID-16470244_E24", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 1066, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T48" } ] }, { "id": "PMID-16470244_E25", "type": "Regulation", "trigger": { "text": [ "perturbing" ], "offsets": [ [ 1080, 1090 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16470244_T48" }, { "role": "Theme", "ref_id": "PMID-16470244_E51" } ] }, { "id": "PMID-16470244_E26", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 148, 158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T7" }, { "role": "ToLoc", "ref_id": "PMID-16470244_T70" } ] }, { "id": "PMID-16470244_E29", "type": "Positive_regulation", "trigger": { "text": [ "facilitates" ], "offsets": [ [ 136, 147 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16470244_E4" }, { "role": "Theme", "ref_id": "PMID-16470244_E26" } ] }, { "id": "PMID-16470244_E32", "type": "Localization", "trigger": { "text": [ "metastases" ], "offsets": [ [ 885, 895 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16470244_T44" }, { "role": "ToLoc", "ref_id": "PMID-16470244_T71" } ] } ]

[ { "id": "PMID-16470244_1", "entity_ids": [ "PMID-16470244_T5", "PMID-16470244_T6" ] }, { "id": "PMID-16470244_2", "entity_ids": [ "PMID-16470244_T11", "PMID-16470244_T25" ] } ]

[]

[ { "id": "PMID-17305525__text", "type": "abstract", "text": [ "New vectors and strategies for cardiovascular gene therapy.\n\nCardiovascular diseases are the major cause of morbidity and mortality in both men and women in industrially developed countries. These disorders may result from impaired angiogenesis, particularly in response to hypoxia. Despite many limitations, gene therapy is still emerging as a potential alternative for patients who are not candidates for traditional revascularization procedures, like angioplasty or vein grafts. This review focuses on recent approaches in the development of new gene delivery vectors, with great respect to newly discovered AAV serotypes and their modified forms. Moreover, some new cardiovascular gene therapy strategies have been highlighted, such as combination of different angiogenic growth factors or simultaneous application of genes and progenitor cells in order to obtain stable and functional blood vessels in ischemic tissue.\n" ], "offsets": [ [ 0, 924 ] ] } ]

[ { "id": "PMID-17305525_T8", "type": "Multi-tissue_structure", "text": [ "vein grafts" ], "offsets": [ [ 469, 480 ] ], "normalized": [] }, { "id": "PMID-17305525_T9", "type": "Drug_or_compound", "text": [ "AAV serotypes" ], "offsets": [ [ 611, 624 ] ], "normalized": [] }, { "id": "PMID-17305525_T12", "type": "Cell", "text": [ "progenitor cells" ], "offsets": [ [ 832, 848 ] ], "normalized": [] }, { "id": "PMID-17305525_T14", "type": "Multi-tissue_structure", "text": [ "blood vessels" ], "offsets": [ [ 890, 903 ] ], "normalized": [] }, { "id": "PMID-17305525_T15", "type": "Tissue", "text": [ "ischemic tissue" ], "offsets": [ [ 907, 922 ] ], "normalized": [] }, { "id": "PMID-17305525_T1000", "type": "Organism", "text": [ "men" ], "offsets": [ [ 140, 143 ] ], "normalized": [] }, { "id": "PMID-17305525_T1001", "type": "Organism", "text": [ "women" ], "offsets": [ [ 148, 153 ] ], "normalized": [] }, { "id": "PMID-17305525_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 371, 379 ] ], "normalized": [] } ]

[ { "id": "PMID-17305525_E1", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 223, 231 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17305525_E2" } ] }, { "id": "PMID-17305525_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 232, 244 ] ] }, "arguments": [] }, { "id": "PMID-17305525_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "revascularization" ], "offsets": [ [ 419, 436 ] ] }, "arguments": [] }, { "id": "PMID-17305525_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 765, 775 ] ] }, "arguments": [] }, { "id": "PMID-17305525_E4", "type": "Development", "trigger": { "text": [ "obtain" ], "offsets": [ [ 861, 867 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17305525_T14" } ] } ]

[]

[]

[ { "id": "PMID-15876269__text", "type": "abstract", "text": [ "Rofecoxib as adjunctive therapy for haemophilic arthropathy.\n\nJoint haemorrhage and subsequent haemophilic arthropathy are significant complications in haemophilia. The pathophysiology involves inflammation and angiogenesis. Cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory agents, which have potent anti-inflammatory, anti-angiogenic and analgesic properties yet do not affect platelet function in the manner of traditional non-steroidal anti-inflammatory drugs. These properties make such agents potentially useful as adjunctive therapy in haemophilia. There is only one prior report describing rofecoxib treatment in a single haemophilia patient. Our objectives were to determine the safety and efficacy of rofecoxib in treating acute haemarthrosis, chronic synovitis, target joints and pain. We conducted a retrospective medical record review of patients treated with rofecoxib for acute haemarthrosis, chronic synovitis, target joint or pain. The safety and efficacy of rofecoxib treatment were determined based on subjective patient reports and physical examinations during follow-up clinic visits. A total of 28 patients between 3 and 37 years of age were treated for a total of 42 courses of rofecoxib treatment. All courses were evaluated for safety and 31 for efficacy. Rofecoxib was used for eight acute haemarthrosis, four target joints, seven cases of synovitis and 12 episodes of pain. Efficacy was demonstrated particularly for chronic synovitis and pain and no serious adverse events occurred. This is the largest study to date evaluating COX-2 inhibitors as adjunctive therapy in haemophilia and suggests that these agents may be an important adjunctive therapy in the management of haemophilia.\n" ], "offsets": [ [ 0, 1722 ] ] } ]

[ { "id": "PMID-15876269_T1", "type": "Drug_or_compound", "text": [ "Rofecoxib" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "PMID-15876269_T2", "type": "Multi-tissue_structure", "text": [ "Joint" ], "offsets": [ [ 62, 67 ] ], "normalized": [] }, { "id": "PMID-15876269_T5", "type": "Gene_or_gene_product", "text": [ "Cyclooxygenase-2" ], "offsets": [ [ 225, 241 ] ], "normalized": [] }, { "id": "PMID-15876269_T6", "type": "Gene_or_gene_product", "text": [ "COX-2" ], "offsets": [ [ 243, 248 ] ], "normalized": [] }, { "id": "PMID-15876269_T9", "type": "Cell", "text": [ "platelet" ], "offsets": [ [ 387, 395 ] ], "normalized": [] }, { "id": "PMID-15876269_T10", "type": "Drug_or_compound", "text": [ "non-steroidal anti-inflammatory drugs" ], "offsets": [ [ 434, 471 ] ], "normalized": [] }, { "id": "PMID-15876269_T11", "type": "Drug_or_compound", "text": [ "rofecoxib" ], "offsets": [ [ 606, 615 ] ], "normalized": [] }, { "id": "PMID-15876269_T12", "type": "Drug_or_compound", "text": [ "rofecoxib" ], "offsets": [ [ 719, 728 ] ], "normalized": [] }, { "id": "PMID-15876269_T13", "type": "Multi-tissue_structure", "text": [ "joints" ], "offsets": [ [ 788, 794 ] ], "normalized": [] }, { "id": "PMID-15876269_T14", "type": "Drug_or_compound", "text": [ "rofecoxib" ], "offsets": [ [ 881, 890 ] ], "normalized": [] }, { "id": "PMID-15876269_T15", "type": "Drug_or_compound", "text": [ "rofecoxib" ], "offsets": [ [ 984, 993 ] ], "normalized": [] }, { "id": "PMID-15876269_T16", "type": "Drug_or_compound", "text": [ "rofecoxib" ], "offsets": [ [ 1209, 1218 ] ], "normalized": [] }, { "id": "PMID-15876269_T17", "type": "Drug_or_compound", "text": [ "Rofecoxib" ], "offsets": [ [ 1289, 1298 ] ], "normalized": [] }, { "id": "PMID-15876269_T18", "type": "Multi-tissue_structure", "text": [ "joints" ], "offsets": [ [ 1351, 1357 ] ], "normalized": [] }, { "id": "PMID-15876269_T20", "type": "Gene_or_gene_product", "text": [ "COX-2" ], "offsets": [ [ 1564, 1569 ] ], "normalized": [] }, { "id": "PMID-15876269_T1000", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 650, 657 ] ], "normalized": [] }, { "id": "PMID-15876269_T1001", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 859, 867 ] ], "normalized": [] }, { "id": "PMID-15876269_T1002", "type": "Organism", "text": [ "patient" ], "offsets": [ [ 1040, 1047 ] ], "normalized": [] }, { "id": "PMID-15876269_T1003", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 1128, 1136 ] ], "normalized": [] }, { "id": "PMID-15876269_T24", "type": "Multi-tissue_structure", "text": [ "joint" ], "offsets": [ [ 942, 947 ] ], "normalized": [] } ]

[ { "id": "PMID-15876269_E1", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 380, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15876269_T9" } ] }, { "id": "PMID-15876269_E2", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 616, 625 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15876269_T11" }, { "role": "Theme", "ref_id": "PMID-15876269_T1000" } ] }, { "id": "PMID-15876269_E3", "type": "Planned_process", "trigger": { "text": [ "treating" ], "offsets": [ [ 732, 740 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15876269_T12" }, { "role": "Theme", "ref_id": "PMID-15876269_T13" } ] }, { "id": "PMID-15876269_E4", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 868, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15876269_T1001" }, { "role": "Instrument", "ref_id": "PMID-15876269_T14" } ] }, { "id": "PMID-15876269_E5", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 994, 1003 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15876269_T15" }, { "role": "Theme", "ref_id": "PMID-15876269_T1002" } ] }, { "id": "PMID-15876269_E6", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1172, 1179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15876269_T1003" } ] }, { "id": "PMID-15876269_E7", "type": "Planned_process", "trigger": { "text": [ "treatment" ], "offsets": [ [ 1219, 1228 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15876269_T16" } ] }, { "id": "PMID-15876269_E8", "type": "Planned_process", "trigger": { "text": [ "used" ], "offsets": [ [ 1303, 1307 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-15876269_T17" }, { "role": "Theme", "ref_id": "PMID-15876269_T18" } ] }, { "id": "PMID-15876269_E9", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 211, 223 ] ] }, "arguments": [] }, { "id": "PMID-15876269_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 333, 343 ] ] }, "arguments": [] }, { "id": "PMID-15876269_E11", "type": "Negative_regulation", "trigger": { "text": [ "properties" ], "offsets": [ [ 358, 368 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15876269_E10" } ] } ]

[ { "id": "PMID-15876269_1", "entity_ids": [ "PMID-15876269_T6", "PMID-15876269_T5" ] } ]

[]

[ { "id": "PMID-17016553__text", "type": "abstract", "text": [ "Imaging tumor angiogenesis.\n\nSince the discovery of vascular-specific growth factors with angiogenic activity, there has been a significant effort to develop cancer drugs that restrict tumorigenesis by targeting the blood supply. In this issue of the JCI, Mancuso et al. use mouse models to better understand the plasticity of the tumor vasculature in the face of antiangiogenic therapy (see the related article beginning on page 2610). They describe a rapid regrowth of the tumor vasculature following withdrawal of VEGFR inhibitors, emphasizing the importance of fully understanding the function of these and similar treatments used in the clinic at the cellular and molecular level.\n" ], "offsets": [ [ 0, 686 ] ] } ]

[ { "id": "PMID-17016553_T1", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 8, 13 ] ], "normalized": [] }, { "id": "PMID-17016553_T3", "type": "Gene_or_gene_product", "text": [ "vascular-specific growth factors" ], "offsets": [ [ 52, 84 ] ], "normalized": [] }, { "id": "PMID-17016553_T4", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 216, 221 ] ], "normalized": [] }, { "id": "PMID-17016553_T6", "type": "Multi-tissue_structure", "text": [ "tumor vasculature" ], "offsets": [ [ 331, 348 ] ], "normalized": [] }, { "id": "PMID-17016553_T9", "type": "Multi-tissue_structure", "text": [ "tumor vasculature" ], "offsets": [ [ 475, 492 ] ], "normalized": [] }, { "id": "PMID-17016553_T11", "type": "Gene_or_gene_product", "text": [ "VEGFR" ], "offsets": [ [ 517, 522 ] ], "normalized": [] }, { "id": "PMID-17016553_T1000", "type": "Organism", "text": [ "mouse" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-17016553_T5", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 158, 164 ] ], "normalized": [] } ]

[ { "id": "PMID-17016553_E2", "type": "Growth", "trigger": { "text": [ "regrowth" ], "offsets": [ [ 459, 467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17016553_T9" } ] }, { "id": "PMID-17016553_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 14, 26 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17016553_T1" } ] }, { "id": "PMID-17016553_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 368, 378 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-8686754__text", "type": "abstract", "text": [ "Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin.\n\nWe have identified several mechanisms by which the angiogenic cytokine vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) likely regulates endothelial cells (EC) migration. VPF/VEGF induced dermal microvascular EC expression of mRNAs encoding the alphav and beta3 integrin subunits resulting in increased levels of the alphavbeta3 heterodimer at the cell surface, and VPF/VEGF also induced mRNA encoding osteopontin (OPN), an alphavbeta3 ligand. OPN promoted EC migration in vitro; and VPF/VEGF induction of alphavbeta3 was accompanied by increased EC migration toward OPN. Because thrombin cleavage of OPN results in substantial enhancement of OPN's adhesive properties, and because VPF/VEGF promotes increased microvascular permeability leading to activation of the extrinsic coagulation pathway, we also investigated whether VPF/VEGF facilitates thrombin cleavage of OPN in vivo. Consistent with this hypothesis, co-injection of VPF/VEGF together with OPN resulted in rapid cleavage of OPN by endogenous thrombin. Furthermore, in comparison with native OPN, thrombin-cleaved OPN stimulated a greater rate of EC migration in vitro, which was additive to the increased migration associated with induction of alpha v beta 3. Thus, these data demonstrate cooperative mechanisms for VPF/VEGF regulation of EC migration involving the alphavbeta3 integrin, the alphavbeta3 ligand OPN, and thrombin cleavage of OPN. These findings also illustrate an operational link between VPF/VEGF induction of EC gene expression and VPF/VEGF enhancement of microvascular permeability, suggesting that these distinct biological activities may act accordingly to stimulate EC migration during angiogenesis.\n" ], "offsets": [ [ 0, 1915 ] ] } ]

[ { "id": "PMID-8686754_T3", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 15, 31 ] ], "normalized": [] }, { "id": "PMID-8686754_T4", "type": "Gene_or_gene_product", "text": [ "vascular permeability factor" ], "offsets": [ [ 45, 73 ] ], "normalized": [] }, { "id": "PMID-8686754_T5", "type": "Gene_or_gene_product", "text": [ "alphavbeta3 integrin" ], "offsets": [ [ 154, 174 ] ], "normalized": [] }, { "id": "PMID-8686754_T6", "type": "Gene_or_gene_product", "text": [ "osteopontin" ], "offsets": [ [ 176, 187 ] ], "normalized": [] }, { "id": "PMID-8686754_T7", "type": "Gene_or_gene_product", "text": [ "thrombin" ], "offsets": [ [ 193, 201 ] ], "normalized": [] }, { "id": "PMID-8686754_T9", "type": "Gene_or_gene_product", "text": [ "vascular permeability factor" ], "offsets": [ [ 275, 303 ] ], "normalized": [] }, { "id": "PMID-8686754_T10", "type": "Gene_or_gene_product", "text": [ "VPF" ], "offsets": [ [ 340, 343 ] ], "normalized": [] }, { "id": "PMID-8686754_T14", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 367, 384 ] ], "normalized": [] }, { "id": "PMID-8686754_T15", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 386, 388 ] ], "normalized": [] }, { "id": "PMID-8686754_T16", "type": "Gene_or_gene_product", "text": [ "VPF" ], "offsets": [ [ 401, 404 ] ], "normalized": [] }, { "id": "PMID-8686754_T19", "type": "Cell", "text": [ "microvascular EC" ], "offsets": [ [ 425, 441 ] ], "normalized": [] }, { "id": "PMID-8686754_T21", "type": "Gene_or_gene_product", "text": [ "alphav" ], "offsets": [ [ 475, 481 ] ], "normalized": [] }, { "id": "PMID-8686754_T22", "type": "Gene_or_gene_product", "text": [ "beta3 integrin subunits" ], "offsets": [ [ 486, 509 ] ], "normalized": [] }, { "id": "PMID-8686754_T24", "type": "Gene_or_gene_product", "text": [ "alphavbeta3" ], "offsets": [ [ 547, 558 ] ], "normalized": [] }, { "id": "PMID-8686754_T25", "type": "Gene_or_gene_product", "text": [ "VPF" ], "offsets": [ [ 596, 599 ] ], "normalized": [] }, { "id": "PMID-8686754_T27", "type": "Gene_or_gene_product", "text": [ "osteopontin" ], "offsets": [ [ 632, 643 ] ], "normalized": [] }, { "id": "PMID-8686754_T28", "type": "Gene_or_gene_product", "text": [ "OPN" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "PMID-8686754_T29", "type": "Gene_or_gene_product", "text": [ "alphavbeta3" ], "offsets": [ [ 654, 665 ] ], "normalized": [] }, { "id": "PMID-8686754_T30", "type": "Gene_or_gene_product", "text": [ "OPN" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "PMID-8686754_T34", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 687, 689 ] ], "normalized": [] }, { "id": "PMID-8686754_T35", "type": "Gene_or_gene_product", "text": [ "VPF" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "PMID-8686754_T37", "type": "Gene_or_gene_product", "text": [ "alphavbeta3" ], "offsets": [ [ 736, 747 ] ], "normalized": [] }, { "id": "PMID-8686754_T42", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 777, 779 ] ], 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[ { "id": "PMID-17157465__text", "type": "abstract", "text": [ "Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer.\n\nThe last 7 years have seen over seven times as many publications indexed by Medline dealing with pomegranate and Punica granatum than in all the years preceding them. Because of this, and the virtual explosion of interest in pomegranate as a medicinal and nutritional product that has followed, this review is accordingly launched. The pomegranate tree, Punica granatum, especially its fruit, possesses a vast ethnomedical history and represents a phytochemical reservoir of heuristic medicinal value. The tree/fruit can be divided into several anatomical compartments: (1) seed, (2) juice, (3) peel, (4) leaf, (5) flower, (6) bark, and (7) roots, each of which has interesting pharmacologic activity. Juice and peels, for example, possess potent antioxidant properties, while juice, peel and oil are all weakly estrogenic and heuristically of interest for the treatment of menopausal symptoms and sequellae. The use of juice, peel and oil have also been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasion and angiogenesis. These may be associated with plant based anti-inflammatory effects, The phytochemistry and pharmacological actions of all Punica granatum components suggest a wide range of clinical applications for the treatment and prevention of cancer, as well as other diseases where chronic inflammation is believed to play an essential etiologic role.\n" ], "offsets": [ [ 0, 1535 ] ] } ]

[ { "id": "PMID-17157465_T1", "type": "Organism_substance", "text": [ "juice" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "PMID-17157465_T2", "type": "Tissue", "text": [ "peel" ], "offsets": [ [ 701, 705 ] ], "normalized": [] }, { "id": "PMID-17157465_T3", "type": "Organism_substance", "text": [ "Juice" ], "offsets": [ [ 808, 813 ] ], "normalized": [] }, { "id": "PMID-17157465_T4", "type": "Tissue", "text": [ "peels" ], "offsets": [ [ 818, 823 ] ], "normalized": [] }, { "id": "PMID-17157465_T5", "type": "Organism_substance", "text": [ "juice" ], "offsets": [ [ 883, 888 ] ], "normalized": [] }, { "id": "PMID-17157465_T6", "type": "Tissue", "text": [ "peel" ], "offsets": [ [ 890, 894 ] ], "normalized": [] }, { "id": "PMID-17157465_T7", "type": "Organism_substance", "text": [ "oil" ], "offsets": [ [ 899, 902 ] ], "normalized": [] }, { "id": "PMID-17157465_T8", "type": "Organism_substance", "text": [ "juice" ], "offsets": [ [ 1026, 1031 ] ], "normalized": [] }, { "id": "PMID-17157465_T9", "type": "Tissue", "text": [ "peel" ], "offsets": [ [ 1033, 1037 ] ], "normalized": [] }, { "id": "PMID-17157465_T10", "type": "Organism_substance", "text": [ "oil" ], "offsets": [ [ 1042, 1045 ] ], "normalized": [] }, { "id": "PMID-17157465_T12", "type": "Cell", "text": [ "tumor cell" ], "offsets": [ [ 1129, 1139 ] ], "normalized": [] }, { "id": "PMID-17157465_T11", "type": "Developing_anatomical_structure", "text": [ "seed" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-17157465_T13", "type": "Organ", "text": [ "leaf" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-17157465_T15", "type": "Organism_subdivision", "text": [ "flower" ], "offsets": [ [ 721, 727 ] ], "normalized": [] }, { "id": "PMID-17157465_T16", "type": "Tissue", "text": [ "bark" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-17157465_T17", "type": "Organ", "text": [ "roots" ], "offsets": [ [ 747, 752 ] ], "normalized": [] }, { "id": "PMID-17157465_T1000", "type": "Organism", "text": [ "Punica granatum" ], "offsets": [ [ 0, 15 ] ], "normalized": [] }, { "id": "PMID-17157465_T1001", "type": "Organism", "text": [ "Punica granatum" ], "offsets": [ [ 219, 234 ] ], "normalized": [] }, { "id": "PMID-17157465_T1002", "type": "Organism", "text": [ "Punica granatum" ], "offsets": [ [ 460, 475 ] ], "normalized": [] }, { "id": "PMID-17157465_T1003", "type": "Organism", "text": [ "Punica granatum" ], "offsets": [ [ 1316, 1331 ] ], "normalized": [] }, { "id": "PMID-17157465_T18", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 97, 103 ] ], "normalized": [] }, { "id": "PMID-17157465_T19", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] } ]

[ { "id": "PMID-17157465_E1", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 1140, 1153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17157465_T12" } ] }, { "id": "PMID-17157465_E2", "type": "Localization", "trigger": { "text": [ "invasion" ], "offsets": [ [ 1167, 1175 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17157465_T12" } ] }, { "id": "PMID-17157465_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1180, 1192 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-12405260__text", "type": "abstract", "text": [ "Brn-3a, a neuronal transcription factor of the POU gene family: indications for its involvement in cancer and angiogenesis.\n\nBrn-3a, a member of the POU gene family (so-called because of the similarity with the group of transcription factors Pit, Oct, and Unc), was found in neuronal cells engaged in the transcription activity of the p1 and p2 promoters of the most powerful antiapoptotic gene, namely, Bcl-2. The alternative splicing of Brn-3a mRNA produces two molecular forms: a longer, Bcl-2 transactivating form, and a shorter inactive form, lacking 84 AA in the aminoterminus. In neuronal cells, following Brn-3a gene transfection and superexpression, an increase of 30 fold of the Bcl-2 protein occurs, leading to apoptosis protection. However, recent works demonstrate that Brn-3a expression is not restricted to neuronal cells, as its activity was detected also in cancer cells of non-neuronal nature. Looking for mechanisms linking Brn-3a to carcinogenesis, we discuss the role of this transcription factor in influencing Bcl-2/p53 antagonism and Bcl-2/VEGF induction of tumor angiogenesis, concluding this review with a proposal for the oncogenic nature of Brn-3a.\n" ], "offsets": [ [ 0, 1177 ] ] } ]

[ { "id": "PMID-12405260_T1", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-12405260_T5", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 125, 131 ] ], "normalized": [] }, { "id": "PMID-12405260_T7", "type": "Gene_or_gene_product", "text": [ "Pit" ], "offsets": [ [ 242, 245 ] ], "normalized": [] }, { "id": "PMID-12405260_T8", "type": "Gene_or_gene_product", "text": [ "Oct" ], "offsets": [ [ 247, 250 ] ], "normalized": [] }, { "id": "PMID-12405260_T9", "type": "Gene_or_gene_product", "text": [ "Unc" ], "offsets": [ [ 256, 259 ] ], "normalized": [] }, { "id": "PMID-12405260_T10", "type": "Cell", "text": [ "neuronal cells" ], "offsets": [ [ 275, 289 ] ], "normalized": [] }, { "id": "PMID-12405260_T11", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 404, 409 ] ], "normalized": [] }, { "id": "PMID-12405260_T13", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 439, 445 ] ], "normalized": [] }, { "id": "PMID-12405260_T14", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 491, 496 ] ], "normalized": [] }, { "id": "PMID-12405260_T15", "type": "Cell", "text": [ "neuronal cells" ], "offsets": [ [ 587, 601 ] ], "normalized": [] }, { "id": "PMID-12405260_T18", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 613, 619 ] ], "normalized": [] }, { "id": "PMID-12405260_T20", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 689, 694 ] ], "normalized": [] }, { "id": "PMID-12405260_T22", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 783, 789 ] ], "normalized": [] }, { "id": "PMID-12405260_T23", "type": "Cell", "text": [ "neuronal cells" ], "offsets": [ [ 822, 836 ] ], "normalized": [] }, { "id": "PMID-12405260_T24", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 875, 887 ] ], "normalized": [] }, { "id": "PMID-12405260_T25", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 943, 949 ] ], "normalized": [] }, { "id": "PMID-12405260_T28", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1033, 1038 ] ], "normalized": [] }, { "id": "PMID-12405260_T29", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1039, 1042 ] ], "normalized": [] }, { "id": "PMID-12405260_T32", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1058, 1063 ] ], "normalized": [] }, { "id": "PMID-12405260_T33", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1064, 1068 ] ], "normalized": [] }, { "id": "PMID-12405260_T35", "type": "Gene_or_gene_product", "text": [ "Brn-3a" ], "offsets": [ [ 1169, 1175 ] ], "normalized": [] }, { "id": "PMID-12405260_T3", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 99, 105 ] ], "normalized": [] }, { "id": "PMID-12405260_T36", "type": "DNA_domain_or_region", "text": [ "p1" ], "offsets": [ [ 335, 337 ] ], "normalized": [] }, { "id": "PMID-12405260_T37", "type": "DNA_domain_or_region", "text": [ "p2 promoters" ], "offsets": [ [ 342, 354 ] ], "normalized": [] }, { "id": "PMID-12405260_T30", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 1082, 1087 ] ], "normalized": [] } ]

[ { "id": "PMID-12405260_E16", "type": "Gene_expression", "trigger": { "text": [ "superexpression" ], "offsets": [ [ 642, 657 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T18" } ] }, { "id": "PMID-12405260_E17", "type": "Planned_process", "trigger": { "text": [ "transfection" ], "offsets": [ [ 625, 637 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-12405260_T18" }, { "role": "Theme", "ref_id": "PMID-12405260_T15" } ] }, { "id": "PMID-12405260_E19", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 662, 670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T20" } ] }, { "id": "PMID-12405260_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 790, 800 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T22" } ] }, { "id": "PMID-12405260_E27", "type": "Negative_regulation", "trigger": { "text": [ "antagonism" ], "offsets": [ [ 1043, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T29" } ] }, { "id": "PMID-12405260_E31", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1069, 1078 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E25" }, { "role": "Cause", "ref_id": "PMID-12405260_T33" } ] }, { "id": "PMID-12405260_E1", "type": "Regulation", "trigger": { "text": [ "engaged" ], "offsets": [ [ 290, 297 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E2" }, { "role": "Cause", "ref_id": "PMID-12405260_T5" }, { "role": "Site", "ref_id": "PMID-12405260_T36" } ] }, { "id": "PMID-12405260_E2", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 305, 318 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T11" } ] }, { "id": "PMID-12405260_E3", "type": "Regulation", "trigger": { "text": [ "engaged" ], "offsets": [ [ 290, 297 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E2" }, { "role": "Cause", "ref_id": "PMID-12405260_T5" }, { "role": "Site", "ref_id": "PMID-12405260_T37" } ] }, { "id": "PMID-12405260_E4", "type": "Gene_expression", "trigger": { "text": [ "produces" ], "offsets": [ [ 451, 459 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T13" } ] }, { "id": "PMID-12405260_E5", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 722, 731 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T15" } ] }, { "id": "PMID-12405260_E6", "type": "Negative_regulation", "trigger": { "text": [ "protection" ], "offsets": [ [ 732, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E5" } ] }, { "id": "PMID-12405260_E7", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 711, 718 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E6" }, { "role": "Cause", "ref_id": "PMID-12405260_E19" } ] }, { "id": "PMID-12405260_E8", "type": "Negative_regulation", "trigger": { "text": [ "restricted" ], "offsets": [ [ 808, 818 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E21" } ] }, { "id": "PMID-12405260_E9", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 984, 988 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12405260_T25" }, { "role": "Theme", "ref_id": "PMID-12405260_E18" } ] }, { "id": "PMID-12405260_E10", "type": "Negative_regulation", "trigger": { "text": [ "influencing" ], "offsets": [ [ 1021, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E27" } ] }, { "id": "PMID-12405260_E11", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1069, 1078 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E25" }, { "role": "Cause", "ref_id": "PMID-12405260_T32" } ] }, { "id": "PMID-12405260_E13", "type": "Negative_regulation", "trigger": { "text": [ "antagonism" ], "offsets": [ [ 1043, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_T28" } ] }, { "id": "PMID-12405260_E14", "type": "Negative_regulation", "trigger": { "text": [ "influencing" ], "offsets": [ [ 1021, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E31" } ] }, { "id": "PMID-12405260_E15", "type": "Negative_regulation", "trigger": { "text": [ "influencing" ], "offsets": [ [ 1021, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E11" } ] }, { "id": "PMID-12405260_E18", "type": "Negative_regulation", "trigger": { "text": [ "influencing" ], "offsets": [ [ 1021, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12405260_E13" } ] }, { "id": "PMID-12405260_E20", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 984, 988 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12405260_T25" }, { "role": "Theme", "ref_id": "PMID-12405260_E10" } ] }, { "id": "PMID-12405260_E22", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 984, 988 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12405260_T25" }, { "role": "Theme", "ref_id": "PMID-12405260_E15" } ] }, { "id": "PMID-12405260_E23", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 984, 988 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12405260_T25" }, { "role": "Theme", "ref_id": "PMID-12405260_E14" } ] }, { "id": "PMID-12405260_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 110, 122 ] ] }, "arguments": [] }, { "id": "PMID-12405260_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1088, 1100 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12405260_T30" } ] } ]

[]

[]

[ { "id": "PMID-19700757__text", "type": "abstract", "text": [ "A key role for the integrin alpha2beta1 in experimental and developmental angiogenesis.\n\nThe alpha2beta1 integrin receptor plays a key role in angiogenesis. Here we investigated the effects of small molecule inhibitors (SMIs) designed to disrupt integrin alpha2 I or beta1 I-like domain function on angiogenesis. In unchallenged endothelial cells, fibrillar collagen induced robust capillary morphogenesis. In contrast, tube formation was significantly reduced by SMI496, a beta1 I-like domain inhibitor and by function-blocking anti-alpha2beta1 but not -alpha1beta1 antibodies. Endothelial cells bound fluorescein-labeled collagen I fibrils, an interaction specifically inhibited by SMI496. Moreover, SMI496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound healing. SMI activities were examined in vivo by supplementing the growth medium of zebrafish embryos expressing green fluorescent protein under the control of the vascular endothelial growth factor receptor-2 promoter. SMI496, but not a control compound, interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels. We further characterized zebrafish alpha2 integrin and discovered that this integrin is highly conserved, especially the I domain. Notably, a similar vascular phenotype was induced by morpholino-mediated knockdown of the integrin alpha2 subunit. By live videomicroscopy, we confirmed that the vessels were largely nonfunctional in the absence of alpha2beta1 integrin. Collectively, our results provide strong biochemical and genetic evidence of a central role for alpha2beta1 integrin in experimental and developmental angiogenesis.\n" ], "offsets": [ [ 0, 1706 ] ] } ]

[ { "id": "PMID-19700757_T1", "type": "Gene_or_gene_product", "text": [ "integrin alpha2beta1" ], "offsets": [ [ 19, 39 ] ], "normalized": [] }, { "id": "PMID-19700757_T3", "type": "Gene_or_gene_product", "text": [ "alpha2beta1 integrin receptor" ], "offsets": [ [ 93, 122 ] ], "normalized": [] }, { "id": "PMID-19700757_T6", "type": "Gene_or_gene_product", "text": [ "integrin alpha2" ], "offsets": [ [ 246, 261 ] ], "normalized": [] }, { "id": "PMID-19700757_T8", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 329, 346 ] ], "normalized": [] }, { "id": "PMID-19700757_T9", "type": "Gene_or_gene_product", "text": [ "fibrillar collagen" ], "offsets": [ [ 348, 366 ] ], "normalized": [] }, { "id": "PMID-19700757_T12", "type": "Tissue", "text": [ "capillary" ], "offsets": [ [ 382, 391 ] ], "normalized": [] }, { "id": "PMID-19700757_T14", "type": "Tissue", "text": [ "tube" ], "offsets": [ [ 420, 424 ] ], "normalized": [] }, { "id": "PMID-19700757_T16", "type": "Drug_or_compound", "text": [ "SMI496" ], "offsets": [ [ 464, 470 ] ], "normalized": [] }, { "id": "PMID-19700757_T17", "type": "Gene_or_gene_product", "text": [ "beta1" ], "offsets": [ [ 474, 479 ] ], "normalized": [] }, { "id": "PMID-19700757_T18", "type": "Drug_or_compound", "text": [ "anti-alpha2beta1" ], "offsets": [ [ 529, 545 ] ], "normalized": [] }, { "id": "PMID-19700757_T19", "type": "Drug_or_compound", "text": [ "-alpha1beta1 antibodies" ], "offsets": [ [ 554, 577 ] ], "normalized": [] }, { "id": "PMID-19700757_T22", "type": "Cell", "text": [ "Endothelial cells" ], "offsets": [ [ 579, 596 ] ], "normalized": [] }, { "id": "PMID-19700757_T23", "type": "Gene_or_gene_product", "text": [ "collagen I fibrils" ], "offsets": [ [ 623, 641 ] ], "normalized": [] }, { "id": "PMID-19700757_T24", "type": "Drug_or_compound", "text": [ "SMI496" ], "offsets": [ [ 684, 690 ] ], "normalized": [] }, { "id": "PMID-19700757_T25", "type": "Drug_or_compound", "text": [ "SMI496" ], "offsets": [ [ 702, 708 ] ], "normalized": [] }, { "id": "PMID-19700757_T26", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 761, 778 ] ], "normalized": [] }, { "id": "PMID-19700757_T28", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 798, 814 ] ], "normalized": [] }, { "id": "PMID-19700757_T29", "type": "Developing_anatomical_structure", "text": [ "embryos" ], "offsets": [ [ 915, 922 ] ], "normalized": [] }, { "id": "PMID-19700757_T30", "type": "Gene_or_gene_product", "text": [ "green fluorescent protein" ], "offsets": [ [ 934, 959 ] ], "normalized": [] }, { "id": "PMID-19700757_T31", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor receptor-2" ], "offsets": [ [ 985, 1030 ] ], "normalized": [] }, { "id": "PMID-19700757_T32", "type": "Drug_or_compound", "text": [ "SMI496" ], "offsets": [ [ 1041, 1047 ] ], "normalized": [] }, { "id": "PMID-19700757_T36", "type": "Multi-tissue_structure", "text": [ "axial vessels" ], "offsets": [ [ 1158, 1171 ] ], "normalized": [] }, { "id": "PMID-19700757_T37", "type": "Gene_or_gene_product", "text": [ "alpha2 integrin" ], "offsets": [ [ 1208, 1223 ] ], "normalized": [] }, { "id": "PMID-19700757_T39", "type": "Gene_or_gene_product", "text": [ "integrin alpha2" ], "offsets": [ [ 1394, 1409 ] ], "normalized": [] }, { "id": "PMID-19700757_T40", "type": "Multi-tissue_structure", "text": [ "vessels" ], "offsets": [ [ 1466, 1473 ] ], "normalized": [] }, { "id": "PMID-19700757_T41", "type": "Gene_or_gene_product", "text": [ "alpha2beta1 integrin" ], "offsets": [ [ 1519, 1539 ] ], "normalized": [] }, { "id": "PMID-19700757_T43", "type": "Gene_or_gene_product", "text": [ "alpha2beta1 integrin" ], "offsets": [ [ 1637, 1657 ] ], "normalized": [] }, { "id": "PMID-19700757_T4", "type": "Gene_or_gene_product", "text": [ "beta1" ], "offsets": [ [ 267, 272 ] ], "normalized": [] }, { "id": "PMID-19700757_T42", "type": "Gene_or_gene_product", "text": [ "integrin" ], "offsets": [ [ 1249, 1257 ] ], "normalized": [] }, { "id": "PMID-19700757_T1000", "type": "Organism", "text": [ "zebrafish" ], "offsets": [ [ 905, 914 ] ], "normalized": [] }, { "id": "PMID-19700757_T1001", "type": "Organism", "text": [ "zebrafish" ], "offsets": [ [ 1198, 1207 ] ], "normalized": [] }, { "id": "PMID-19700757_T33", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1031, 1039 ] ], "normalized": [] }, { "id": "PMID-19700757_T61", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 716, 720 ] ], "normalized": [] } ]

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"trigger": { "text": [ "unchallenged" ], "offsets": [ [ 316, 328 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T8" } ] }, { "id": "PMID-19700757_E3", "type": "Development", "trigger": { "text": [ "morphogenesis" ], "offsets": [ [ 392, 405 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T12" } ] }, { "id": "PMID-19700757_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 367, 374 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19700757_T9" }, { "role": "Theme", "ref_id": "PMID-19700757_E3" } ] }, { "id": "PMID-19700757_E5", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 425, 434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T14" } ] }, { "id": "PMID-19700757_E6", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 453, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_E5" }, { "role": "Cause", "ref_id": "PMID-19700757_T16" } ] }, { "id": "PMID-19700757_E7", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 453, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_E5" }, { "role": "Cause", "ref_id": "PMID-19700757_T18" } ] }, { "id": "PMID-19700757_E8", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 453, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_E5" }, { "role": "Cause", "ref_id": "PMID-19700757_T19" } ] }, { "id": "PMID-19700757_E9", "type": "Planned_process", "trigger": { "text": [ "labeled" ], "offsets": [ [ 615, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T23" } ] }, { "id": "PMID-19700757_E10", "type": "Death", "trigger": { "text": [ "cytoskeletal collapse" ], "offsets": [ [ 736, 757 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T26" } ] }, { "id": "PMID-19700757_E12", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 709, 715 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19700757_T25" }, { "role": "Theme", "ref_id": "PMID-19700757_E10" } ] }, { "id": "PMID-19700757_E14", "type": "Negative_regulation", "trigger": { "text": [ "delayed" ], "offsets": [ [ 790, 797 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T28" }, { "role": "Cause", "ref_id": "PMID-19700757_T25" } ] }, { "id": "PMID-19700757_E15", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 923, 933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T30" } ] }, { "id": "PMID-19700757_E16", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 970, 977 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19700757_T31" }, { "role": "CSite", "ref_id": "PMID-19700757_T33" }, { "role": "Theme", "ref_id": "PMID-19700757_E15" } ] }, { "id": "PMID-19700757_E17", "type": "Negative_regulation", "trigger": { "text": [ "interfered" ], "offsets": [ [ 1077, 1087 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_E26" }, { "role": "Cause", "ref_id": "PMID-19700757_E19" } ] }, { "id": "PMID-19700757_E18", "type": "Development", "trigger": { "text": [ "sprouting" ], "offsets": [ [ 1139, 1148 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_T36" } ] }, { "id": "PMID-19700757_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1128, 1138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19700757_E18" }, { "role": "Cause", "ref_id": "PMID-19700757_T32" } ] }, { "id": "PMID-19700757_E22", "type": "Regulation", "trigger": { "text": [ "central role" ], "offsets": [ [ 1620, 1632 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19700757_T43" }, { "role": "Theme", "ref_id": "PMID-19700757_E28" } ] }, { "id": "PMID-19700757_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 74, 86 ] ] }, "arguments": [] }, { "id": "PMID-19700757_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 143, 155 ] ] }, "arguments": [] }, { "id": "PMID-19700757_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 299, 311 ] ] }, "arguments": [] }, { "id": "PMID-19700757_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1093, 1105 ] ] }, "arguments": [] }, { "id": "PMID-19700757_E28", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1692, 1704 ] ] }, "arguments": [] } ]

[]

[ { "id": "PMID-19700757_R1", "type": "frag", "arg1_id": "PMID-19700757_T4", "arg2_id": "PMID-19700757_T6", "normalized": [] } ]

[ { "id": "PMID-1388088__text", "type": "abstract", "text": [ "Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat.\n\nInterleukin-1 (IL-1) synthesis in the brain is stimulated by mechanical injury and IL-1 mimics some effects of injury, such as gliosis and neovascularization. We report that neuronal death resulting from focal cerebral ischaemia (middle cerebral artery occlusion, 24 h) is significantly inhibited (by 50%) in rats injected with a recombinant IL-1 receptor antagonist (IL-1ra, 10 micrograms, icv 30 min before and 10 min after ischaemia). Excitotoxic damage due to striatal infusion of an NMDA-receptor agonist (cis-2,4-methanoglutamate) was also markedly inhibited (71%) by injection of the IL-1ra. These data indicate that endogenous IL-1 is a mediator of ischaemic and excitotoxic brain damage, and that inhibitors of IL-1 action may be of therapeutic value in the treatment of acute or chronic neuronal death.\n" ], "offsets": [ [ 0, 911 ] ] } ]

[ { "id": "PMID-1388088_T1", "type": "Gene_or_gene_product", "text": [ "Interleukin-1 receptor antagonist" ], "offsets": [ [ 0, 33 ] ], "normalized": [] }, { "id": "PMID-1388088_T5", "type": "Cell", "text": [ "neuronal" ], "offsets": [ [ 69, 77 ] ], "normalized": [] }, { "id": "PMID-1388088_T7", "type": "Gene_or_gene_product", "text": [ "Interleukin-1" ], "offsets": [ [ 98, 111 ] ], "normalized": [] }, { "id": "PMID-1388088_T8", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 113, 117 ] ], "normalized": [] }, { "id": "PMID-1388088_T9", "type": "Organ", "text": [ "brain" ], "offsets": [ [ 136, 141 ] ], "normalized": [] }, { "id": "PMID-1388088_T10", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 181, 185 ] ], "normalized": [] }, { "id": "PMID-1388088_T14", "type": "Cell", "text": [ "neuronal" ], "offsets": [ [ 272, 280 ] ], "normalized": [] }, { "id": "PMID-1388088_T16", "type": "Multi-tissue_structure", "text": [ "cerebral artery" ], "offsets": [ [ 335, 350 ] ], "normalized": [] }, { "id": "PMID-1388088_T18", "type": "Gene_or_gene_product", "text": [ "IL-1 receptor antagonist" ], "offsets": [ [ 440, 464 ] ], "normalized": [] }, { "id": "PMID-1388088_T20", "type": "Gene_or_gene_product", "text": [ "IL-1ra" ], "offsets": [ [ 466, 472 ] ], "normalized": [] }, { "id": "PMID-1388088_T22", "type": "Drug_or_compound", "text": [ "NMDA" ], "offsets": [ [ 586, 590 ] ], "normalized": [] }, { "id": "PMID-1388088_T23", "type": "Drug_or_compound", "text": [ "cis-2,4-methanoglutamate" ], "offsets": [ [ 609, 633 ] ], "normalized": [] }, { "id": "PMID-1388088_T24", "type": "Gene_or_gene_product", "text": [ "IL-1ra" ], "offsets": [ [ 689, 695 ] ], "normalized": [] }, { "id": "PMID-1388088_T25", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-1388088_T27", "type": "Organ", "text": [ "brain" ], "offsets": [ [ 781, 786 ] ], "normalized": [] }, { "id": "PMID-1388088_T28", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-1388088_T30", "type": "Cell", "text": [ "neuronal" ], "offsets": [ [ 895, 903 ] ], "normalized": [] }, { "id": "PMID-1388088_T1000", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 92, 95 ] ], "normalized": [] }, { "id": "PMID-1388088_T1001", "type": "Organism", "text": [ "rats" ], "offsets": [ [ 407, 411 ] ], "normalized": [] } ]

[ { "id": "PMID-1388088_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 34, 42 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_E4" }, { "role": "Cause", "ref_id": "PMID-1388088_T1" } ] }, { "id": "PMID-1388088_E4", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 78, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_T5" } ] }, { "id": "PMID-1388088_E6", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 119, 128 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_T7" } ] }, { "id": "PMID-1388088_E13", "type": "Death", "trigger": { "text": [ "death" ], "offsets": [ [ 281, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_T14" } ] }, { "id": "PMID-1388088_E26", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 787, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_T27" } ] }, { "id": "PMID-1388088_E29", "type": "Death", "trigger": { "text": [ "death" ], "offsets": [ [ 904, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_T30" } ] }, { "id": "PMID-1388088_E1", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 145, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_E6" } ] }, { "id": "PMID-1388088_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 385, 394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1388088_E13" } ] }, { "id": "PMID-1388088_E5", "type": "Planned_process", "trigger": { "text": [ "injected" ], "offsets": [ [ 412, 420 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1388088_T18" }, { "role": "Theme", "ref_id": "PMID-1388088_T1001" } ] }, { "id": "PMID-1388088_E7", "type": "Planned_process", "trigger": { "text": [ "injection" ], "offsets": [ [ 672, 681 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1388088_T24" } ] }, { "id": "PMID-1388088_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 237, 255 ] ] }, "arguments": [] }, { "id": "PMID-1388088_E9", "type": "Positive_regulation", "trigger": { "text": [ "mediator" ], "offsets": [ [ 743, 751 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1388088_T25" }, { "role": "Theme", "ref_id": "PMID-1388088_E26" } ] }, { "id": "PMID-1388088_E10", "type": "Planned_process", "trigger": { "text": [ "infusion" ], "offsets": [ [ 571, 579 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1388088_T23" } ] } ]

[ { "id": "PMID-1388088_1", "entity_ids": [ "PMID-1388088_T18", "PMID-1388088_T20" ] }, { "id": "PMID-1388088_2", "entity_ids": [ "PMID-1388088_T7", "PMID-1388088_T8" ] } ]

[]

[ { "id": "PMID-17210799__text", "type": "abstract", "text": [ "Activation of vascular endothelial growth factor through reactive oxygen species mediates 20-hydroxyeicosatetraenoic acid-induced endothelial cell proliferation.\n\n20-Hydroxyeicosatetraenoic acid (20-HETE) is formed by the omega-hydroxylation of arachidonic acid by cytochrome P450 4A and 4F enzymes, and it induces angiogenic responses in vivo. To test the hypothesis that 20-HETE increases endothelial cell (EC) proliferation via vascular endothelial growth factor (VEGF), we studied the effects of WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid], a 20-HETE analog on human macrovascular or microvascular EC. WIT003, as well as pure 20-HETE, stimulated EC proliferation by approximately 40%. These proliferative effects were accompanied by increased VEGF expression and release that were observed as early as 4 h after 20-HETE agonist addition. This was accompanied by increased phosphorylation of the VEGF receptor 2. The proliferative effects of 20-HETE were markedly inhibited by a VEGF-neutralizing antibody. Polyethylene glycol-superoxide dismutase (PEG-SOD) markedly inhibited both the increases in VEGF expression and the proliferative effects of 20-HETE. In contrast, administration of the NAD(P)H oxidase inhibitor apocynin had no effect to the proliferative response to 20-HETE. The 20-HETE agonist markedly increased superoxide formation as reflected by an increase in dihydroethidium staining of EC, and this increase was inhibited by PEG-SOD but not by apocynin. 20-HETE also increased the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in EC, whereas an inhibitor of MAPK [U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] suppressed the proliferative and the VEGF changes but not the pro-oxidant effects of 20-HETE. These data suggest that 20-HETE stimulates superoxide formation by pathways other than apocynin-sensitive NAD(P)H oxidase, thereby activating MAPK and then enhancing VEGF synthesis that drives EC proliferation. Thus, 20-HETE may be involved in the regulation of EC functions, such as angiogenesis.\n" ], "offsets": [ [ 0, 2070 ] ] } ]

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"PMID-17210799_T12", "type": "Gene_or_gene_product", "text": [ "cytochrome P450 4A" ], "offsets": [ [ 265, 283 ] ], "normalized": [] }, { "id": "PMID-17210799_T15", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 373, 380 ] ], "normalized": [] }, { "id": "PMID-17210799_T19", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 391, 407 ] ], "normalized": [] }, { "id": "PMID-17210799_T20", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 409, 411 ] ], "normalized": [] }, { "id": "PMID-17210799_T21", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 431, 465 ] ], "normalized": [] }, { "id": "PMID-17210799_T22", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 467, 471 ] ], "normalized": [] }, { "id": "PMID-17210799_T23", "type": "Drug_or_compound", "text": [ "WIT003" ], "offsets": [ [ 500, 506 ] ], "normalized": [] }, { "id": "PMID-17210799_T24", "type": "Drug_or_compound", "text": [ "20-hydroxyeicosa-5(Z),14(Z)-dienoic acid" ], "offsets": [ [ 508, 548 ] ], "normalized": [] }, { "id": "PMID-17210799_T25", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 553, 560 ] ], "normalized": [] }, { "id": "PMID-17210799_T26", "type": "Cell", "text": [ "microvascular EC" ], "offsets": [ [ 594, 610 ] ], "normalized": [] }, { "id": "PMID-17210799_T27", "type": "Drug_or_compound", "text": [ "WIT003" ], "offsets": [ [ 612, 618 ] ], "normalized": [] }, { "id": "PMID-17210799_T28", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 636, 643 ] ], "normalized": [] }, { "id": "PMID-17210799_T32", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 656, 658 ] ], "normalized": [] }, { "id": "PMID-17210799_T37", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 753, 757 ] ], "normalized": [] }, { "id": "PMID-17210799_T39", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 822, 829 ] ], "normalized": [] }, { "id": "PMID-17210799_T41", "type": "Gene_or_gene_product", "text": [ "VEGF receptor 2" ], "offsets": [ [ 905, 920 ] ], "normalized": [] }, { "id": "PMID-17210799_T42", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 951, 958 ] ], "normalized": [] }, { "id": "PMID-17210799_T45", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 988, 992 ] ], "normalized": [] }, { "id": "PMID-17210799_T46", "type": "Drug_or_compound", "text": [ "Polyethylene glycol-superoxide dismutase" ], "offsets": [ [ 1016, 1056 ] ], "normalized": [] }, { "id": "PMID-17210799_T47", "type": "Drug_or_compound", "text": [ "PEG-SOD" ], "offsets": [ [ 1058, 1065 ] ], "normalized": [] }, { "id": "PMID-17210799_T51", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1108, 1112 ] ], "normalized": [] }, { "id": "PMID-17210799_T52", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1157, 1164 ] ], "normalized": [] }, { "id": "PMID-17210799_T54", "type": "Gene_or_gene_product", "text": [ "NAD(P)H oxidase" ], "offsets": [ [ 1201, 1216 ] ], "normalized": [] }, { "id": "PMID-17210799_T55", "type": "Drug_or_compound", "text": [ "apocynin" ], "offsets": [ [ 1227, 1235 ] ], "normalized": [] }, { "id": "PMID-17210799_T57", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1283, 1290 ] ], "normalized": [] }, { "id": "PMID-17210799_T59", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1296, 1303 ] ], "normalized": [] }, { "id": "PMID-17210799_T60", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1411, 1413 ] ], "normalized": [] }, { "id": "PMID-17210799_T61", "type": "Drug_or_compound", "text": [ "PEG-SOD" ], "offsets": [ [ 1450, 1457 ] ], "normalized": [] }, { "id": "PMID-17210799_T62", "type": "Drug_or_compound", "text": [ "apocynin" ], "offsets": [ [ 1469, 1477 ] ], "normalized": [] }, { "id": "PMID-17210799_T63", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1479, 1486 ] ], "normalized": [] }, { "id": "PMID-17210799_T66", "type": "Gene_or_gene_product", "text": [ "p42/p44 mitogen-activated protein kinase" ], "offsets": [ [ 1525, 1565 ] ], "normalized": [] }, { "id": "PMID-17210799_T67", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1567, 1571 ] ], "normalized": [] }, { "id": "PMID-17210799_T68", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1576, 1578 ] ], "normalized": [] }, { "id": "PMID-17210799_T69", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1604, 1608 ] ], "normalized": [] }, { "id": "PMID-17210799_T70", "type": "Drug_or_compound", "text": [ "U0126" ], "offsets": [ [ 1610, 1615 ] ], "normalized": [] }, { "id": "PMID-17210799_T71", "type": "Drug_or_compound", "text": [ "1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene" ], "offsets": [ [ 1617, 1676 ] ], "normalized": [] }, { "id": "PMID-17210799_T73", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1715, 1719 ] ], "normalized": [] }, { "id": "PMID-17210799_T74", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1763, 1770 ] ], "normalized": [] }, { "id": "PMID-17210799_T75", "type": "Drug_or_compound", "text": [ "20-HETE" ], "offsets": [ [ 1796, 1803 ] ], "normalized": [] }, { "id": "PMID-17210799_T76", "type": "Drug_or_compound", "text": [ "apocynin" ], "offsets": [ [ 1859, 1867 ] ], "normalized": [] }, { "id": "PMID-17210799_T77", "type": "Gene_or_gene_product", "text": [ "NAD(P)H oxidase" ], "offsets": [ [ 1878, 1893 ] ], "normalized": [] }, { "id": "PMID-17210799_T79", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1914, 1918 ] ], "normalized": [] }, { "id": "PMID-17210799_T82", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1938, 1942 ] ], "normalized": [] }, { "id": "PMID-17210799_T86", "type": "Cell", "text": [ "EC" ], "offsets": [ [ 1965, 1967 ] ], "normalized": [] }, { "id": "PMID-17210799_T87", "type": "Drug_or_compound", "text": 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"PMID-17210799_T103", "type": "Drug_or_compound", "text": [ "superoxide" ], "offsets": [ [ 1815, 1825 ] ], "normalized": [] } ]

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[ { "id": "PMID-19318806__text", "type": "abstract", "text": [ "The semaphorin 7A receptor Plexin C1 is lost during melanoma metastasis.\n\nThe transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.\n" ], "offsets": [ [ 0, 1522 ] ] } ]

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[]

[ { "id": "PMID-16406676__text", "type": "abstract", "text": [ "Regulation of tumor angiogenesis by thrombospondin-1.\n\nAngiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGF-beta) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.\n" ], "offsets": [ [ 0, 881 ] ] } ]

[ { "id": "PMID-16406676_T2", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "PMID-16406676_T4", "type": "Gene_or_gene_product", "text": [ "thrombospondin-1" ], "offsets": [ [ 36, 52 ] ], "normalized": [] }, { "id": "PMID-16406676_T7", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 122, 128 ] ], "normalized": [] }, { "id": "PMID-16406676_T8", "type": "Gene_or_gene_product", "text": [ "Thrombospondin-1" ], "offsets": [ [ 130, 146 ] ], "normalized": [] }, { "id": "PMID-16406676_T9", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 148, 153 ] ], "normalized": [] }, { "id": "PMID-16406676_T13", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 214, 219 ] ], "normalized": [] }, { "id": "PMID-16406676_T16", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 248, 253 ] ], "normalized": [] }, { "id": "PMID-16406676_T19", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 304, 309 ] ], "normalized": [] }, { "id": "PMID-16406676_T23", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 331, 336 ] ], "normalized": [] }, { "id": "PMID-16406676_T24", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 360, 365 ] ], "normalized": [] }, { "id": "PMID-16406676_T25", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 383, 386 ] ], "normalized": [] }, { "id": "PMID-16406676_T26", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 428, 431 ] ], "normalized": [] }, { "id": "PMID-16406676_T27", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 436, 439 ] ], "normalized": [] }, { "id": "PMID-16406676_T28", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 441, 446 ] ], "normalized": [] }, { "id": "PMID-16406676_T36", "type": "Cell", "text": [ "endothelial cell" ], "offsets": [ [ 483, 499 ] ], "normalized": [] }, { "id": "PMID-16406676_T38", "type": "Gene_or_gene_product", "text": [ "transforming growth factor beta" ], "offsets": [ [ 582, 613 ] ], "normalized": [] }, { "id": "PMID-16406676_T39", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 615, 623 ] ], "normalized": [] }, { "id": "PMID-16406676_T40", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 628, 633 ] ], "normalized": [] }, { "id": "PMID-16406676_T43", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "PMID-16406676_T45", "type": "Gene_or_gene_product", "text": [ "TSP-1" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "PMID-16406676_T49", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 784, 789 ] ], "normalized": [] } ]

[ { "id": "PMID-16406676_E12", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 195, 210 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T13" } ] }, { "id": "PMID-16406676_E14", "type": "Regulation", "trigger": { "text": [ "alter" ], "offsets": [ [ 242, 247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E15" }, { "role": "Cause", "ref_id": "PMID-16406676_E6" } ] }, { "id": "PMID-16406676_E15", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 254, 260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T16" } ] }, { "id": "PMID-16406676_E20", "type": "Negative_regulation", "trigger": { "text": [ "down-regulated" ], "offsets": [ [ 392, 406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E22" }, { "role": "Cause", "ref_id": "PMID-16406676_T26" } ] }, { "id": "PMID-16406676_E21", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 340, 352 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T25" }, { "role": "Theme", "ref_id": "PMID-16406676_E22" } ] }, { "id": "PMID-16406676_E22", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 317, 327 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T23" } ] }, { "id": "PMID-16406676_E33", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 514, 527 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T36" } ] }, { "id": "PMID-16406676_E35", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 500, 509 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T36" } ] }, { "id": "PMID-16406676_E37", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 568, 578 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T40" }, { "role": "Theme", "ref_id": "PMID-16406676_T38" } ] }, { "id": "PMID-16406676_E41", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 662, 672 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E42" } ] }, { "id": "PMID-16406676_E42", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 682, 693 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T43" } ] }, { "id": "PMID-16406676_E48", "type": "Development", "trigger": { "text": [ "progression" ], "offsets": [ [ 790, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T49" } ] }, { "id": "PMID-16406676_E1", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 97, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T7" } ] }, { "id": "PMID-16406676_E2", "type": "Localization", "trigger": { "text": [ "metastasis" ], "offsets": [ [ 108, 118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_T7" } ] }, { "id": "PMID-16406676_E3", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E18" }, { "role": "Cause", "ref_id": "PMID-16406676_T4" } ] }, { "id": "PMID-16406676_E4", "type": "Regulation", "trigger": { "text": [ "plays a critical role" ], "offsets": [ [ 68, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_E19" }, { "role": "Theme", "ref_id": "PMID-16406676_E1" } ] }, { "id": "PMID-16406676_E5", "type": "Regulation", "trigger": { "text": [ "plays a critical role" ], "offsets": [ [ 68, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_E19" }, { "role": "Theme", "ref_id": "PMID-16406676_E2" } ] }, { "id": "PMID-16406676_E6", "type": "Regulation", "trigger": { "text": [ "modulating" ], "offsets": [ [ 264, 274 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_E12" }, { "role": "Theme", "ref_id": "PMID-16406676_E24" } ] }, { "id": "PMID-16406676_E7", "type": "Negative_regulation", "trigger": { "text": [ "down-regulated" ], "offsets": [ [ 392, 406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E22" }, { "role": "Cause", "ref_id": "PMID-16406676_T27" } ] }, { "id": "PMID-16406676_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 447, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E25" }, { "role": "Cause", "ref_id": "PMID-16406676_E10" } ] }, { "id": "PMID-16406676_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 472, 482 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T28" }, { "role": "Theme", "ref_id": "PMID-16406676_E35" } ] }, { "id": "PMID-16406676_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 472, 482 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T28" }, { "role": "Theme", "ref_id": "PMID-16406676_E33" } ] }, { "id": "PMID-16406676_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 447, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16406676_E25" }, { "role": "Cause", "ref_id": "PMID-16406676_E9" } ] }, { "id": "PMID-16406676_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 753, 763 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T45" }, { "role": "Theme", "ref_id": "PMID-16406676_E26" } ] }, { "id": "PMID-16406676_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 753, 763 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_T45" }, { "role": "Theme", "ref_id": "PMID-16406676_E48" } ] }, { "id": "PMID-16406676_E17", "type": "Regulation", "trigger": { "text": [ "plays a crucial role" ], "offsets": [ [ 634, 654 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16406676_E37" }, { "role": "Theme", "ref_id": "PMID-16406676_E41" } ] }, { "id": "PMID-16406676_E18", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 20, 32 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16406676_T2" } ] }, { "id": "PMID-16406676_E19", "type": "Blood_vessel_development", "trigger": { "text": [ "Angiogenesis" ], "offsets": [ [ 55, 67 ] ] }, "arguments": [] }, { "id": "PMID-16406676_E23", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 167, 179 ] ] }, "arguments": [] }, { "id": "PMID-16406676_E24", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 275, 287 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16406676_T19" } ] }, { "id": "PMID-16406676_E25", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 456, 468 ] ] }, "arguments": [] }, { "id": "PMID-16406676_E26", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 767, 779 ] ] }, "arguments": [] } ]

[ { "id": "PMID-16406676_1", "entity_ids": [ "PMID-16406676_T38", "PMID-16406676_T39" ] }, { "id": "PMID-16406676_2", "entity_ids": [ "PMID-16406676_T8", "PMID-16406676_T9" ] } ]

[]

[ { "id": "PMID-19514363__text", "type": "abstract", "text": [ "[Role of the tumor suppressor ARF in oncogenesis]\n\nThe paper reviews the data available in the literature on a role of the tumor suppressor ARF in oncogenesis and considers the structure of a gene encoding ARF protein. The p53-dependent and p-53-independent functions of this protein are under many studies. There is evidence for the implication of ARF in angiogenesis. There is more and more information on the role of ARF in the regulation of a cell cycle, apoptosis, and autophagy. The importance of this tumor suppressor in the mechanisms of carcinogenesis is beyond question as the inactivation of ARF suppressor activity leads to the rapid growth of neoplasia. However, the exact mechanisms of ARF action yet remain unclear and require further studies by different specialists at both the molecular genetic and other levels of investigation.\n" ], "offsets": [ [ 0, 848 ] ] } ]

[ { "id": "PMID-19514363_T1", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 13, 18 ] ], "normalized": [] }, { "id": "PMID-19514363_T2", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 30, 33 ] ], "normalized": [] }, { "id": "PMID-19514363_T3", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 123, 128 ] ], "normalized": [] }, { "id": "PMID-19514363_T4", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 140, 143 ] ], "normalized": [] }, { "id": "PMID-19514363_T5", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 206, 209 ] ], "normalized": [] }, { "id": "PMID-19514363_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 223, 226 ] ], "normalized": [] }, { "id": "PMID-19514363_T7", "type": "Gene_or_gene_product", "text": [ "p-53" ], "offsets": [ [ 241, 245 ] ], "normalized": [] }, { "id": "PMID-19514363_T9", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 349, 352 ] ], "normalized": [] }, { "id": "PMID-19514363_T11", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 420, 423 ] ], "normalized": [] }, { "id": "PMID-19514363_T12", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 508, 513 ] ], "normalized": [] }, { "id": "PMID-19514363_T14", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 603, 606 ] ], "normalized": [] }, { "id": "PMID-19514363_T15", "type": "Gene_or_gene_product", "text": [ "ARF" ], "offsets": [ [ 700, 703 ] ], "normalized": [] }, { "id": "PMID-19514363_T18", "type": "Pathological_formation", "text": [ "neoplasia" ], "offsets": [ [ 656, 665 ] ], "normalized": [] }, { "id": "PMID-19514363_T21", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 447, 451 ] ], "normalized": [] } ]

[ { "id": "PMID-19514363_E13", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 587, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_T14" } ] }, { "id": "PMID-19514363_E1", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 246, 257 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_T5" }, { "role": "Cause", "ref_id": "PMID-19514363_T7" } ] }, { "id": "PMID-19514363_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 227, 236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_T5" }, { "role": "Cause", "ref_id": "PMID-19514363_T6" } ] }, { "id": "PMID-19514363_E3", "type": "Regulation", "trigger": { "text": [ "implication" ], "offsets": [ [ 334, 345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_E8" }, { "role": "Cause", "ref_id": "PMID-19514363_T9" } ] }, { "id": "PMID-19514363_E4", "type": "Growth", "trigger": { "text": [ "growth" ], "offsets": [ [ 646, 652 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_T18" } ] }, { "id": "PMID-19514363_E5", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 627, 632 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19514363_E13" }, { "role": "Theme", "ref_id": "PMID-19514363_E4" } ] }, { "id": "PMID-19514363_E6", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 431, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_E7" } ] }, { "id": "PMID-19514363_E7", "type": "Death", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19514363_T21" } ] }, { "id": "PMID-19514363_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 356, 368 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-12414659__text", "type": "abstract", "text": [ "Roles of cell adhesion molecules in tumor angiogenesis induced by cotransplantation of cancer and endothelial cells to nude rats.\n\nRoles of cell adhesion molecules mediating the interaction of cancer and endothelial cells in tumor angiogenesis were investigated using new in vitro and in vivo model systems with a cultured murine endothelial cell line (F-2) and human cultured epidermoid cancer cells (A431). The A431 cells exhibited typical in vitro cell adhesion to the endothelial F-2 cells. The initial step of adhesion was mediated by sialyl Lewis(x) (Le(x)) and sialyl Le(a), the carbohydrate determinants expressed on the cancer cells, and E-selectin expressed constitutively on F-2 cells. Prolonged culture led to the implantation of cancer cells into the monolayer of the F-2 cells, which was mediated mainly by alpha(3)beta(1)-integrin. F-2 cells cultured on Matrigel showed evident tube formation, and coculture of F-2 cells with A431 cells led to the formation of A431 cell nests constantly surrounded by tube-like networks consisting of F-2 cells. This in vitro morphogenesis was inhibited by the addition of anti-sialyl Le(x)/Le(a) or anti-beta(1)-integrin antibodies, which led to the formation of cancer cell aggregates that were independent from the F-2 cell networks. This in vitro morphological appearance was exactly reproduced in the in vivo tumors, which were formed when the mixture of A431 and F-2 cells at the ratio of 10:1 were cotransplanted s.c. into the back of nude rats. The tumors of A431 supplemented with F-2 cells were profoundly vascularized throughout by the tubular structures formed by F-2 cells, the lumen of which contained the host rat blood cells. The tumor mass thus formed was an average 5.8-fold as large as control A431 tumors that were grown without F-2 cells. The co-injection of anti-Le(x)/Le(a) or anti-beta(1)-integrin antibodies produced a marked reduction in the size of A431 tumors, which were not vascularized and accompanied an independent tiny remnant clump of F-2 cells. The size of these A431 tumors did not differ significantly from those of control A431 tumors raised without F-2 cells. These results indicate that the interaction of tumor cells and endothelial cells in orderly tumor angiomorphogenesis is highly dependent on the action of cell adhesion molecules mediating the adhesion of cancer cells to endothelial cells, inhibition of which remarkably retards tumor growth and angiogenesis.\n" ], "offsets": [ [ 0, 2458 ] ] } ]

[ { "id": "PMID-12414659_T2", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 36, 41 ] ], "normalized": [] }, { "id": "PMID-12414659_T6", "type": "Cell", "text": [ "cancer" ], "offsets": [ [ 87, 93 ] ], "normalized": [] }, { "id": "PMID-12414659_T7", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 98, 115 ] ], "normalized": [] }, { "id": "PMID-12414659_T10", "type": "Cell", "text": [ "cancer" ], "offsets": [ [ 193, 199 ] ], "normalized": [] }, { "id": "PMID-12414659_T11", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 204, 221 ] ], "normalized": [] }, { "id": "PMID-12414659_T12", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 225, 230 ] ], "normalized": [] }, { "id": "PMID-12414659_T14", "type": "Cell", "text": [ "endothelial cell line" ], "offsets": [ [ 330, 351 ] ], "normalized": [] }, { "id": "PMID-12414659_T15", "type": "Cell", "text": [ "F-2" ], "offsets": [ [ 353, 356 ] ], "normalized": [] }, { "id": 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[ { "id": "PMID-16221381__text", "type": "abstract", "text": [ "The merits of vascular targeting for gynecologic malignancies.\n\nNeovascularization is an early and critical step in tumor development and progression. Tumor vessels are distinct from their normal counterparts morphologically as well as at a molecular level. Recent studies on factors involved in tumor vascular development have identified new therapeutic targets for inhibiting tumor neovascularization and thus tumor progression. However, the process of tumor blood vessel formation is complex, and each tumor exhibits unique features in its vasculature. An understanding of the relative contribution of various pathways in the development of tumor vasculature is critical for developing effective and selective therapeutic approaches. Several such agents are currently in clinical trials, and many others are under development. In this review, the mechanisms and factors involved in tumor blood vessel formation are discussed. In addition, selected novel classes of antivascular therapies, including those targeting tumor endothelial cells and other components of the tumor vasculature, are summarized.\n" ], "offsets": [ [ 0, 1105 ] ] } ]

[ { "id": "PMID-16221381_T4", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 116, 121 ] ], "normalized": [] }, { "id": "PMID-16221381_T5", "type": "Multi-tissue_structure", "text": [ "Tumor vessels" ], "offsets": [ [ 151, 164 ] ], "normalized": [] }, { "id": "PMID-16221381_T10", "type": "Multi-tissue_structure", "text": [ "tumor vascular" ], "offsets": [ [ 296, 310 ] ], "normalized": [] }, { "id": "PMID-16221381_T11", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 378, 383 ] ], "normalized": [] }, { "id": "PMID-16221381_T14", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 412, 417 ] ], "normalized": [] }, { "id": "PMID-16221381_T17", "type": "Multi-tissue_structure", "text": [ "tumor blood vessel" ], "offsets": [ [ 455, 473 ] ], "normalized": [] }, { "id": "PMID-16221381_T19", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 505, 510 ] ], "normalized": [] }, { "id": "PMID-16221381_T20", "type": "Multi-tissue_structure", "text": [ "vasculature" ], "offsets": [ [ 543, 554 ] ], "normalized": [] }, { "id": "PMID-16221381_T23", "type": "Multi-tissue_structure", "text": [ "tumor vasculature" ], "offsets": [ [ 644, 661 ] ], "normalized": [] }, { "id": "PMID-16221381_T27", "type": "Multi-tissue_structure", "text": [ "tumor blood vessel" ], "offsets": [ [ 885, 903 ] ], "normalized": [] }, { "id": "PMID-16221381_T31", "type": "Cell", "text": [ "tumor endothelial cells" ], "offsets": [ [ 1018, 1041 ] ], "normalized": [] }, { "id": "PMID-16221381_T33", "type": "Multi-tissue_structure", "text": [ "tumor vasculature" ], "offsets": [ [ 1070, 1087 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-17488804__text", "type": "abstract", "text": [ "Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells.\n\nFrequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased through A3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.\n" ], "offsets": [ [ 0, 1986 ] ] } ]

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"type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 369, 377 ] ], "normalized": [] }, { "id": "PMID-17488804_T15", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 396, 430 ] ], "normalized": [] }, { "id": "PMID-17488804_T16", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 432, 436 ] ], "normalized": [] }, { "id": "PMID-17488804_T17", "type": "Gene_or_gene_product", "text": [ "interleukin-8" ], "offsets": [ [ 442, 455 ] ], "normalized": [] }, { "id": "PMID-17488804_T18", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 457, 461 ] ], "normalized": [] }, { "id": "PMID-17488804_T20", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "PMID-17488804_T22", "type": "Gene_or_gene_product", "text": [ "hypoxia-inducible factor-1" ], "offsets": [ [ 518, 544 ] ], "normalized": [] }, { "id": "PMID-17488804_T23", "type": "Gene_or_gene_product", "text": [ "HIF-1" ], "offsets": [ [ 546, 551 ] ], "normalized": [] }, { "id": "PMID-17488804_T25", "type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 668, 676 ] ], "normalized": [] }, { "id": "PMID-17488804_T27", "type": "Gene_or_gene_product", "text": [ "HIF-1" ], "offsets": [ [ 680, 685 ] ], "normalized": [] }, { "id": "PMID-17488804_T29", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 714, 718 ] ], "normalized": [] }, { "id": "PMID-17488804_T31", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 723, 727 ] ], "normalized": [] }, { "id": "PMID-17488804_T32", "type": "Cell", "text": [ "colon cancer cell line HT29" ], "offsets": [ [ 752, 779 ] ], "normalized": [] }, { "id": "PMID-17488804_T33", "type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 828, 836 ] ], "normalized": [] }, { "id": "PMID-17488804_T36", "type": "Drug_or_compound", "text": [ "adenosine" ], "offsets": [ [ 860, 869 ] ], "normalized": [] }, { "id": "PMID-17488804_T37", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 878, 888 ] ], "normalized": [] }, { "id": "PMID-17488804_T38", "type": "Cell", "text": [ "cancer cells" ], "offsets": [ [ 913, 925 ] ], "normalized": [] }, { "id": "PMID-17488804_T40", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 940, 950 ] ], "normalized": [] }, { "id": "PMID-17488804_T41", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 955, 959 ] ], "normalized": [] }, { "id": "PMID-17488804_T43", "type": "Gene_or_gene_product", "text": [ "A3 adenosine receptor" ], "offsets": [ [ 982, 1003 ] ], "normalized": [] }, { "id": "PMID-17488804_T45", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1040, 1044 ] ], "normalized": [] }, { "id": "PMID-17488804_T46", "type": "Gene_or_gene_product", "text": [ "A2B" ], "offsets": [ [ 1066, 1069 ] ], "normalized": [] }, { "id": "PMID-17488804_T47", "type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 1106, 1114 ] ], "normalized": [] }, { "id": "PMID-17488804_T50", "type": "Drug_or_compound", "text": [ "adenosine" ], "offsets": [ [ 1137, 1146 ] ], "normalized": [] }, { "id": "PMID-17488804_T51", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "PMID-17488804_T53", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1182, 1186 ] ], "normalized": [] }, { "id": "PMID-17488804_T55", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1191, 1195 ] ], "normalized": [] }, { "id": "PMID-17488804_T56", "type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 1225, 1233 ] ], "normalized": [] }, { "id": "PMID-17488804_T60", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase 1" ], "offsets": [ [ 1273, 1312 ] ], "normalized": [] }, { "id": "PMID-17488804_T61", "type": "Gene_or_gene_product", "text": [ "ERK1" 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cells" ], "offsets": [ [ 1847, 1865 ] ], "normalized": [] }, { "id": "PMID-17488804_T93", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 1872, 1882 ] ], "normalized": [] }, { "id": "PMID-17488804_T94", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 1883, 1887 ] ], "normalized": [] }, { "id": "PMID-17488804_T95", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1888, 1892 ] ], "normalized": [] }, { "id": "PMID-17488804_T97", "type": "Drug_or_compound", "text": [ "caffeine" ], "offsets": [ [ 1922, 1930 ] ], "normalized": [] }, { "id": "PMID-17488804_T99", "type": "Cell", "text": [ "colon cancer cell" ], "offsets": [ [ 1960, 1977 ] ], "normalized": [] }, { "id": "PMID-17488804_T19", "type": "Pathological_formation", "text": [ "colorectal cancer" ], "offsets": [ [ 259, 276 ] ], "normalized": [] }, { "id": "PMID-17488804_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMID-17488804_T1003", "type": "Organism", "text": [ "human" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "PMID-17488804_T87", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1160, 1168 ] ], "normalized": [] }, { "id": "PMID-17488804_T57", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1313, 1314 ] ], "normalized": [] }, { "id": "PMID-17488804_T58", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1321, 1322 ] ], "normalized": [] }, { "id": "PMID-17488804_T104", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1598, 1602 ] ], "normalized": [] }, { "id": "PMID-17488804_T105", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 1095, 1100 ] ], "normalized": [] } ]

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"id": "PMID-17488804_E23", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1129, 1136 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_E21" }, { "role": "Theme", "ref_id": "PMID-17488804_E54" } ] }, { "id": "PMID-17488804_E24", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1129, 1136 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_E21" }, { "role": "Theme", "ref_id": "PMID-17488804_E22" } ] }, { "id": "PMID-17488804_E25", "type": "Regulation", "trigger": { "text": [ "involve" ], "offsets": [ [ 1243, 1250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E59" } ] }, { "id": "PMID-17488804_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1255, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T62" } ] }, { "id": "PMID-17488804_E29", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1255, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T57" } ] }, { "id": "PMID-17488804_E30", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1255, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T63" } ] }, { "id": "PMID-17488804_E31", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E66" } ] }, { "id": "PMID-17488804_E32", "type": "Regulation", "trigger": { "text": [ "involve" ], "offsets": [ [ 1243, 1250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E27" } ] }, { "id": "PMID-17488804_E33", "type": "Regulation", "trigger": { "text": [ "involve" ], "offsets": [ [ 1243, 1250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E29" } ] }, { "id": "PMID-17488804_E36", "type": "Regulation", "trigger": { "text": [ "involve" ], "offsets": [ [ 1243, 1250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E30" } ] }, { "id": "PMID-17488804_E37", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1381, 1388 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T68" }, { "role": "Theme", "ref_id": "PMID-17488804_E67" } ] }, { "id": "PMID-17488804_E38", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 1419, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T71" } ] }, { "id": "PMID-17488804_E40", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 1473, 1485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T73" } ] }, { "id": "PMID-17488804_E41", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1359, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E70" } ] }, { "id": "PMID-17488804_E43", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1359, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E72" } ] }, { "id": "PMID-17488804_E45", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1359, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E40" } ] }, { "id": "PMID-17488804_E46", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E41" } ] }, { "id": "PMID-17488804_E47", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E43" } ] }, { "id": "PMID-17488804_E50", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17488804_T56" }, { "role": "Theme", "ref_id": "PMID-17488804_E45" } ] }, { "id": "PMID-17488804_E51", "type": "Planned_process", "trigger": { "text": [ "treated" ], "offsets": [ [ 1680, 1687 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T81" }, { "role": "Instrument", "ref_id": "PMID-17488804_T83" } ] }, { "id": "PMID-17488804_E52", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 1761, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_T86" } ] }, { "id": "PMID-17488804_E53", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1713, 1722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E52" } ] }, { "id": "PMID-17488804_E55", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 496, 508 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17488804_T20" } ] }, { "id": "PMID-17488804_E56", "type": "Pathway", "trigger": { "text": [ "mechanism" ], "offsets": [ [ 1903, 1912 ] ] }, "arguments": [] }, { "id": "PMID-17488804_E57", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1893, 1902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E56" }, { "role": "Cause", "ref_id": "PMID-17488804_T95" } ] }, { "id": "PMID-17488804_E58", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1893, 1902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E56" }, { "role": "Cause", "ref_id": "PMID-17488804_T94" } ] }, { "id": "PMID-17488804_E60", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1893, 1902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17488804_E56" }, { "role": "Cause", "ref_id": "PMID-17488804_T93" } ] } ]

[ { "id": "PMID-17488804_1", "entity_ids": [ "PMID-17488804_T60", "PMID-17488804_T61" ] }, { "id": "PMID-17488804_2", "entity_ids": [ "PMID-17488804_T22", "PMID-17488804_T23" ] }, { "id": "PMID-17488804_3", "entity_ids": [ "PMID-17488804_T15", "PMID-17488804_T16" ] }, { "id": "PMID-17488804_4", "entity_ids": [ "PMID-17488804_T17", "PMID-17488804_T18" ] }, { "id": "PMID-17488804_5", "entity_ids": [ "PMID-17488804_T57", "PMID-17488804_T58" ] } ]

[ { "id": "PMID-17488804_R1", "type": "frag", "arg1_id": "PMID-17488804_T57", "arg2_id": "PMID-17488804_T60", "normalized": [] }, { "id": "PMID-17488804_R2", "type": "frag", "arg1_id": "PMID-17488804_T58", "arg2_id": "PMID-17488804_T61", "normalized": [] } ]

[ { "id": "PMID-18537682__text", "type": "abstract", "text": [ "Research advances of endostatin and its short internal fragments.\n\nEndostatin, the C-terminal fragment of collagen XVIII, is a potent angiogenesis inhibitor. At present, there are a large number of research papers on endostatin. However, the action mechanism of endostatin is still a matter of ongoing discussion. The objective of this review is to elucidate its origin and elementary structure, and to discuss its structure basis of activity and action mechanisms based on the latest research. Furthermore, some published studies reporting the antiangiogenic effects of endostatin-derived peptides were also reviewed. It is proposed that the amino acid sequence of endostatin contains both angiosuppressive and angiostimulatory domains. Short endostatin fragments may be exploited as a new angiogenesis inhibitor for therapeutic applications, in substitution of the full length endostatin. These studies on endostatin fragments also shed light on our understanding of the molecular action mechanisms of endostatin.\n" ], "offsets": [ [ 0, 1016 ] ] } ]

[ { "id": "PMID-18537682_T1", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 21, 31 ] ], "normalized": [] }, { "id": "PMID-18537682_T2", "type": "Gene_or_gene_product", "text": [ "Endostatin" ], "offsets": [ [ 67, 77 ] ], "normalized": [] }, { "id": "PMID-18537682_T3", "type": "Gene_or_gene_product", "text": [ "collagen XVIII" ], "offsets": [ [ 106, 120 ] ], "normalized": [] }, { "id": "PMID-18537682_T6", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 217, 227 ] ], "normalized": [] }, { "id": "PMID-18537682_T7", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 262, 272 ] ], "normalized": [] }, { "id": "PMID-18537682_T10", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 571, 581 ] ], "normalized": [] }, { "id": "PMID-18537682_T11", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 666, 676 ] ], "normalized": [] }, { "id": "PMID-18537682_T15", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 744, 754 ] ], "normalized": [] }, { "id": "PMID-18537682_T18", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 879, 889 ] ], "normalized": [] }, { "id": "PMID-18537682_T19", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 908, 918 ] ], "normalized": [] }, { "id": "PMID-18537682_T20", "type": "Gene_or_gene_product", "text": [ "endostatin" ], "offsets": [ [ 1004, 1014 ] ], "normalized": [] } ]

[ { "id": "PMID-18537682_E1", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 134, 146 ] ] }, "arguments": [] }, { "id": "PMID-18537682_E2", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenic" ], "offsets": [ [ 549, 559 ] ] }, "arguments": [] }, { "id": "PMID-18537682_E3", "type": "Blood_vessel_development", "trigger": { "text": [ "angiosuppressive" ], "offsets": [ [ 691, 707 ] ] }, "arguments": [] }, { "id": "PMID-18537682_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "angiostimulatory" ], "offsets": [ [ 712, 728 ] ] }, "arguments": [] }, { "id": "PMID-18537682_E5", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 791, 803 ] ] }, "arguments": [] }, { "id": "PMID-18537682_E6", "type": "Negative_regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 560, 567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18537682_E2" } ] } ]

[]

[]

[ { "id": "PMID-2255190__text", "type": "abstract", "text": [ "Expression of basic fibroblast growth factor in normal human tissues.\n\nThe distribution of basic fibroblast growth factor (bFGF) was studied immunohistochemically in fresh frozen sections of normal human tissues. Immunodetection was performed with a specific anti-bFGF mouse monoclonal antibody that was found to react with recombinant human bFGF in Western blot analysis, and to specifically neutralize the mitogenic activity of bFGF on bovine vascular endothelial cells. Expression of bFGF on normal human tissues was ubiquitously detected in the basement membranes of all size blood vessels, but was not found in epidermal or epithelial basement membranes of a variety of tissues tested. Intensity and patterns of localization in blood vessels was consistent in various tissues, but varied among different regions of the vascular bed. Whereas homogeneous and intense immunoreactivity were observed in large and intermediate size blood vessels, heterogeneity of expression was found in capillaries. The most intense immunoreactivity was observed in branching capillaries. Endothelial cell staining was heterogeneous and varied in different regions. Strong staining for bFGF was also found in cardiac muscle fibers, smooth muscle cells of mid-size blood vessels, the gut and the myometrium, in central nervous system neurons and cerebellar Purkinje cells, and on epithelial cells of the bronchi, colon, endometrium, and sweat gland ducts of the skin. The presence of bFGF in the extracellular compartment of a diverse variety of organs may play a role in angiogenesis. However, the function of bFGF in parenchymal cells remains to be determined.\n" ], "offsets": [ [ 0, 1647 ] ] } ]

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[ { "id": "PMID-18669910__text", "type": "abstract", "text": [ "Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia.\n\nBone marrow-derived mesenchymal stem cells (BM-MSC) have been demonstrated to be an attractive therapeutic cell source for tissue regeneration and repair. However, it remains unknown whether or not allogeneic transplantation of mesenchymal stem cells (MSC) derived from fetal membranes (FM), which are generally discarded as medical waste after delivery, has therapeutic potential. FM-MSC were obtained from Lewis rats and had surface antigen expression and multipotent potential partly similar to those of BM-MSC. Compared with BM-MSC, FM-MSC secreted a comparable amount of hepatocyte growth factor despite a small amount of vascular endothelial growth factor. FM-MSC and BM-MSC both expressed major histocompatibility complex (MHC) class I but not MHC class II antigens and did not elicit allogeneic lymphocyte proliferation in mixed lymphocyte culture. FM-MSC or BM-MSC obtained from Lewis rats were injected into a MHC-mismatched August-Copenhagen-Irish rat model of hind limb ischemia. Three weeks after injection, blood perfusion and capillary density were significantly higher in the FM-MSC and BM-MSC groups than in the phosphate-buffered saline group, and allogeneic FM-MSC and BM-MSC were still observed. In nonischemic hind limb tissues, allogeneic FM-MSC and BM-MSC injection were associated with a comparatively small amount of T lymphocyte infiltration, compared with the injection of allogeneic splenic lymphocytes. In conclusion, allogeneic FM-MSC injection did not elicit a lymphocyte proliferative response and provided significant improvement in a rat model of hind limb ischemia, comparable to the response to BM-MSC. Thus, allogeneic injection of FM-MSC may be a new therapeutic strategy for the treatment of severe peripheral vascular disease. Disclosure of potential conflicts of interest is found at the end of this article.\n" ], "offsets": [ [ 0, 1992 ] ] } ]

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"Multi-tissue_structure", "text": [ "FM" ], "offsets": [ [ 429, 431 ] ], "normalized": [] }, { "id": "PMID-18669910_T15", "type": "Cell", "text": [ "FM-MSC" ], "offsets": [ [ 524, 530 ] ], "normalized": [] }, { "id": "PMID-18669910_T16", "type": "Cell", "text": [ "BM-MSC" ], "offsets": [ [ 649, 655 ] ], "normalized": [] }, { "id": "PMID-18669910_T17", "type": "Cell", "text": [ "BM-MSC" ], "offsets": [ [ 671, 677 ] ], "normalized": [] }, { "id": "PMID-18669910_T19", "type": "Cell", "text": [ "FM-MSC" ], "offsets": [ [ 679, 685 ] ], "normalized": [] }, { "id": "PMID-18669910_T20", "type": "Gene_or_gene_product", "text": [ "hepatocyte growth factor" ], "offsets": [ [ 718, 742 ] ], "normalized": [] }, { "id": "PMID-18669910_T21", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 769, 803 ] ], "normalized": [] }, { "id": "PMID-18669910_T22", "type": "Cell", "text": [ "FM-MSC" ], "offsets": [ [ 805, 811 ] ], "normalized": [] }, { "id": "PMID-18669910_T23", "type": "Cell", "text": [ "BM-MSC" ], "offsets": [ [ 816, 822 ] ], "normalized": [] }, { "id": "PMID-18669910_T24", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 945, 955 ] ], "normalized": [] }, { "id": "PMID-18669910_T25", "type": "Cell", "text": [ "lymphocyte" ], "offsets": [ [ 979, 989 ] ], "normalized": [] }, { "id": "PMID-18669910_T26", "type": "Cell", "text": [ "FM-MSC" ], "offsets": [ [ 999, 1005 ] ], "normalized": [] }, { "id": "PMID-18669910_T27", "type": "Cell", "text": [ "BM-MSC" ], "offsets": [ [ 1009, 1015 ] ], "normalized": [] }, { "id": "PMID-18669910_T28", "type": "Organism_subdivision", "text": [ "hind limb" ], "offsets": [ [ 1114, 1123 ] ], "normalized": [] }, { "id": "PMID-18669910_T29", "type": "Organism_substance", "text": [ "blood" ], "offsets": [ [ 1163, 1168 ] ], "normalized": [] }, { "id": "PMID-18669910_T30", "type": "Cell", "text": [ "FM-MSC" ], "offsets": [ [ 1234, 1240 ] ], "normalized": [] }, { "id": "PMID-18669910_T31", 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"angiogenesis" ], "offsets": [ [ 90, 102 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-19758109__text", "type": "abstract", "text": [ "AVE8062: a new combretastatin derivative vascular disrupting agent.\n\nAngiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.\n" ], "offsets": [ [ 0, 1495 ] ] } ]

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[]

[ { "id": "PMID-1869637__text", "type": "abstract", "text": [ "Intracerebral grafting of cultured autologous skin fibroblasts into the rat striatum: an assessment of graft size and ultrastructure.\n\nTo identify a suitable donor cell population for gene therapy applications to the central nervous system, primary fibroblasts isolated from skin biopsies and maintained in culture are employed as autologous cells for intracerebral grafting within the adult rat striatum. Results from the present investigation reveal that cultured primary skin fibroblasts cease to proliferate once they reach confluence; these cells are thus contact inhibited in vitro. Following implantation within the striatum, the volume of the primary fibroblast grafts, stained immunohistochemically for fibronectin, does not differ significantly at 3 and 8 weeks. The graft size is dependent on the density of the cell suspension, but not dependent on either the number of passages the cells are taken through in culture prior to grafting or on the postoperative survival period. Ultrastructural evidence reveals that at 8 weeks the grafts are composed primarily of collagen and fibroblasts with rough endoplasmic reticulum and vesicles. Reactive astrocytic processes and phagocytic cells are also present in the grafts. The grafts are extensively vascularized with capillaries composed of nonfenestrated endothelium; intercellular junctions are evident at sites of apposition between endothelial cells. It is concluded that primary skin fibroblasts are able to survive for at least 8 weeks following intracerebral implantation and continue to synthesize collagen and fibronectin in vivo. Also, the grafts maintain a constant volume between 3 and 8 weeks, thereby indicating that primary skin fibroblasts do not produce tumors. Finally, dynamic host-to-graft interactions--including phagocytic migration, astrocytic hypertrophy and infiltration within the grafts, and angiogenesis--are features that constitute the structural integration of primary skin fibroblasts grafted within the adult rat central nervous system.\n" ], "offsets": [ [ 0, 2028 ] ] } ]

[ { "id": "PMID-1869637_T2", "type": "Cell", "text": [ "skin fibroblasts" ], "offsets": [ [ 46, 62 ] ], "normalized": [] }, { "id": "PMID-1869637_T3", "type": "Multi-tissue_structure", "text": [ "striatum" ], "offsets": [ [ 76, 84 ] ], "normalized": [] }, { "id": "PMID-1869637_T4", "type": "Anatomical_system", "text": [ "central nervous system" ], "offsets": [ [ 217, 239 ] ], "normalized": [] }, { "id": "PMID-1869637_T5", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 249, 260 ] ], "normalized": [] }, { "id": "PMID-1869637_T6", "type": "Multi-tissue_structure", "text": [ "skin biopsies" ], "offsets": [ [ 275, 288 ] ], "normalized": [] }, { "id": "PMID-1869637_T7", "type": "Multi-tissue_structure", "text": [ "striatum" ], "offsets": [ [ 396, 404 ] ], "normalized": [] }, { "id": "PMID-1869637_T9", "type": "Cell", "text": [ "skin fibroblasts" ], "offsets": [ [ 474, 490 ] ], "normalized": [] }, { "id": "PMID-1869637_T10", "type": "Multi-tissue_structure", "text": [ "striatum" ], "offsets": [ [ 623, 631 ] ], "normalized": [] }, { "id": "PMID-1869637_T11", "type": "Tissue", "text": [ "fibroblast grafts" ], "offsets": [ [ 659, 676 ] ], "normalized": [] }, { "id": "PMID-1869637_T12", "type": "Gene_or_gene_product", "text": [ "fibronectin" ], "offsets": [ [ 712, 723 ] ], "normalized": [] }, { "id": "PMID-1869637_T13", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 1075, 1083 ] ], "normalized": [] }, { "id": "PMID-1869637_T14", "type": "Cell", "text": [ "fibroblasts" ], "offsets": [ [ 1088, 1099 ] ], "normalized": [] }, { "id": "PMID-1869637_T15", "type": "Cellular_component", "text": [ "astrocytic processes" ], "offsets": [ [ 1156, 1176 ] ], "normalized": [] }, { "id": "PMID-1869637_T16", "type": "Cell", "text": [ "phagocytic cells" ], "offsets": [ [ 1181, 1197 ] ], "normalized": [] }, { "id": "PMID-1869637_T17", "type": "Tissue", "text": [ "capillaries" ], "offsets": [ [ 1275, 1286 ] ], "normalized": [] }, { "id": "PMID-1869637_T18", "type": "Tissue", "text": [ "endothelium" ], "offsets": [ [ 1314, 1325 ] ], "normalized": [] }, { "id": "PMID-1869637_T19", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 1394, 1411 ] ], "normalized": [] }, { "id": "PMID-1869637_T21", "type": "Cell", "text": [ "skin fibroblasts" ], "offsets": [ [ 1442, 1458 ] ], "normalized": [] }, { "id": "PMID-1869637_T22", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 1564, 1572 ] ], "normalized": [] }, { "id": "PMID-1869637_T23", "type": "Gene_or_gene_product", "text": [ "fibronectin" ], "offsets": [ [ 1577, 1588 ] ], "normalized": [] }, { "id": "PMID-1869637_T25", "type": "Cell", "text": [ "skin fibroblasts" ], "offsets": [ [ 1697, 1713 ] ], "normalized": [] }, { "id": "PMID-1869637_T26", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 1729, 1735 ] ], "normalized": [] }, { "id": "PMID-1869637_T29", "type": "Cell", "text": [ "skin fibroblasts" ], "offsets": [ [ 1958, 1974 ] ], "normalized": [] }, { "id": "PMID-1869637_T30", "type": "Anatomical_system", "text": [ "central nervous system" ], "offsets": [ [ 2004, 2026 ] ], "normalized": [] }, { "id": "PMID-1869637_T1", "type": "Tissue", "text": [ "graft" ], "offsets": [ [ 103, 108 ] ], "normalized": [] }, { "id": "PMID-1869637_T8", "type": "Tissue", "text": [ "graft" ], "offsets": [ [ 777, 782 ] ], "normalized": [] }, { "id": "PMID-1869637_T1000", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 72, 75 ] ], "normalized": [] }, { "id": "PMID-1869637_T1001", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 392, 395 ] ], "normalized": [] }, { "id": "PMID-1869637_T1002", "type": "Organism", "text": [ "rat" ], "offsets": [ [ 2000, 2003 ] ], "normalized": [] }, { "id": "PMID-1869637_T35", "type": "Tissue", "text": [ "grafts" ], "offsets": [ [ 1042, 1048 ] ], "normalized": [] }, { "id": "PMID-1869637_T36", "type": "Tissue", "text": [ "grafts" ], "offsets": [ [ 1222, 1228 ] ], "normalized": [] }, { "id": "PMID-1869637_T37", "type": "Tissue", "text": [ "grafts" ], "offsets": [ [ 1234, 1240 ] ], "normalized": [] }, { "id": "PMID-1869637_T40", "type": "Tissue", "text": [ "grafts" ], "offsets": [ [ 1608, 1614 ] ], "normalized": [] }, { "id": "PMID-1869637_T42", "type": "Tissue", "text": [ "graft" ], "offsets": [ [ 1762, 1767 ] ], "normalized": [] }, { "id": "PMID-1869637_T43", "type": "Tissue", "text": [ "grafts" ], "offsets": [ [ 1865, 1871 ] ], "normalized": [] }, { "id": "PMID-1869637_T45", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 1111, 1132 ] ], "normalized": [] }, { "id": "PMID-1869637_T46", "type": "Cellular_component", "text": [ "vesicles" ], "offsets": [ [ 1137, 1145 ] ], "normalized": [] }, { "id": "PMID-1869637_T28", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 164, 168 ] ], "normalized": [] }, { "id": "PMID-1869637_T47", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "PMID-1869637_T48", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 342, 347 ] ], "normalized": [] }, { "id": "PMID-1869637_T49", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 546, 551 ] ], "normalized": [] }, { "id": "PMID-1869637_T52", "type": "Cell", "text": [ "cells" ], "offsets": [ [ 895, 900 ] ], "normalized": [] } ]

[ { "id": "PMID-1869637_E1", "type": "Planned_process", "trigger": { "text": [ "Intracerebral grafting" ], "offsets": [ [ 0, 22 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1869637_T2" }, { "role": "Theme", "ref_id": "PMID-1869637_T3" } ] }, { "id": "PMID-1869637_E2", "type": "Planned_process", "trigger": { "text": [ "intracerebral grafting" ], "offsets": [ [ 352, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T7" }, { "role": "Instrument", "ref_id": "PMID-1869637_T48" } ] }, { "id": "PMID-1869637_E4", "type": "Planned_process", "trigger": { "text": [ "isolated" ], "offsets": [ [ 261, 269 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T5" } ] }, { "id": "PMID-1869637_E5", "type": "Planned_process", "trigger": { "text": [ "cultured" ], "offsets": [ [ 457, 465 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T9" } ] }, { "id": "PMID-1869637_E6", "type": "Cell_proliferation", "trigger": { "text": [ "proliferate" ], "offsets": [ [ 500, 511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T9" } ] }, { "id": "PMID-1869637_E7", "type": "Planned_process", "trigger": { "text": [ "implantation" ], "offsets": [ [ 599, 611 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T10" }, { "role": "Instrument", "ref_id": "PMID-1869637_T11" } ] }, { "id": "PMID-1869637_E8", "type": "Death", "trigger": { "text": [ "survive" ], "offsets": [ [ 1471, 1478 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T21" } ] }, { "id": "PMID-1869637_E9", "type": "Gene_expression", "trigger": { "text": [ "synthesize" ], "offsets": [ [ 1553, 1563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T22" } ] }, { "id": "PMID-1869637_E10", "type": "Gene_expression", "trigger": { "text": [ "synthesize" ], "offsets": [ [ 1553, 1563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T23" } ] }, { "id": "PMID-1869637_E11", "type": "Development", "trigger": { "text": [ "produce" ], "offsets": [ [ 1721, 1728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T26" } ] }, { "id": "PMID-1869637_E12", "type": "Planned_process", "trigger": { "text": [ "grafted" ], "offsets": [ [ 1975, 1982 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1869637_T29" }, { "role": "Theme", "ref_id": "PMID-1869637_T30" } ] }, { "id": "PMID-1869637_E3", "type": "Binding", "trigger": { "text": [ "contact" ], "offsets": [ [ 561, 568 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T49" } ] }, { "id": "PMID-1869637_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 569, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_E3" } ] }, { "id": "PMID-1869637_E14", "type": "Planned_process", "trigger": { "text": [ "passages" ], "offsets": [ [ 882, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T52" } ] }, { "id": "PMID-1869637_E15", "type": "Planned_process", "trigger": { "text": [ "culture" ], "offsets": [ [ 922, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1869637_T52" } ] }, { "id": "PMID-1869637_E16", "type": "Planned_process", "trigger": { "text": [ "grafting" ], "offsets": [ [ 939, 947 ] ] }, "arguments": [ { "role": "Instrument", "ref_id": "PMID-1869637_T52" } ] }, { "id": "PMID-1869637_E17", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 1877, 1889 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-17981770__text", "type": "abstract", "text": [ "Role of telomeres in vascular senescence.\n\nTelomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.\n" ], "offsets": [ [ 0, 1103 ] ] } ]

[ { "id": "PMID-17981770_T3", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 128, 139 ] ], "normalized": [] }, { "id": "PMID-17981770_T5", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 273, 283 ] ], "normalized": [] }, { "id": "PMID-17981770_T8", "type": "Cell", "text": [ "vascular cell" ], "offsets": [ [ 417, 430 ] ], "normalized": [] }, { "id": "PMID-17981770_T12", "type": "Gene_or_gene_product", "text": [ "telomerase" ], "offsets": [ [ 660, 670 ] ], "normalized": [] }, { "id": "PMID-17981770_T17", "type": "Cell", "text": [ "leukocytes" ], "offsets": [ [ 807, 817 ] ], "normalized": [] }, { "id": "PMID-17981770_T9", "type": "Multi-tissue_structure", "text": [ "vascular" ], "offsets": [ [ 598, 606 ] ], "normalized": [] }, { "id": "PMID-17981770_T1000", "type": "Organism", "text": [ "human" ], "offsets": [ [ 472, 477 ] ], "normalized": [] }, { "id": "PMID-17981770_T1001", "type": "Organism", "text": [ "Mice" ], "offsets": [ [ 672, 676 ] ], "normalized": [] }, { "id": "PMID-17981770_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 821, 829 ] ], "normalized": [] }, { "id": "PMID-17981770_T22", "type": "Pathological_formation", "text": [ "atherosclerotic lesions" ], "offsets": [ [ 478, 501 ] ], "normalized": [] } ]

[ { "id": "PMID-17981770_E1", "type": "Breakdown", "trigger": { "text": [ "dysfunction" ], "offsets": [ [ 607, 618 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17981770_T9" } ] }, { "id": "PMID-17981770_E2", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 629, 638 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17981770_E3" }, { "role": "Theme", "ref_id": "PMID-17981770_E1" } ] }, { "id": "PMID-17981770_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 646, 656 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17981770_T12" } ] }, { "id": "PMID-17981770_E4", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 740, 758 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-10752531__text", "type": "abstract", "text": [ "Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis.\n\nLong-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term ( less than 18 mo, n = 6) or long-term( greater than 18 mo, n = 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca(2+)-dependent NOS and, as shown by immunoblotting, an upregulation of endothelial NOS. The biologic relevance of increased NOS in long-term PD was demonstrated by enhanced nitrotyrosine immunoreactivity and a significant increase in vascular density and endothelial area in the peritoneum. Immunoblotting and immunostaining studies demonstrated an upregulation of vascular endothelial growth factor (VEGF) mostly along the endothelium lining peritoneal blood vessels in long-term PD patients. In the latter, VEGF colocalized with the advanced glycation end product pentosidine deposits. These data provide a morphologic (angiogenesis and increased endothelial area) and molecular (enhanced NOS activity and endothelial NOS upregulation) basis for explaining the permeability changes observed in long-term PD. They also support the implication of local advanced glycation end product deposits and liberation of VEGF in that process.\n" ], "offsets": [ [ 0, 2061 ] ] } ]

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[]

[ { "id": "PMID-17532651__text", "type": "abstract", "text": [ "Medical therapy for intermittent claudication.\n\nMedical therapy to improve symptoms, stabilise the underlying vascular disease and improve lower limb outcomes is an important and effective adjunct to lifestyle modification and surgical or endovascular interventions in patients with IC. Randomised placebo controlled trials have shown that the phosphodiesterase III inhibitor cilostazol 100mg bid improves pain-free and maximum walking distance, as well as quality of life, in a range of patients with intermittent claudication in whom there is no evidence of tissue necrosis or rest pain. This review summarises the evidence from 8 pivotal trials of cilostazol involving over 2000 patients with intermittent claudication treated for up to 6 months. There is comparatively less evidence to support the use of other treatment modalities for relief of symptoms in intermittent claudication, but there is considerable interest in therapeutic angiogenesis to promote new vessel formation and enhance collateralisation of the lower limb using recombinant growth factor proteins or gene transfer strategies. The rationale for therapeutic angiogenesis is discussed, together with the most recent results from randomised trials in patients with peripheral arterial disease.\n" ], "offsets": [ [ 0, 1266 ] ] } ]

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[]

[]

[ { "id": "PMID-1377534__text", "type": "abstract", "text": [ "Angiogenesis--biomedical technology.\n\nAll of these studies show that angiogenesis research can benefit from new biomedical technology tools currently being developed, as well as contribute by providing new technologies that can be used in other areas of medicine. It is hoped that the chapters in this book in this area will provide the reader with an up-to-date appreciation of some of the exciting research that is currently being pursued.\n" ], "offsets": [ [ 0, 442 ] ] } ]

[]

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[]

[]

[ { "id": "PMID-19637749__text", "type": "abstract", "text": [ "[Ambiguity role of neutrophils in oncogenesis]\n\nThe review is focused on the participation of polymorphonuclear granulocytes (neutrophils) in development and spreading of a tumor. We consider both the well known functions of neutrophils (degranulation, production of reactive oxygen species (ROS)) and the recently shown one (presentation of an antigene). The special attention is focused on the ambiguity of the neutrophil role in oncogenesis. The dominant view is that neutrophils display exclusively antitumor properties. The update information testifies about protumoral activity of neutrophils: they migrate to a tumor and promote angiogenesis and metastasis at late stages of the tumor. It is interesting that certain components of neutrophil cytotoxic arsenal (ROS, cytokines, specific enzymes) participate both in antitumoral defenses of an organism and protumoral activity.\n" ], "offsets": [ [ 0, 883 ] ] } ]

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[]

[ { "id": "PMID-19118244__text", "type": "abstract", "text": [ "Involvement of PTEN promoter methylation in cerebral cavernous malformations.\n\nBACKGROUND AND PURPOSE: Cerebral cavernous malformations (CCMs) are prevalent cerebral vascular lesions involving aberrant angiogenesis. However, the underlying mechanism is poorly understood. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is frequently deficient in various pathologies due to mutation or epigenetic alterations. PTEN promoter hypermethylation is a major epigenetic silencing mechanism leading to activation of angiogenesis in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in CCMs. METHODS: PTEN promoter methylation was detected in surgical specimens of CCMs (n=69) by methylation-specific polymerase chain reaction. The methylation status was correlated to the clinical manifestations and to PTEN expression, which was analyzed by both Western blot and immunohistochemistry. To investigate the endothelial proliferation and the potential signaling pathways affected by PTEN methylation, proliferating cell nuclear antigen as well as phosphor-Akt and phosphor-Erk1,2 were detected by immunofluorescence and Western blot, respectively, in CCM specimens. RESULTS: Methylation-specific polymerase chain reaction revealed PTEN promoter methylation in 15.9% CCMs. Strikingly, 5 of 6 familial CCMs showed PTEN promoter methylation (83.3%), which was significantly higher than in sporadic cases (9.4%; P<0.001). In addition, PTEN promoter methylation appeared more frequently in multiple CCMs, including familial cases (46.7%), than that in single-lesioned CCMs (11.8%; P<0.05). Immunostaining and Western blot revealed a more significant PTEN downregulation in PTEN-methylated CCMs in comparison to PTEN-unmethylated CCMs. Reduced PTEN expression was inversely correlated to the expression of proliferating cell nuclear antigen and to the activation of Erk1,2, but not of Akt. CONCLUSIONS: We reported here for the first time the involvement of PTEN promoter methylation in CCMs, particularly in familial CCMs, suggesting this epigenetic alteration as a potential pathomechanism of CCMs. The identification of Erk1,2 as triggered signaling in the lesions may be valuable for the development of effective therapy for this disease.\n" ], "offsets": [ [ 0, 2307 ] ] } ]

[ { "id": "PMID-19118244_T2", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 15, 19 ] ], "normalized": [] }, { "id": "PMID-19118244_T4", "type": "Gene_or_gene_product", "text": [ "Phosphatase and tension homolog deleted on chromosome 10" ], "offsets": [ [ 272, 328 ] ], "normalized": [] }, { "id": "PMID-19118244_T5", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 330, 334 ] ], "normalized": [] }, { "id": "PMID-19118244_T6", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 339, 344 ] ], "normalized": [] }, { "id": "PMID-19118244_T8", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 447, 451 ] ], "normalized": [] }, { "id": "PMID-19118244_T12", "type": "Pathological_formation", "text": [ "tumors" ], "offsets": [ [ 561, 567 ] ], "normalized": [] }, { "id": "PMID-19118244_T14", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "PMID-19118244_T16", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 673, 677 ] ], "normalized": [] }, { "id": "PMID-19118244_T18", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 876, 880 ] ], "normalized": [] }, { "id": "PMID-19118244_T21", "type": "Cell", "text": [ "endothelial" ], "offsets": [ [ 978, 989 ] ], "normalized": [] }, { "id": "PMID-19118244_T23", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1053, 1057 ] ], "normalized": [] }, { "id": "PMID-19118244_T24", "type": "Gene_or_gene_product", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 1071, 1105 ] ], "normalized": [] }, { "id": "PMID-19118244_T25", "type": "Gene_or_gene_product", "text": [ "phosphor-Akt" ], "offsets": [ [ 1117, 1129 ] ], "normalized": [] }, { "id": "PMID-19118244_T26", "type": "Gene_or_gene_product", "text": [ "phosphor-Erk1,2" ], "offsets": [ [ 1134, 1149 ] ], "normalized": [] }, { "id": "PMID-19118244_T28", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1301, 1305 ] ], "normalized": [] }, { "id": "PMID-19118244_T30", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1382, 1386 ] ], "normalized": [] }, { "id": "PMID-19118244_T32", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1501, 1505 ] ], "normalized": [] }, { "id": "PMID-19118244_T34", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1715, 1719 ] ], "normalized": [] }, { "id": "PMID-19118244_T35", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1738, 1742 ] ], "normalized": [] }, { "id": "PMID-19118244_T36", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1776, 1780 ] ], "normalized": [] }, { "id": "PMID-19118244_T39", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 1808, 1812 ] ], "normalized": [] }, { "id": "PMID-19118244_T41", "type": "Gene_or_gene_product", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 1870, 1904 ] ], "normalized": [] }, { "id": "PMID-19118244_T43", "type": "Gene_or_gene_product", "text": [ "Erk1" ], "offsets": [ [ 1930, 1934 ] ], "normalized": [] }, { "id": "PMID-19118244_T44", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1949, 1952 ] ], "normalized": [] }, { "id": "PMID-19118244_T46", "type": "Gene_or_gene_product", "text": [ "PTEN" ], "offsets": [ [ 2022, 2026 ] ], "normalized": [] }, { "id": "PMID-19118244_T47", "type": "Gene_or_gene_product", "text": [ "Erk1" ], "offsets": [ [ 2187, 2191 ] ], "normalized": [] }, { "id": "PMID-19118244_T55", "type": "Pathological_formation", "text": [ "cerebral cavernous malformations" ], "offsets": [ [ 44, 76 ] ], "normalized": [] }, { "id": "PMID-19118244_T56", "type": "Pathological_formation", "text": [ "Cerebral cavernous malformations" ], "offsets": [ [ 103, 135 ] ], "normalized": [] }, { "id": "PMID-19118244_T57", "type": "Pathological_formation", "text": [ "cerebral vascular lesions" ], "offsets": [ [ 157, 182 ] ], "normalized": [] }, { "id": "PMID-19118244_T9", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 20, 28 ] ], "normalized": [] }, { "id": "PMID-19118244_T48", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 452, 460 ] ], "normalized": [] }, { "id": "PMID-19118244_T49", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 621, 629 ] ], "normalized": [] }, { "id": "PMID-19118244_T50", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 678, 686 ] ], "normalized": [] }, { "id": "PMID-19118244_T51", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1306, 1314 ] ], "normalized": [] }, { "id": "PMID-19118244_T52", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1387, 1395 ] ], "normalized": [] }, { "id": "PMID-19118244_T53", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 1506, 1514 ] ], "normalized": [] }, { "id": "PMID-19118244_T54", "type": "DNA_domain_or_region", "text": [ "promoter" ], "offsets": [ [ 2027, 2035 ] ], "normalized": [] }, { "id": "PMID-19118244_T63", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 1935, 1936 ] ], "normalized": [] }, { "id": "PMID-19118244_T64", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 2192, 2193 ] ], "normalized": [] }, { "id": "PMID-19118244_T65", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 137, 141 ] ], "normalized": [] }, { "id": "PMID-19118244_T66", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 658, 662 ] ], "normalized": [] }, { "id": "PMID-19118244_T67", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 737, 741 ] ], "normalized": [] }, { "id": "PMID-19118244_T68", "type": "Pathological_formation", "text": [ "CCM" ], "offsets": [ [ 1221, 1224 ] ], "normalized": [] }, { "id": "PMID-19118244_T69", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1336, 1340 ] ], "normalized": [] }, { "id": "PMID-19118244_T70", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1564, 1568 ] ], "normalized": [] }, { "id": "PMID-19118244_T71", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1754, 1758 ] ], "normalized": [] }, { "id": "PMID-19118244_T72", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 2051, 2055 ] ], "normalized": [] }, { "id": "PMID-19118244_T73", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 2082, 2086 ] ], "normalized": [] }, { "id": "PMID-19118244_T74", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 2159, 2163 ] ], "normalized": [] }, { "id": "PMID-19118244_T75", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1794, 1798 ] ], "normalized": [] }, { "id": "PMID-19118244_T76", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1370, 1374 ] ], "normalized": [] }, { "id": "PMID-19118244_T77", "type": "Pathological_formation", "text": [ "CCMs" ], "offsets": [ [ 1633, 1637 ] ], "normalized": [] }, { "id": "PMID-19118244_T78", "type": "Pathological_formation", "text": [ "lesions" ], "offsets": [ [ 2224, 2231 ] ], "normalized": [] } ]

[ { "id": "PMID-19118244_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 29, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T2" }, { "role": "Site", "ref_id": "PMID-19118244_T9" } ] }, { "id": "PMID-19118244_E7", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 461, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T8" }, { "role": "Site", "ref_id": "PMID-19118244_T48" } ] }, { "id": "PMID-19118244_E10", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 531, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_E12" } ] }, { "id": "PMID-19118244_E13", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 630, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T14" }, { "role": "Site", "ref_id": "PMID-19118244_T49" } ] }, { "id": "PMID-19118244_E15", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 687, 698 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-19118244_T50" }, { "role": "Theme", "ref_id": "PMID-19118244_T16" } ] }, { "id": "PMID-19118244_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T18" } ] }, { "id": "PMID-19118244_E19", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 990, 1003 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T21" } ] }, { "id": "PMID-19118244_E22", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1058, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T23" } ] }, { "id": "PMID-19118244_E27", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1315, 1326 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T28" }, { "role": "Site", "ref_id": "PMID-19118244_T51" } ] }, { "id": "PMID-19118244_E29", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1396, 1407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T30" }, { "role": "Site", "ref_id": "PMID-19118244_T52" } ] }, { "id": "PMID-19118244_E31", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1515, 1526 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T32" }, { "role": "Site", "ref_id": "PMID-19118244_T53" } ] }, { "id": "PMID-19118244_E33", "type": "Negative_regulation", "trigger": { "text": [ "downregulation" ], "offsets": [ [ 1720, 1734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T34" } ] }, { "id": "PMID-19118244_E37", "type": "Negative_regulation", "trigger": { "text": [ "Reduced" ], "offsets": [ [ 1800, 1807 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_E38" } ] }, { "id": "PMID-19118244_E38", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1813, 1823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T39" } ] }, { "id": "PMID-19118244_E40", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1856, 1866 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T41" } ] }, { "id": "PMID-19118244_E42", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1916, 1926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T43" } ] }, { "id": "PMID-19118244_E45", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 2036, 2047 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-19118244_T54" }, { "role": "Theme", "ref_id": "PMID-19118244_T46" } ] }, { "id": "PMID-19118244_E2", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 371, 380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T4" } ] }, { "id": "PMID-19118244_E3", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 520, 527 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19118244_E7" }, { "role": "Theme", "ref_id": "PMID-19118244_E10" } ] }, { "id": "PMID-19118244_E4", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 1041, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_E19" }, { "role": "Cause", "ref_id": "PMID-19118244_E22" } ] }, { "id": "PMID-19118244_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1743, 1753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T35" } ] }, { "id": "PMID-19118244_E6", "type": "DNA_methylation", "trigger": { "text": [ "unmethylated" ], "offsets": [ [ 1781, 1793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T36" } ] }, { "id": "PMID-19118244_E8", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1916, 1926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T63" } ] }, { "id": "PMID-19118244_E9", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1916, 1926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19118244_T44" } ] }, { "id": "PMID-19118244_E11", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 202, 214 ] ] }, "arguments": [] }, { "id": "PMID-19118244_E12", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 545, 557 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19118244_T12" } ] } ]

[ { "id": "PMID-19118244_1", "entity_ids": [ "PMID-19118244_T4", "PMID-19118244_T5" ] }, { "id": "PMID-19118244_2", "entity_ids": [ "PMID-19118244_T56", "PMID-19118244_T65" ] } ]

[ { "id": "PMID-19118244_R1", "type": "frag", "arg1_id": "PMID-19118244_T63", "arg2_id": "PMID-19118244_T43", "normalized": [] }, { "id": "PMID-19118244_R2", "type": "frag", "arg1_id": "PMID-19118244_T64", "arg2_id": "PMID-19118244_T47", "normalized": [] } ]

[ { "id": "PMID-18996355__text", "type": "abstract", "text": [ "A novel integrin alpha5beta1 antagonistic peptide, A5-1, screened by Protein Chip system as a potent angiogenesis inhibitor.\n\nIntegrin alpha5beta1 immobilized on a ProteoChip was used to screen new antagonistic peptides from multiple hexapeptide sub-libraries of the positional scanning synthetic peptide combinatorial library (PS-SPCL). The integrin alpha5beta1-Fibronectin interaction was demonstrated on the chip. A novel peptide ligand, A5-1 (VILVLF), with high affinity to integrin alpha5beta1 was identified from the hexapeptide libraries with this chip-based screening method on the basis of a competitive inhibition assay. A5-1 inhibits the integrin-fibronectin interaction in a dose-dependent manner (IC(50); 1.56+/-0.28 microM. In addition, it inhibits human umbilical vein endothelial cell proliferation, migration, adhesion, tubular network formation, and bFGF-induced neovascularization in a chick chorioallantoic membrane. These results suggest that A5-1 will be a potent inhibitor of neovascularization.\n" ], "offsets": [ [ 0, 1019 ] ] } ]

[ { "id": "PMID-18996355_T1", "type": "Gene_or_gene_product", "text": [ "integrin alpha5beta1" ], "offsets": [ [ 8, 28 ] ], "normalized": [] }, { "id": "PMID-18996355_T2", "type": "Gene_or_gene_product", "text": [ "A5-1" ], "offsets": [ [ 51, 55 ] ], "normalized": [] }, { "id": "PMID-18996355_T5", "type": "Gene_or_gene_product", "text": [ "Integrin alpha5beta1" ], "offsets": [ [ 126, 146 ] ], "normalized": [] }, { "id": "PMID-18996355_T7", "type": "Gene_or_gene_product", "text": [ "integrin alpha5beta1" ], "offsets": [ [ 342, 362 ] ], "normalized": [] }, { "id": "PMID-18996355_T8", "type": "Gene_or_gene_product", "text": [ "Fibronectin" ], "offsets": [ [ 363, 374 ] ], "normalized": [] }, { "id": "PMID-18996355_T10", "type": "Gene_or_gene_product", "text": [ "A5-1" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "PMID-18996355_T11", "type": "Gene_or_gene_product", "text": [ "VILVLF" ], "offsets": [ [ 447, 453 ] ], "normalized": [] }, { "id": "PMID-18996355_T12", "type": "Gene_or_gene_product", "text": [ "integrin alpha5beta1" ], "offsets": [ [ 478, 498 ] ], "normalized": [] }, { "id": "PMID-18996355_T13", "type": "Gene_or_gene_product", "text": [ "A5-1" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "PMID-18996355_T16", "type": "Gene_or_gene_product", "text": [ "integrin" ], "offsets": [ [ 649, 657 ] ], "normalized": [] }, { "id": "PMID-18996355_T17", "type": "Gene_or_gene_product", "text": [ "fibronectin" ], "offsets": [ [ 658, 669 ] ], "normalized": [] }, { "id": "PMID-18996355_T26", "type": "Cell", "text": [ "human umbilical vein endothelial cell" ], "offsets": [ [ 763, 800 ] ], "normalized": [] }, { "id": "PMID-18996355_T29", "type": "Multi-tissue_structure", "text": [ "tubular network" ], "offsets": [ [ 837, 852 ] ], "normalized": [] }, { "id": "PMID-18996355_T30", "type": "Gene_or_gene_product", "text": [ "bFGF" ], "offsets": [ [ 868, 872 ] ], "normalized": [] }, { "id": "PMID-18996355_T32", "type": "Multi-tissue_structure", "text": [ "chorioallantoic membrane" ], "offsets": [ [ 911, 935 ] ], "normalized": [] }, { "id": "PMID-18996355_T33", "type": "Gene_or_gene_product", "text": [ "A5-1" ], "offsets": [ [ 964, 968 ] ], "normalized": [] }, { "id": "PMID-18996355_T1001", "type": "Organism", "text": [ "chick" ], "offsets": [ [ 905, 910 ] ], "normalized": [] } ]

[ { "id": "PMID-18996355_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 375, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T8" }, { "role": "Theme", "ref_id": "PMID-18996355_T7" } ] }, { "id": "PMID-18996355_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 636, 644 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E15" } ] }, { "id": "PMID-18996355_E15", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 670, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T17" }, { "role": "Theme", "ref_id": "PMID-18996355_T16" } ] }, { "id": "PMID-18996355_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 754, 762 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E24" } ] }, { "id": "PMID-18996355_E20", "type": "Binding", "trigger": { "text": [ "adhesion" ], "offsets": [ [ 827, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T26" } ] }, { "id": "PMID-18996355_E22", "type": "Localization", "trigger": { "text": [ "migration" ], "offsets": [ [ 816, 825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T26" } ] }, { "id": "PMID-18996355_E24", "type": "Cell_proliferation", "trigger": { "text": [ "proliferation" ], "offsets": [ [ 801, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T26" } ] }, { "id": "PMID-18996355_E1", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 853, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18996355_T29" } ] }, { "id": "PMID-18996355_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 873, 880 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T30" }, { "role": "Theme", "ref_id": "PMID-18996355_E9" } ] }, { "id": "PMID-18996355_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 754, 762 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E22" } ] }, { "id": "PMID-18996355_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 754, 762 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E20" } ] }, { "id": "PMID-18996355_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 754, 762 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E1" } ] }, { "id": "PMID-18996355_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 754, 762 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18996355_T13" }, { "role": "Theme", "ref_id": "PMID-18996355_E9" } ] }, { "id": "PMID-18996355_E8", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 101, 113 ] ] }, "arguments": [] }, { "id": "PMID-18996355_E9", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 881, 899 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-18996355_T32" } ] }, { "id": "PMID-18996355_E10", "type": "Blood_vessel_development", "trigger": { "text": [ "neovascularization" ], "offsets": [ [ 999, 1017 ] ] }, "arguments": [] } ]

[ { "id": "PMID-18996355_1", "entity_ids": [ "PMID-18996355_T10", "PMID-18996355_T11" ] } ]

[]

[ { "id": "PMID-17040495__text", "type": "abstract", "text": [ "Collagen-poly glycolic acid hybrid matrix with basic fibroblast growth factor accelerated angiogenesis and granulation tissue formation in diabetic mice.\n\nBecause poor skin wound healing associated with diabetes is thought to be partly a result from impaired angiogenesis, treatments that improve angiogenesis could have important clinical applications. We herein report the effects of novel developed material, collagen-poly glycolic acid fiber hybrid matrix, being used together with basic fibroblast growth factor to promote wound healing of full-thickness skin defects on the back of type 2 diabetic Lepr(db) mice. Our data indicates that this therapeutic approach markedly promotes angiogenesis and granulation tissue formation in comparison with other conditions 14 days after wounding.\n" ], "offsets": [ [ 0, 793 ] ] } ]

[ { "id": "PMID-17040495_T2", "type": "Gene_or_gene_product", "text": [ "Collagen" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-17040495_T3", "type": "Drug_or_compound", "text": [ "poly glycolic acid" ], "offsets": [ [ 9, 27 ] ], "normalized": [] }, { "id": "PMID-17040495_T4", "type": "Gene_or_gene_product", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 47, 77 ] ], "normalized": [] }, { "id": "PMID-17040495_T9", "type": "Tissue", "text": [ "granulation tissue" ], "offsets": [ [ 107, 125 ] ], "normalized": [] }, { "id": "PMID-17040495_T10", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 168, 172 ] ], "normalized": [] }, { "id": "PMID-17040495_T16", "type": "Gene_or_gene_product", "text": [ "collagen" ], "offsets": [ [ 412, 420 ] ], "normalized": [] }, { "id": "PMID-17040495_T17", "type": "Drug_or_compound", "text": [ "poly glycolic acid" ], "offsets": [ [ 421, 439 ] ], "normalized": [] }, { "id": "PMID-17040495_T18", "type": "Gene_or_gene_product", "text": [ "basic fibroblast growth factor" ], "offsets": [ [ 486, 516 ] ], "normalized": [] }, { "id": "PMID-17040495_T20", "type": "Organ", "text": [ "skin" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-17040495_T25", "type": "Tissue", "text": [ "granulation tissue" ], "offsets": [ [ 704, 722 ] ], "normalized": [] }, { "id": "PMID-17040495_T1000", "type": "Organism", "text": [ "mice" ], "offsets": [ [ 148, 152 ] ], "normalized": [] }, { "id": "PMID-17040495_T1001", "type": "Organism", "text": [ "Lepr(db) mice" ], "offsets": [ [ 604, 617 ] ], "normalized": [] }, { "id": "PMID-17040495_T15", "type": "Gene_or_gene_product", "text": [ "Lepr" ], "offsets": [ [ 604, 608 ] ], "normalized": [] } ]

[ { "id": "PMID-17040495_E7", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 126, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_T9" } ] }, { "id": "PMID-17040495_E12", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 250, 258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_E14" } ] }, { "id": "PMID-17040495_E23", "type": "Development", "trigger": { "text": [ "formation" ], "offsets": [ [ 723, 732 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_T25" } ] }, { "id": "PMID-17040495_E1", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T4" }, { "role": "Theme", "ref_id": "PMID-17040495_E13" } ] }, { "id": "PMID-17040495_E2", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T3" }, { "role": "Theme", "ref_id": "PMID-17040495_E13" } ] }, { "id": "PMID-17040495_E3", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T2" }, { "role": "Theme", "ref_id": "PMID-17040495_E13" } ] }, { "id": "PMID-17040495_E4", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T4" }, { "role": "Theme", "ref_id": "PMID-17040495_E7" } ] }, { "id": "PMID-17040495_E5", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T3" }, { "role": "Theme", "ref_id": "PMID-17040495_E7" } ] }, { "id": "PMID-17040495_E6", "type": "Positive_regulation", "trigger": { "text": [ "accelerated" ], "offsets": [ [ 78, 89 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17040495_T2" }, { "role": "Theme", "ref_id": "PMID-17040495_E7" } ] }, { "id": "PMID-17040495_E9", "type": "Positive_regulation", "trigger": { "text": [ "improve" ], "offsets": [ [ 289, 296 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_E15" } ] }, { "id": "PMID-17040495_E10", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 678, 686 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_E16" } ] }, { "id": "PMID-17040495_E11", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 678, 686 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17040495_E23" } ] }, { "id": "PMID-17040495_E13", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 90, 102 ] ] }, "arguments": [] }, { "id": "PMID-17040495_E14", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 259, 271 ] ] }, "arguments": [] }, { "id": "PMID-17040495_E15", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 297, 309 ] ] }, "arguments": [] }, { "id": "PMID-17040495_E16", "type": "Blood_vessel_development", "trigger": { "text": [ "angiogenesis" ], "offsets": [ [ 687, 699 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-16556061__text", "type": "abstract", "text": [ "Circulating endothelial cells in malignant disease.\n\nCancer is a disease largely dependent on neoangiogenesis. Cancer neoangiogenesis is often disordered and abnormal, with evidence of coexisting vascular endothelial dysfunction. A novel method of assessing vascular endothelial function in cancer is via the quantification of circulating endothelial cells (CEC). Unusual in healthy individuals, their presence in elevated numbers often indicates substantial vascular endothelial perturbation. Another interesting cell type is the endothelial progenitor cell (EPC), whose numbers increase in the presence of vascular damage. Recent research suggests that EPCs have an important role in tumor vasculogenesis. Another marker being investigated in the context of vascular dysfunction and coagulopathy is the endothelial microparticle (EMP). Thus, CECs, EPCs and EMPs may represent potentially novel methods for evaluating the vascular status of cancer patients. This review will summarize the current position of CECs, EPCs and EMPs in cell biology terms, with particular emphasis on their relationship to malignant disease.\n" ], "offsets": [ [ 0, 1122 ] ] } ]

[ { "id": "PMID-16556061_T1", "type": "Cell", "text": [ "endothelial cells" ], "offsets": [ [ 12, 29 ] ], "normalized": [] }, { "id": "PMID-16556061_T5", "type": "Tissue", "text": [ "vascular endothelial" ], "offsets": [ [ 196, 216 ] ], "normalized": [] }, { "id": "PMID-16556061_T9", "type": "Tissue", "text": [ "vascular endothelial" ], "offsets": [ [ 258, 278 ] ], "normalized": [] }, { "id": "PMID-16556061_T11", "type": "Cell", "text": [ "circulating endothelial cells" ], "offsets": [ [ 327, 356 ] ], "normalized": [] }, { "id": "PMID-16556061_T12", "type": "Cell", "text": [ "CEC" ], "offsets": [ [ 358, 361 ] ], "normalized": [] }, { "id": "PMID-16556061_T14", "type": "Tissue", "text": [ "vascular endothelial" ], "offsets": [ [ 459, 479 ] ], "normalized": [] }, { "id": "PMID-16556061_T16", "type": "Cell", "text": [ "endothelial progenitor cell" ], "offsets": [ [ 531, 558 ] ], "normalized": [] }, { "id": "PMID-16556061_T17", "type": "Cell", "text": [ "EPC" ], "offsets": [ [ 560, 563 ] ], "normalized": [] }, { "id": "PMID-16556061_T21", "type": "Tissue", "text": [ "vascular" ], "offsets": [ [ 608, 616 ] ], "normalized": [] }, { "id": "PMID-16556061_T22", "type": "Cell", "text": [ "EPCs" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "PMID-16556061_T23", "type": "Pathological_formation", "text": [ "tumor" ], "offsets": [ [ 686, 691 ] ], "normalized": [] }, { "id": "PMID-16556061_T26", "type": "Tissue", "text": [ "vascular" ], "offsets": [ [ 760, 768 ] ], "normalized": [] }, { "id": "PMID-16556061_T27", "type": "Cellular_component", "text": [ "endothelial microparticle" ], "offsets": [ [ 805, 830 ] ], "normalized": [] }, { "id": "PMID-16556061_T28", "type": "Cellular_component", "text": [ "EMP" ], "offsets": [ [ 832, 835 ] ], "normalized": [] }, { "id": "PMID-16556061_T29", "type": "Cell", "text": [ "CECs" ], "offsets": [ [ 844, 848 ] ], "normalized": [] }, { "id": "PMID-16556061_T30", "type": "Cell", "text": [ "EPCs" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "PMID-16556061_T31", "type": "Cellular_component", "text": [ "EMPs" ], "offsets": [ [ 859, 863 ] ], "normalized": [] }, { "id": "PMID-16556061_T32", "type": "Cell", "text": [ "CECs" ], "offsets": [ [ 1010, 1014 ] ], "normalized": [] }, { "id": "PMID-16556061_T33", "type": "Cell", "text": [ "EPCs" ], "offsets": [ [ 1016, 1020 ] ], "normalized": [] }, { "id": "PMID-16556061_T34", "type": "Cellular_component", "text": [ "EMPs" ], "offsets": [ [ 1025, 1029 ] ], "normalized": [] }, { "id": "PMID-16556061_T6", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 291, 297 ] ], "normalized": [] }, { "id": "PMID-16556061_T1000", "type": "Pathological_formation", "text": [ "Cancer" ], "offsets": [ [ 53, 59 ] ], "normalized": [] }, { "id": "PMID-16556061_T1001", "type": "Pathological_formation", "text": [ "Cancer" ], "offsets": [ [ 111, 117 ] ], "normalized": [] }, { "id": "PMID-16556061_T1002", "type": "Organism", "text": [ "patients" ], "offsets": [ [ 949, 957 ] ], "normalized": [] }, { "id": "PMID-16556061_T35", "type": "Pathological_formation", "text": [ "cancer" ], "offsets": [ [ 942, 948 ] ], "normalized": [] }, { "id": "PMID-16556061_T36", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 514, 518 ] ], "normalized": [] }, { "id": "PMID-16556061_T37", "type": "Cell", "text": [ "cell" ], "offsets": [ [ 1033, 1037 ] ], "normalized": [] } ]

[ { "id": "PMID-16556061_E19", "type": "Breakdown", "trigger": { "text": [ "damage" ], "offsets": [ [ 617, 623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16556061_T21" } ] }, { "id": "PMID-16556061_E1", "type": "Breakdown", "trigger": { "text": [ "dysfunction" ], "offsets": [ [ 217, 228 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16556061_T5" } ] }, { "id": "PMID-16556061_E2", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 580, 588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16556061_T16" } ] }, { "id": "PMID-16556061_E3", "type": "Regulation", "trigger": { "text": [ "have an important role" ], "offsets": [ [ 660, 682 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16556061_T22" }, { "role": "Theme", "ref_id": "PMID-16556061_E9" } ] }, { "id": "PMID-16556061_E5", "type": "Breakdown", "trigger": { "text": [ "dysfunction" ], "offsets": [ [ 769, 780 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16556061_T26" } ] }, { "id": "PMID-16556061_E6", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 94, 109 ] ] }, "arguments": [] }, { "id": "PMID-16556061_E7", "type": "Blood_vessel_development", "trigger": { "text": [ "neoangiogenesis" ], "offsets": [ [ 118, 133 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16556061_T1001" } ] }, { "id": "PMID-16556061_E9", "type": "Blood_vessel_development", "trigger": { "text": [ "vasculogenesis" ], "offsets": [ [ 692, 706 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-16556061_T23" } ] }, { "id": "PMID-16556061_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 81, 90 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16556061_E6" }, { "role": "Theme", "ref_id": "PMID-16556061_T1000" } ] } ]

[ { "id": "PMID-16556061_1", "entity_ids": [ "PMID-16556061_T16", "PMID-16556061_T17" ] }, { "id": "PMID-16556061_2", "entity_ids": [ "PMID-16556061_T11", "PMID-16556061_T12" ] }, { "id": "PMID-16556061_3", "entity_ids": [ "PMID-16556061_T27", "PMID-16556061_T28" ] } ]

[]

[ { "id": "PMID-19481797__text", "type": "abstract", "text": [ "Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling.\n\nPromoting angiogenesis via delivery of vascular endothelial growth factor (VEGF) and other angiogenic factors is both a potential therapy for cardiovascular diseases and a critical aspect for tissue regeneration. The recent demonstration that VEGF signaling is modulated by the Notch signaling pathway, however, suggests that inhibiting Notch signaling may enhance regional neovascularization, by altering the responsiveness of local endothelial cells to angiogenic stimuli. We tested this possibility with in vitro assays using human endothelial cells, as well as in a rodent hindlimb ischemia model. Treatment of cultured human endothelial cells with DAPT, a gamma secretase inhibitor, increased cell migration and sprout formation in response to VEGF stimulation with a biphasic dependence on DAPT concentration. Further, delivery of an appropriate combination of DAPT and VEGF from an injectable alginate hydrogel system into ischemic hindlimbs led to a faster recovery of blood flow than VEGF or DAPT alone; perfusion levels reached 80% of the normal level by week 4 with combined DAPT and VEGF delivery. Direct intramuscular or intraperitoneal injection of DAPT did not result in the same level of improvement, suggesting that appropriate presentation of DAPT (gel delivery) is important for its activity. DAPT delivery from the hydrogels also did not lead to any adverse side effects, in contrast to systemic introduction of DAPT. Altogether, these results suggest a new approach to promote angiogenesis by controlling Notch signaling, and may provide new options to treat patients with diseases that diminish angiogenic responsiveness.\n" ], "offsets": [ [ 0, 1730 ] ] } ]

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[]

[ { "id": "PMID-14604834__text", "type": "abstract", "text": [ "Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels.\n\nThe vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.\n" ], "offsets": [ [ 0, 1399 ] ] } ]

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[]