data/mlee_validation.jsonl

{"input": "UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice.\n\nUFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective. Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis. Moreover, we have found that gamma-hydroxybutyric acid and gamma-butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabolites.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 36, "end": 48}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 480, "end": 492}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 527, "end": 539}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 649, "end": 661}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 868, "end": 880}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1002, "end": 1014}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1325, "end": 1337}, "arguments": []}], "Negative_regulation": [{"trigger": {"text": "inhibit", "start": 24, "end": 31}, "arguments": [{"role": "Cause", "text": "UFT", "start": 0, "end": 3}, {"role": "Theme", "text": "angiogenesis", "start": 36, "end": 48}]}, {"trigger": {"text": "inhibitory effect", "start": 428, "end": 445}, "arguments": [{"role": "Cause", "text": "UFT", "start": 449, "end": 452}, {"role": "Theme", "text": "angiogenesis", "start": 480, "end": 492}]}, {"trigger": {"text": "inhibitory effect", "start": 662, "end": 679}, "arguments": [{"role": "Cause", "text": "UFT", "start": 629, "end": 632}, {"role": "Theme", "text": "angiogenesis", "start": 649, "end": 661}]}, {"trigger": {"text": "effective", "start": 739, "end": 748}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 649, "end": 661}, {"role": "Cause", "text": "5-fluorouracil", "start": 689, "end": 703}]}, {"trigger": {"text": "effective", "start": 739, "end": 748}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 649, "end": 661}, {"role": "Cause", "text": "doxifluridine", "start": 715, "end": 728}]}, {"trigger": {"text": "inhibition", "start": 854, "end": 864}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 868, "end": 880}]}, {"trigger": {"text": "inhibitory effect", "start": 1015, "end": 1032}, "arguments": [{"role": "Cause", "text": "gamma-hydroxybutyric acid", "start": 911, "end": 936}, {"role": "Theme", "text": "angiogenesis", "start": 1002, "end": 1014}]}, {"trigger": {"text": "inhibitory effect", "start": 1015, "end": 1032}, "arguments": [{"role": "Cause", "text": "gamma-butyrolactone", "start": 941, "end": 960}, {"role": "Theme", "text": "angiogenesis", "start": 1002, "end": 1014}]}, {"trigger": {"text": "inhibitory effect", "start": 1338, "end": 1355}, "arguments": [{"role": "Cause", "text": "UFT", "start": 1306, "end": 1309}, {"role": "Theme", "text": "angiogenesis", "start": 1325, "end": 1337}]}, {"trigger": {"text": "inhibitory effect", "start": 1338, "end": 1355}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1325, "end": 1337}, {"role": "Cause", "text": "fluorinated pyrimidines", "start": 1371, "end": 1394}]}], "Planned_process": [{"trigger": {"text": "treat", "start": 281, "end": 286}, "arguments": [{"role": "Instrument", "text": "UFT", "start": 139, "end": 142}, {"role": "Theme", "text": "patients", "start": 294, "end": 302}]}, {"trigger": {"text": "chemotherapy", "start": 325, "end": 337}, "arguments": [{"role": "Theme", "text": "patients", "start": 294, "end": 302}]}, {"trigger": {"text": "implantation", "start": 554, "end": 566}, "arguments": [{"role": "Instrument", "text": "RENCA cells", "start": 591, "end": 602}, {"role": "Theme", "text": "mice", "start": 608, "end": 612}]}, {"trigger": {"text": "administered", "start": 1074, "end": 1086}, "arguments": [{"role": "Instrument", "text": "gamma-hydroxybutyric acid", "start": 911, "end": 936}]}, {"trigger": {"text": "administered", "start": 1074, "end": 1086}, "arguments": [{"role": "Instrument", "text": "gamma-butyrolactone", "start": 941, "end": 960}]}, {"trigger": {"text": "administration", "start": 1204, "end": 1218}, "arguments": [{"role": "Instrument", "text": "UFT", "start": 1222, "end": 1225}]}], "Positive_regulation": [{"trigger": {"text": "induced", "start": 49, "end": 56}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 36, "end": 48}, {"role": "Cause", "text": "renal cell carcinoma", "start": 67, "end": 87}]}, {"trigger": {"text": "induced", "start": 472, "end": 479}, "arguments": [{"role": "Cause", "text": "RENCA cell", "start": 461, "end": 471}, {"role": "Theme", "text": "angiogenesis", "start": 480, "end": 492}]}, {"trigger": {"text": "induced", "start": 543, "end": 550}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 527, "end": 539}, {"role": "Cause", "text": "implantation", "start": 554, "end": 566}]}, {"trigger": {"text": "amplified", "start": 1041, "end": 1050}, "arguments": [{"role": "Theme", "text": "gamma-hydroxybutyric acid", "start": 911, "end": 936}]}, {"trigger": {"text": "amplified", "start": 1041, "end": 1050}, "arguments": [{"role": "Theme", "text": "gamma-butyrolactone", "start": 941, "end": 960}]}], "Regulation": [{"trigger": {"text": "ineffective", "start": 835, "end": 846}, "arguments": [{"role": "Cause", "text": "uracil", "start": 819, "end": 825}, {"role": "Theme", "text": "inhibition", "start": 854, "end": 864}]}]}}, "schema": []}
{"input": "Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions.\n\nNitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0-64% and 0-63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 256, "end": 268}, "arguments": [{"role": "AtLoc", "text": "tumour", "start": 249, "end": 255}]}], "Growth": [{"trigger": {"text": "growth", "start": 419, "end": 425}, "arguments": [{"role": "Theme", "text": "vascular", "start": 410, "end": 418}]}, {"trigger": {"text": "growth", "start": 774, "end": 780}, "arguments": [{"role": "Theme", "text": "adenocarcinoma", "start": 784, "end": 798}]}, {"trigger": {"text": "growth", "start": 884, "end": 890}, "arguments": [{"role": "Theme", "text": "tumour", "start": 877, "end": 883}]}, {"trigger": {"text": "growth", "start": 1290, "end": 1296}, "arguments": [{"role": "Theme", "text": "tumour", "start": 1283, "end": 1289}]}], "Localization": [{"trigger": {"text": "reach", "start": 377, "end": 382}, "arguments": [{"role": "Theme", "text": "oxygen", "start": 367, "end": 373}, {"role": "ToLoc", "text": "tumour tissue", "start": 383, "end": 396}]}], "Negative_regulation": [{"trigger": {"text": "inhibition", "start": 22, "end": 32}, "arguments": [{"role": "Theme", "text": "Nitric oxide synthase", "start": 0, "end": 21}]}, {"trigger": {"text": "activity", "start": 68, "end": 76}, "arguments": [{"role": "Theme", "text": "tumour", "start": 61, "end": 67}, {"role": "Cause", "text": "melphalan", "start": 82, "end": 91}]}, {"trigger": {"text": "Inhibition", "start": 270, "end": 280}, "arguments": [{"role": "Theme", "text": "NO synthase", "start": 284, "end": 295}, {"role": "Cause", "text": "L-NAME", "start": 299, "end": 305}]}, {"trigger": {"text": "effect", "start": 334, "end": 340}, "arguments": [{"role": "Theme", "text": "tumour", "start": 327, "end": 333}]}, {"trigger": {"text": "limiting", "start": 344, "end": 352}, "arguments": [{"role": "Cause", "text": "Inhibition", "start": 270, "end": 280}, {"role": "Theme", "text": "reach", "start": 377, "end": 382}]}, {"trigger": {"text": "effect", "start": 443, "end": 449}, "arguments": [{"role": "Theme", "text": "tumour", "start": 436, "end": 442}, {"role": "Cause", "text": "L-NAME", "start": 453, "end": 459}]}, {"trigger": {"text": "inhibited", "start": 764, "end": 773}, "arguments": [{"role": "Cause", "text": "treatment", "start": 742, "end": 751}, {"role": "Theme", "text": "growth", "start": 774, "end": 780}]}, {"trigger": {"text": "impaired", "start": 836, "end": 844}, "arguments": [{"role": "Theme", "text": "renal", "start": 845, "end": 850}]}, {"trigger": {"text": "reduced", "start": 869, "end": 876}, "arguments": [{"role": "Theme", "text": "growth", "start": 884, "end": 890}]}, {"trigger": {"text": "effect", "start": 1112, "end": 1118}, "arguments": [{"role": "Theme", "text": "tumour", "start": 1105, "end": 1111}, {"role": "Cause", "text": "added", "start": 1152, "end": 1157}]}, {"trigger": {"text": "Inhibition", "start": 1249, "end": 1259}, "arguments": [{"role": "Theme", "text": "NO synthase", "start": 1263, "end": 1274}]}, {"trigger": {"text": "reduces", "start": 1275, "end": 1282}, "arguments": [{"role": "Cause", "text": "Inhibition", "start": 1249, "end": 1259}, {"role": "Theme", "text": "growth", "start": 1290, "end": 1296}]}, {"trigger": {"text": "effect", "start": 1373, "end": 1379}, "arguments": [{"role": "Theme", "text": "tumour", "start": 1366, "end": 1372}, {"role": "Cause", "text": "L-NAME", "start": 1383, "end": 1389}]}], "Planned_process": [{"trigger": {"text": "administration", "start": 475, "end": 489}, "arguments": [{"role": "Instrument", "text": "L-NAME", "start": 453, "end": 459}, {"role": "Theme", "text": "rats", "start": 555, "end": 559}]}, {"trigger": {"text": "administration", "start": 580, "end": 594}, "arguments": [{"role": "Instrument", "text": "L-NAME", "start": 598, "end": 604}, {"role": "Instrument", "text": "TNF", "start": 626, "end": 629}, {"role": "Instrument", "text": "melphalan", "start": 634, "end": 643}]}, {"trigger": {"text": "treatment", "start": 742, "end": 751}, "arguments": [{"role": "Instrument", "text": "L-NAME", "start": 757, "end": 763}]}, {"trigger": {"text": "added", "start": 1152, "end": 1157}, "arguments": [{"role": "Instrument", "text": "L-NAME", "start": 1141, "end": 1147}, {"role": "Instrument", "text": "melphalan", "start": 1192, "end": 1201}, {"role": "Instrument", "text": "TNF", "start": 1206, "end": 1209}]}, {"trigger": {"text": "treatment", "start": 1511, "end": 1520}, "arguments": [{"role": "Theme", "text": "tumours", "start": 1530, "end": 1537}]}], "Positive_regulation": [{"trigger": {"text": "results", "start": 33, "end": 40}, "arguments": [{"role": "Cause", "text": "inhibition", "start": 22, "end": 32}, {"role": "Theme", "text": "activity", "start": 68, "end": 76}]}, {"trigger": {"text": "stimulating", "start": 237, "end": 248}, "arguments": [{"role": "Cause", "text": "Nitric oxide", "start": 158, "end": 170}, {"role": "Theme", "text": "angiogenesis", "start": 256, "end": 268}]}, {"trigger": {"text": "induce", "start": 312, "end": 318}, "arguments": [{"role": "Theme", "text": "effect", "start": 334, "end": 340}, {"role": "Cause", "text": "limiting", "start": 344, "end": 352}]}, {"trigger": {"text": "induce", "start": 312, "end": 318}, "arguments": [{"role": "Theme", "text": "effect", "start": 334, "end": 340}, {"role": "Cause", "text": "affecting", "start": 400, "end": 409}]}], "Regulation": [{"trigger": {"text": "affecting", "start": 400, "end": 409}, "arguments": [{"role": "Cause", "text": "Inhibition", "start": 270, "end": 280}, {"role": "Theme", "text": "growth", "start": 419, "end": 425}]}, {"trigger": {"text": "role", "start": 1488, "end": 1492}, "arguments": [{"role": "Cause", "text": "L-NAME", "start": 1496, "end": 1502}, {"role": "Theme", "text": "treatment", "start": 1511, "end": 1520}]}]}}, "schema": []}
{"input": "Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia.\n\nAngiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently VEGF-B and VEGF-C, two new VEGF family members, have been identified that bind to the tyrosine kinase receptors flt-1 (VEGFR1), KDR (VEGFR2), and flt-4 (VEGFR3). Although the importance of VEGF-A has been shown in renal carcinomas, the contribution of these new ligands in kidney tumors is not clear. We have, therefore, measured the mRNA level of VEGF-B and VEGF-C together with their receptors by RNase protection assay (RPA) in 26 normal kidney samples and 45 renal cell cancers. We observed a significant up-regulation of VEGF-B (P = 0.002) but not VEGF-C (P = 0.3) in neoplastic kidney compared with normal tissues. In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09). There was also a significant correlation between VEGF-C and both of its receptors flt-4 (P = 0.006) and KDR (P = 0.03) but no association between VEGF-B and its receptor flt-1 (P = 0.23). A significant increase was observed in flt-1 (P  less than  0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas. No significant association was demonstrated between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with patient sex, patient age, or tumor size (P  greater than  0.05). The effect of von Hippel-Lindau (VHL) gene and hypoxia on VEGF-B and VEGF-C expression in the renal carcinoma cell line 786-0 transfected with wild-type and mutant VHL was determined by growing cells under 21% O2- and 0.1% O2. In wild-type VHL cells, whereas VEGF-A was significantly up-regulated under hypoxic compared with normoxic conditions (P  less than  0.001), expression of VEGF-C was reduced (P  less than  0.002). Nevertheless, the repression of VEGF-C was lost in mutant VHL cell lines under hypoxia. In contrast VEGF-B was not regulated by VHL despite clear up-regulation in vivo. These findings strongly support an enhanced role for this pathway in clear cell carcinomas by regulating angiogenesis and/or lymphangiogenesis. The study shows that clear cell tumors are able to up-regulate angiogenic growth factor receptors more efficiently than chromophil (papillary), that clear cell tumors can use pathways independent of VHL to regulate angiogenesis, and that this combined regulation may account for their more aggressive phenotype, which suggests that targeting VEGFR1 (flt-l) may be particularly effective in these tumor types.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 361, "end": 367}, {"role": "Theme", "text": "flt-1", "start": 473, "end": 478}]}, {"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 361, "end": 367}, {"role": "Theme", "text": "KDR", "start": 489, "end": 492}]}, {"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 361, "end": 367}, {"role": "Theme", "text": "flt-4", "start": 507, "end": 512}]}, {"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 372, "end": 378}, {"role": "Theme", "text": "flt-1", "start": 473, "end": 478}]}, {"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 372, "end": 378}, {"role": "Theme", "text": "KDR", "start": 489, "end": 492}]}, {"trigger": {"text": "bind", "start": 435, "end": 439}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 372, "end": 378}, {"role": "Theme", "text": "flt-4", "start": 507, "end": 512}]}], "Blood_vessel_development": [{"trigger": {"text": "Angiogenesis", "start": 170, "end": 182}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 257, "end": 267}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 2441, "end": 2453}, "arguments": []}, {"trigger": {"text": "lymphangiogenesis", "start": 2461, "end": 2478}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 2543, "end": 2553}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 2695, "end": 2707}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "growing", "start": 1929, "end": 1936}, "arguments": [{"role": "Theme", "text": "cells", "start": 1937, "end": 1942}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 78, "end": 88}, "arguments": [{"role": "Theme", "text": "Vascular endothelial growth factor-B", "start": 0, "end": 36}]}, {"trigger": {"text": "expression", "start": 78, "end": 88}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor-C", "start": 41, "end": 77}]}, {"trigger": {"text": "expression", "start": 1509, "end": 1519}, "arguments": [{"role": "Theme", "text": "flt-1", "start": 1396, "end": 1401}]}, {"trigger": {"text": "expression", "start": 1509, "end": 1519}, "arguments": [{"role": "Theme", "text": "KDR", "start": 1425, "end": 1428}]}, {"trigger": {"text": "expression", "start": 1509, "end": 1519}, "arguments": [{"role": "Theme", "text": "flt-4", "start": 1445, "end": 1450}]}, {"trigger": {"text": "expression", "start": 1509, "end": 1519}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 1470, "end": 1476}]}, {"trigger": {"text": "expression", "start": 1509, "end": 1519}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 1491, "end": 1497}]}, {"trigger": {"text": "expression", "start": 1819, "end": 1829}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 1801, "end": 1807}]}, {"trigger": {"text": "expression", "start": 1819, "end": 1829}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 1812, "end": 1818}]}, {"trigger": {"text": "expression", "start": 2111, "end": 2121}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 2125, "end": 2131}]}], "Growth": [{"trigger": {"text": "growth", "start": 206, "end": 212}, "arguments": [{"role": "Theme", "text": "tumor", "start": 200, "end": 205}]}], "Localization": [{"trigger": {"text": "metastasis", "start": 217, "end": 227}, "arguments": [{"role": "Theme", "text": "tumor", "start": 200, "end": 205}]}], "Negative_regulation": [{"trigger": {"text": "reduced", "start": 2136, "end": 2143}, "arguments": [{"role": "Theme", "text": "expression", "start": 2111, "end": 2121}]}, {"trigger": {"text": "repression", "start": 2185, "end": 2195}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 2199, "end": 2205}]}], "Planned_process": [{"trigger": {"text": "transfected", "start": 1869, "end": 1880}, "arguments": [{"role": "Theme", "text": "786-0", "start": 1863, "end": 1868}, {"role": "Instrument", "text": "VHL", "start": 1907, "end": 1910}]}], "Positive_regulation": [{"trigger": {"text": "essential", "start": 186, "end": 195}, "arguments": [{"role": "Cause", "text": "Angiogenesis", "start": 170, "end": 182}, {"role": "Theme", "text": "growth", "start": 206, "end": 212}]}, {"trigger": {"text": "essential", "start": 186, "end": 195}, "arguments": [{"role": "Cause", "text": "Angiogenesis", "start": 170, "end": 182}, {"role": "Theme", "text": "metastasis", "start": 217, "end": 227}]}, {"trigger": {"text": "up-regulation", "start": 870, "end": 883}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 887, "end": 893}]}, {"trigger": {"text": "up-regulation", "start": 870, "end": 883}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 914, "end": 920}]}, {"trigger": {"text": "up-regulation", "start": 1085, "end": 1098}, "arguments": [{"role": "Theme", "text": "flt-1", "start": 1107, "end": 1112}]}, {"trigger": {"text": "up-regulation", "start": 1085, "end": 1098}, "arguments": [{"role": "Theme", "text": "KDR", "start": 1133, "end": 1136}]}, {"trigger": {"text": "up-regulation", "start": 1085, "end": 1098}, "arguments": [{"role": "Theme", "text": "flt-4", "start": 1151, "end": 1156}]}, {"trigger": {"text": "increase", "start": 1371, "end": 1379}, "arguments": [{"role": "Theme", "text": "expression", "start": 1509, "end": 1519}]}, {"trigger": {"text": "up-regulated", "start": 2027, "end": 2039}, "arguments": [{"role": "Theme", "text": "VEGF-A", "start": 2002, "end": 2008}]}, {"trigger": {"text": "up-regulation", "start": 2313, "end": 2326}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 2267, "end": 2273}, {"role": "Cause", "text": "VHL", "start": 2295, "end": 2298}]}], "Regulation": [{"trigger": {"text": "effect", "start": 1747, "end": 1753}, "arguments": [{"role": "Cause", "text": "von Hippel-Lindau", "start": 1757, "end": 1774}, {"role": "Theme", "text": "expression", "start": 1819, "end": 1829}]}, {"trigger": {"text": "regulated", "start": 2282, "end": 2291}, "arguments": [{"role": "Theme", "text": "VEGF-B", "start": 2267, "end": 2273}, {"role": "Cause", "text": "VHL", "start": 2295, "end": 2298}]}, {"trigger": {"text": "regulating", "start": 2430, "end": 2440}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 2441, "end": 2453}]}, {"trigger": {"text": "regulating", "start": 2430, "end": 2440}, "arguments": [{"role": "Theme", "text": "lymphangiogenesis", "start": 2461, "end": 2478}]}, {"trigger": {"text": "regulate", "start": 2686, "end": 2694}, "arguments": [{"role": "Cause", "text": "VHL", "start": 2679, "end": 2682}, {"role": "Theme", "text": "angiogenesis", "start": 2695, "end": 2707}]}]}}, "schema": []}
{"input": "Retinal microangiopathies overlying pigment epithelial detachment in age-related macular degeneration.\n\nPURPOSE: To evaluate alterations in the retinal vasculature overlying pigment epithelial detachments (PED) in exudative age-related macular degeneration (ARMD) using indocyanine green and fluorescein angiography. METHODS: Forty-one patients (41 eyes) with a clinical diagnosis of exudative ARMD with PED underwent simultaneous fluorescein and indocyanine green angiography, also under high (10 degrees ) magnification. Vascular abnormalities in the retina were compared between patients with vascularized (n = 34, group 1) and nonvascularized (n = 7, group 2) PED on indocyanine green angiography and correlated with the size of the PED and the presence of serous retinal detachment. RESULTS: In all, 67 vascular abnormalities were found by indocyanine green angiography and only 22 by fluorescein angiography; this finding was statistically significant (P  less than  0.0001). The finding of retinal vasculopathy (32 patients in group 1 and two patients in group 2) was directly correlated with the presence of choroidal neovascularizations (P = 0.002). There was also a direct correlation between the presence of choroidal neovascularization and size of the PED (P = 0.03). The number of retinal vascular findings was not significantly correlated with serous elevation of the retina. CONCLUSIONS: Retinal vasculopathies may be observed in eyes with PED and are detectable by indocyanine green and fluorescein angiography.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularizations", "start": 1126, "end": 1145}, "arguments": []}, {"trigger": {"text": "neovascularization", "start": 1229, "end": 1247}, "arguments": []}], "Breakdown": [{"trigger": {"text": "detachment", "start": 55, "end": 65}, "arguments": [{"role": "Theme", "text": "pigment epithelial", "start": 36, "end": 54}]}, {"trigger": {"text": "degeneration", "start": 89, "end": 101}, "arguments": [{"role": "Theme", "text": "macular", "start": 81, "end": 88}]}, {"trigger": {"text": "detachments", "start": 193, "end": 204}, "arguments": [{"role": "Theme", "text": "pigment epithelial", "start": 174, "end": 192}]}, {"trigger": {"text": "degeneration", "start": 244, "end": 256}, "arguments": [{"role": "Theme", "text": "macular", "start": 236, "end": 243}]}, {"trigger": {"text": "detachment", "start": 776, "end": 786}, "arguments": [{"role": "Theme", "text": "serous retinal", "start": 761, "end": 775}]}], "Planned_process": [{"trigger": {"text": "angiography", "start": 465, "end": 476}, "arguments": [{"role": "Theme", "text": "eyes", "start": 349, "end": 353}, {"role": "Instrument", "text": "fluorescein", "start": 431, "end": 442}, {"role": "Instrument", "text": "indocyanine green", "start": 447, "end": 464}]}, {"trigger": {"text": "angiography", "start": 1515, "end": 1526}, "arguments": [{"role": "Theme", "text": "eyes", "start": 1445, "end": 1449}, {"role": "Instrument", "text": "indocyanine green", "start": 1481, "end": 1498}, {"role": "Instrument", "text": "fluorescein", "start": 1503, "end": 1514}]}], "Positive_regulation": [{"trigger": {"text": "elevation", "start": 1365, "end": 1374}, "arguments": [{"role": "Theme", "text": "retina", "start": 1382, "end": 1388}]}], "Remodeling": [{"trigger": {"text": "alterations", "start": 125, "end": 136}, "arguments": [{"role": "Theme", "text": "retinal vasculature", "start": 144, "end": 163}]}]}}, "schema": []}
{"input": "Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells.\n\nEndothelial cell migration is an essential step in vasculogenesis and angiogenesis, in which receptor tyrosine kinases play a pivotal role. We investigated the mechanism by which ephrin-B1 promotes membrane ruffling in human aortic endothelial cells, because membrane ruffling heralds cell body migration. We especially focused on the role of Crk adaptor protein in EphB-mediated signaling. Using DsRed-tagged Crk and a fluorescent time-lapse microscope, we showed that Crk was recruited to the nascent focal complex after ephrin-B1 stimulation. Furthermore, we found that p130(Cas), but not paxillin, recruited Crk to the nascent focal complex. The necessity of Crk in ephrin-B1-induced membrane ruffling was shown both by the overexpression of dominant negative Crk mutants and by the depletion of Crk by using RNA interference. Then, we examined the role of two major downstream molecules of Crk, Rac1 and Rap1. The dominant negative mutant of Rac1 completely inhibited ephrin-B1-induced membrane ruffling and focal complex assembly. In contrast, rap1GAPII, a negative regulator of Rap1, did not inhibit ephrin-B1-induced membrane ruffling. However, in rap1GAPII-expressing cells, ephrin-B1 did not induce membrane spreading, probably due to instability of the focal complex. These results indicated that Crk plays a critical role in Rac1-induced membrane ruffling and Rap1-mediated nascent focal complex stabilization contributing to ephrin-B1-induced human aortic endothelial cells migration.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "assembly", "start": 90, "end": 98}, "arguments": [{"role": "Theme", "text": "focal complex", "start": 76, "end": 89}]}, {"trigger": {"text": "assembly", "start": 1162, "end": 1170}, "arguments": [{"role": "Theme", "text": "focal complex", "start": 1148, "end": 1161}]}], "Blood_vessel_development": [{"trigger": {"text": "vasculogenesis", "start": 186, "end": 200}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 205, "end": 217}, "arguments": []}], "Gene_expression": [{"trigger": {"text": "expressing", "start": 1301, "end": 1311}, "arguments": [{"role": "Theme", "text": "rap1GAPII", "start": 1291, "end": 1300}]}], "Localization": [{"trigger": {"text": "ruffling", "start": 63, "end": 71}, "arguments": [{"role": "Theme", "text": "membrane", "start": 54, "end": 62}]}, {"trigger": {"text": "migration", "start": 152, "end": 161}, "arguments": [{"role": "Theme", "text": "Endothelial cell", "start": 135, "end": 151}]}, {"trigger": {"text": "ruffling", "start": 342, "end": 350}, "arguments": [{"role": "Theme", "text": "membrane", "start": 333, "end": 341}]}, {"trigger": {"text": "ruffling", "start": 403, "end": 411}, "arguments": [{"role": "Theme", "text": "membrane", "start": 394, "end": 402}]}, {"trigger": {"text": "migration", "start": 430, "end": 439}, "arguments": [{"role": "Theme", "text": "cell body", "start": 420, "end": 429}]}, {"trigger": {"text": "recruited", "start": 613, "end": 622}, "arguments": [{"role": "Theme", "text": "Crk", "start": 605, "end": 608}, {"role": "ToLoc", "text": "nascent focal complex", "start": 630, "end": 651}]}, {"trigger": {"text": "recruited", "start": 737, "end": 746}, "arguments": [{"role": "Theme", "text": "Crk", "start": 747, "end": 750}, {"role": "ToLoc", "text": "nascent focal complex", "start": 758, "end": 779}]}, {"trigger": {"text": "ruffling", "start": 832, "end": 840}, "arguments": [{"role": "Theme", "text": "membrane", "start": 823, "end": 831}]}, {"trigger": {"text": "ruffling", "start": 1135, "end": 1143}, "arguments": [{"role": "Theme", "text": "membrane", "start": 1126, "end": 1134}]}, {"trigger": {"text": "ruffling", "start": 1269, "end": 1277}, "arguments": [{"role": "Theme", "text": "membrane", "start": 1260, "end": 1268}]}, {"trigger": {"text": "spreading", "start": 1353, "end": 1362}, "arguments": [{"role": "Theme", "text": "membrane", "start": 1344, "end": 1352}]}, {"trigger": {"text": "ruffling", "start": 1494, "end": 1502}, "arguments": [{"role": "Theme", "text": "membrane", "start": 1485, "end": 1493}]}, {"trigger": {"text": "migration", "start": 1622, "end": 1631}, "arguments": [{"role": "Theme", "text": "aortic endothelial cells", "start": 1597, "end": 1621}]}], "Negative_regulation": [{"trigger": {"text": "depletion", "start": 922, "end": 931}, "arguments": [{"role": "Theme", "text": "Crk", "start": 935, "end": 938}]}, {"trigger": {"text": "inhibited", "start": 1098, "end": 1107}, "arguments": [{"role": "Cause", "text": "Rac1", "start": 1082, "end": 1086}, {"role": "Theme", "text": "induced", "start": 1118, "end": 1125}]}, {"trigger": {"text": "inhibit", "start": 1234, "end": 1241}, "arguments": [{"role": "Cause", "text": "rap1GAPII", "start": 1185, "end": 1194}, {"role": "Theme", "text": "ruffling", "start": 1269, "end": 1277}]}], "Pathway": [{"trigger": {"text": "signaling", "start": 515, "end": 524}, "arguments": []}], "Planned_process": [{"trigger": {"text": "tagged", "start": 538, "end": 544}, "arguments": [{"role": "Instrument", "text": "DsRed", "start": 532, "end": 537}, {"role": "Theme", "text": "Crk", "start": 545, "end": 548}]}, {"trigger": {"text": "stabilization", "start": 1543, "end": 1556}, "arguments": [{"role": "Theme", "text": "nascent focal complex", "start": 1521, "end": 1542}]}], "Positive_regulation": [{"trigger": {"text": "required", "start": 23, "end": 31}, "arguments": [{"role": "Cause", "text": "Crk", "start": 16, "end": 19}, {"role": "Theme", "text": "ruffling", "start": 63, "end": 71}]}, {"trigger": {"text": "required", "start": 23, "end": 31}, "arguments": [{"role": "Cause", "text": "Crk", "start": 16, "end": 19}, {"role": "Theme", "text": "assembly", "start": 90, "end": 98}]}, {"trigger": {"text": "induced", "start": 46, "end": 53}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 36, "end": 45}, {"role": "Theme", "text": "ruffling", "start": 63, "end": 71}]}, {"trigger": {"text": "induced", "start": 46, "end": 53}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 36, "end": 45}, {"role": "Theme", "text": "assembly", "start": 90, "end": 98}]}, {"trigger": {"text": "essential", "start": 168, "end": 177}, "arguments": [{"role": "Cause", "text": "migration", "start": 152, "end": 161}, {"role": "Theme", "text": "vasculogenesis", "start": 186, "end": 200}]}, {"trigger": {"text": "essential", "start": 168, "end": 177}, "arguments": [{"role": "Cause", "text": "migration", "start": 152, "end": 161}, {"role": "Theme", "text": "angiogenesis", "start": 205, "end": 217}]}, {"trigger": {"text": "promotes", "start": 324, "end": 332}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 314, "end": 323}, {"role": "Theme", "text": "ruffling", "start": 342, "end": 350}]}, {"trigger": {"text": "mediated", "start": 506, "end": 514}, "arguments": [{"role": "Cause", "text": "EphB", "start": 501, "end": 505}, {"role": "Theme", "text": "signaling", "start": 515, "end": 524}]}, {"trigger": {"text": "stimulation", "start": 668, "end": 679}, "arguments": [{"role": "Theme", "text": "recruited", "start": 613, "end": 622}, {"role": "Cause", "text": "ephrin-B1", "start": 658, "end": 667}]}, {"trigger": {"text": "recruited", "start": 737, "end": 746}, "arguments": [{"role": "Cause", "text": "p130(Cas)", "start": 708, "end": 717}, {"role": "Theme", "text": "recruited", "start": 737, "end": 746}]}, {"trigger": {"text": "recruited", "start": 737, "end": 746}, "arguments": [{"role": "Cause", "text": "paxillin", "start": 727, "end": 735}, {"role": "Theme", "text": "recruited", "start": 737, "end": 746}]}, {"trigger": {"text": "necessity", "start": 785, "end": 794}, "arguments": [{"role": "Cause", "text": "Crk", "start": 798, "end": 801}, {"role": "Theme", "text": "ruffling", "start": 832, "end": 840}]}, {"trigger": {"text": "induced", "start": 815, "end": 822}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 805, "end": 814}, {"role": "Theme", "text": "ruffling", "start": 832, "end": 840}]}, {"trigger": {"text": "induced", "start": 1118, "end": 1125}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 1108, "end": 1117}, {"role": "Theme", "text": "ruffling", "start": 1135, "end": 1143}]}, {"trigger": {"text": "induced", "start": 1118, "end": 1125}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 1108, "end": 1117}, {"role": "Theme", "text": "assembly", "start": 1162, "end": 1170}]}, {"trigger": {"text": "induced", "start": 1252, "end": 1259}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 1242, "end": 1251}, {"role": "Theme", "text": "ruffling", "start": 1269, "end": 1277}]}, {"trigger": {"text": "induce", "start": 1337, "end": 1343}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 1319, "end": 1328}, {"role": "Theme", "text": "spreading", "start": 1353, "end": 1362}]}, {"trigger": {"text": "induced", "start": 1477, "end": 1484}, "arguments": [{"role": "Cause", "text": "Rac1", "start": 1472, "end": 1476}, {"role": "Theme", "text": "ruffling", "start": 1494, "end": 1502}]}, {"trigger": {"text": "induced", "start": 1583, "end": 1590}, "arguments": [{"role": "Cause", "text": "ephrin-B1", "start": 1573, "end": 1582}, {"role": "Theme", "text": "migration", "start": 1622, "end": 1631}]}], "Regulation": [{"trigger": {"text": "play a pivotal role", "start": 254, "end": 273}, "arguments": [{"role": "Theme", "text": "vasculogenesis", "start": 186, "end": 200}, {"role": "Cause", "text": "receptor tyrosine kinases", "start": 228, "end": 253}]}, {"trigger": {"text": "play a pivotal role", "start": 254, "end": 273}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 205, "end": 217}, {"role": "Cause", "text": "receptor tyrosine kinases", "start": 228, "end": 253}]}, {"trigger": {"text": "role", "start": 470, "end": 474}, "arguments": [{"role": "Cause", "text": "Crk", "start": 478, "end": 481}, {"role": "Theme", "text": "signaling", "start": 515, "end": 524}]}, {"trigger": {"text": "plays a critical role", "start": 1447, "end": 1468}, "arguments": [{"role": "Cause", "text": "Crk", "start": 1443, "end": 1446}, {"role": "Theme", "text": "ruffling", "start": 1494, "end": 1502}]}, {"trigger": {"text": "plays a critical role", "start": 1447, "end": 1468}, "arguments": [{"role": "Cause", "text": "Crk", "start": 1443, "end": 1446}, {"role": "Theme", "text": "stabilization", "start": 1543, "end": 1556}]}, {"trigger": {"text": "mediated", "start": 1512, "end": 1520}, "arguments": [{"role": "Cause", "text": "Rap1", "start": 1507, "end": 1511}, {"role": "Theme", "text": "stabilization", "start": 1543, "end": 1556}]}, {"trigger": {"text": "contributing", "start": 1557, "end": 1569}, "arguments": [{"role": "Cause", "text": "Crk", "start": 1443, "end": 1446}, {"role": "Theme", "text": "migration", "start": 1622, "end": 1631}]}]}}, "schema": []}
{"input": "Postoperative progression of pulmonary metastasis in osteosarcoma.\n\nEarly relapse with distant metastasis often is observed in patients with cancer after resection of the primary tumor. It is considered that resection of the primary tumor induces activation of systemic angiogenesis and enhances progression of remote metastasis. The authors show that resection of the primary osteosarcoma tumor enhances progression of pulmonary metastasis in animal osteosarcoma models. Matrigel plug neovascularization assay revealed that systemic angiogenic activity was elevated after primary tumor removal (tumor intact group, 1.61 +/- 0.21 g/dL; tumor removed group, 4.92 +/- 0.35 g/dL). In addition, serum concentration of the angiogenesis inhibitor, endostatin, decreased significantly after primary tumor removal. Treatment with the antiangiogenic reagent TNP-470 suppressed postoperative progression of pulmonary metastasis. These results indicate the possibility that activation of angiogenic activity after resection of osteosarcoma tumors enhances progression of pulmonary metastasis. The current data also suggest that administration of antiangiogenic reagents can prevent progression of pulmonary metastasis in osteosarcoma postoperatively.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 270, "end": 282}, "arguments": []}, {"trigger": {"text": "neovascularization", "start": 486, "end": 504}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 534, "end": 544}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 718, "end": 730}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 830, "end": 840}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 977, "end": 987}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1139, "end": 1149}, "arguments": []}], "Localization": [{"trigger": {"text": "metastasis", "start": 39, "end": 49}, "arguments": [{"role": "ToLoc", "text": "pulmonary", "start": 29, "end": 38}, {"role": "Theme", "text": "osteosarcoma", "start": 53, "end": 65}]}, {"trigger": {"text": "metastasis", "start": 95, "end": 105}, "arguments": [{"role": "Theme", "text": "tumor", "start": 179, "end": 184}]}, {"trigger": {"text": "metastasis", "start": 318, "end": 328}, "arguments": [{"role": "Theme", "text": "tumor", "start": 233, "end": 238}]}, {"trigger": {"text": "metastasis", "start": 430, "end": 440}, "arguments": [{"role": "Theme", "text": "osteosarcoma tumor", "start": 377, "end": 395}, {"role": "ToLoc", "text": "pulmonary", "start": 420, "end": 429}]}, {"trigger": {"text": "metastasis", "start": 907, "end": 917}, "arguments": [{"role": "Theme", "text": "tumor", "start": 792, "end": 797}, {"role": "ToLoc", "text": "pulmonary", "start": 897, "end": 906}]}, {"trigger": {"text": "metastasis", "start": 1070, "end": 1080}, "arguments": [{"role": "Theme", "text": "osteosarcoma tumors", "start": 1016, "end": 1035}, {"role": "ToLoc", "text": "pulmonary", "start": 1060, "end": 1069}]}, {"trigger": {"text": "metastasis", "start": 1196, "end": 1206}, "arguments": [{"role": "ToLoc", "text": "pulmonary", "start": 1186, "end": 1195}, {"role": "Theme", "text": "osteosarcoma", "start": 1210, "end": 1222}]}], "Negative_regulation": [{"trigger": {"text": "decreased", "start": 754, "end": 763}, "arguments": [{"role": "Theme", "text": "endostatin", "start": 742, "end": 752}]}, {"trigger": {"text": "suppressed", "start": 857, "end": 867}, "arguments": [{"role": "Cause", "text": "Treatment", "start": 807, "end": 816}, {"role": "Theme", "text": "progression", "start": 882, "end": 893}]}, {"trigger": {"text": "prevent", "start": 1163, "end": 1170}, "arguments": [{"role": "Cause", "text": "administration", "start": 1117, "end": 1131}, {"role": "Theme", "text": "progression", "start": 1171, "end": 1182}]}], "Planned_process": [{"trigger": {"text": "resection", "start": 154, "end": 163}, "arguments": [{"role": "Theme", "text": "tumor", "start": 179, "end": 184}]}, {"trigger": {"text": "resection", "start": 208, "end": 217}, "arguments": [{"role": "Theme", "text": "tumor", "start": 233, "end": 238}]}, {"trigger": {"text": "resection", "start": 352, "end": 361}, "arguments": [{"role": "Theme", "text": "osteosarcoma tumor", "start": 377, "end": 395}]}, {"trigger": {"text": "removal", "start": 587, "end": 594}, "arguments": [{"role": "Theme", "text": "tumor", "start": 581, "end": 586}]}, {"trigger": {"text": "removal", "start": 798, "end": 805}, "arguments": [{"role": "Theme", "text": "tumor", "start": 792, "end": 797}]}, {"trigger": {"text": "Treatment", "start": 807, "end": 816}, "arguments": [{"role": "Instrument", "text": "TNP-470", "start": 849, "end": 856}]}, {"trigger": {"text": "resection", "start": 1003, "end": 1012}, "arguments": [{"role": "Theme", "text": "osteosarcoma tumors", "start": 1016, "end": 1035}]}, {"trigger": {"text": "administration", "start": 1117, "end": 1131}, "arguments": [{"role": "Theme", "text": "osteosarcoma", "start": 1210, "end": 1222}]}], "Positive_regulation": [{"trigger": {"text": "progression", "start": 14, "end": 25}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 39, "end": 49}]}, {"trigger": {"text": "induces", "start": 239, "end": 246}, "arguments": [{"role": "Cause", "text": "resection", "start": 208, "end": 217}, {"role": "Theme", "text": "activation", "start": 247, "end": 257}]}, {"trigger": {"text": "activation", "start": 247, "end": 257}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 270, "end": 282}]}, {"trigger": {"text": "enhances", "start": 287, "end": 295}, "arguments": [{"role": "Cause", "text": "resection", "start": 208, "end": 217}, {"role": "Theme", "text": "progression", "start": 296, "end": 307}]}, {"trigger": {"text": "progression", "start": 296, "end": 307}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 318, "end": 328}]}, {"trigger": {"text": "enhances", "start": 396, "end": 404}, "arguments": [{"role": "Cause", "text": "resection", "start": 352, "end": 361}, {"role": "Theme", "text": "progression", "start": 405, "end": 416}]}, {"trigger": {"text": "progression", "start": 405, "end": 416}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 430, "end": 440}]}, {"trigger": {"text": "elevated", "start": 558, "end": 566}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 534, "end": 544}]}, {"trigger": {"text": "progression", "start": 882, "end": 893}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 907, "end": 917}]}, {"trigger": {"text": "activation", "start": 963, "end": 973}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 977, "end": 987}]}, {"trigger": {"text": "enhances", "start": 1036, "end": 1044}, "arguments": [{"role": "Cause", "text": "activation", "start": 963, "end": 973}, {"role": "Theme", "text": "progression", "start": 1045, "end": 1056}]}, {"trigger": {"text": "progression", "start": 1045, "end": 1056}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 1070, "end": 1080}]}, {"trigger": {"text": "progression", "start": 1171, "end": 1182}, "arguments": [{"role": "Theme", "text": "metastasis", "start": 1196, "end": 1206}]}]}}, "schema": []}
{"input": "Antiapoptotic effect of coagulation factor VIIa.\n\nBinding of factor VIIa (FVIIa) to its cellular receptor tissue factor (TF) was previously shown to induce various intracellular signaling events, which were thought to be responsible for TF-mediated biologic effects, including angiogenesis, tumor metastasis, and restenosis. To understand the mechanisms behind these processes, we have examined the effect of FVIIa on apoptosis. Serum deprivation-induced apoptosis of BHK(+TF) cells was characterized by apoptotic blebs, nuclei with chromatin-condensed bodies, DNA degradation, and activation of caspase 3. FVIIa markedly decreased the number of cells with apoptotic morphology and prevented the DNA degradation as measured by means of TdT-mediated dUTP nick end labeling (TUNEL). The antiapoptotic effect of FVIIa was confirmed by the observation that FVIIa attenuated caspase 3 activation. FVIIa-induced antiapoptotic effect was dependent on its proteolytic activity and TF but independent of factor Xa and thrombin. FVIIa-induced cell survival correlated with the activation of Akt and was inhibited markedly by the specific PI3-kinase inhibitor, LY294002. Blocking the activation of p44/42 mitogen-activated protein kinase (MAPK) by the specific mitogen-induced extracellular kinase (MEK) inhibitor, U0126, impaired modestly the ability of FVIIa to promote cell survival. In conclusion, FVIIa binding to TF provided protection against apoptosis induced by growth factor deprivation, primarily through activation of PI3-kinase/Akt pathway, and to a lesser extent, p44/42 MAPK pathway.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "Binding", "start": 50, "end": 57}, "arguments": [{"role": "Theme", "text": "factor VIIa", "start": 61, "end": 72}, {"role": "Theme", "text": "tissue factor", "start": 106, "end": 119}]}, {"trigger": {"text": "binding", "start": 1397, "end": 1404}, "arguments": [{"role": "Theme", "text": "FVIIa", "start": 1391, "end": 1396}, {"role": "Theme", "text": "TF", "start": 1408, "end": 1410}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 277, "end": 289}, "arguments": []}], "Death": [{"trigger": {"text": "apoptosis", "start": 455, "end": 464}, "arguments": [{"role": "Theme", "text": "BHK(+TF) cells", "start": 468, "end": 482}]}, {"trigger": {"text": "survival", "start": 1038, "end": 1046}, "arguments": [{"role": "Theme", "text": "cell", "start": 1033, "end": 1037}]}, {"trigger": {"text": "survival", "start": 1366, "end": 1374}, "arguments": [{"role": "Theme", "text": "cell", "start": 1361, "end": 1365}]}], "Localization": [{"trigger": {"text": "metastasis", "start": 297, "end": 307}, "arguments": [{"role": "Theme", "text": "tumor", "start": 291, "end": 296}]}], "Negative_regulation": [{"trigger": {"text": "attenuated", "start": 859, "end": 869}, "arguments": [{"role": "Cause", "text": "FVIIa", "start": 853, "end": 858}, {"role": "Theme", "text": "activation", "start": 880, "end": 890}]}, {"trigger": {"text": "Blocking", "start": 1160, "end": 1168}, "arguments": [{"role": "Theme", "text": "activation", "start": 1173, "end": 1183}, {"role": "Cause", "text": "U0126", "start": 1304, "end": 1309}]}, {"trigger": {"text": "impaired", "start": 1311, "end": 1319}, "arguments": [{"role": "Cause", "text": "Blocking", "start": 1160, "end": 1168}, {"role": "Theme", "text": "promote", "start": 1353, "end": 1360}]}], "Pathway": [{"trigger": {"text": "pathway", "start": 1534, "end": 1541}, "arguments": [{"role": "Participant", "text": "PI3-kinase", "start": 1519, "end": 1529}, {"role": "Participant2", "text": "Akt", "start": 1530, "end": 1533}]}, {"trigger": {"text": "pathway", "start": 1579, "end": 1586}, "arguments": [{"role": "Participant", "text": "p44/42 MAPK", "start": 1567, "end": 1578}]}], "Positive_regulation": [{"trigger": {"text": "induce", "start": 149, "end": 155}, "arguments": [{"role": "Cause", "text": "Binding", "start": 50, "end": 57}, {"role": "Theme", "text": "angiogenesis", "start": 277, "end": 289}]}, {"trigger": {"text": "induce", "start": 149, "end": 155}, "arguments": [{"role": "Cause", "text": "Binding", "start": 50, "end": 57}, {"role": "Theme", "text": "metastasis", "start": 297, "end": 307}]}, {"trigger": {"text": "mediated", "start": 240, "end": 248}, "arguments": [{"role": "Cause", "text": "TF", "start": 237, "end": 239}, {"role": "Theme", "text": "angiogenesis", "start": 277, "end": 289}]}, {"trigger": {"text": "mediated", "start": 240, "end": 248}, "arguments": [{"role": "Cause", "text": "TF", "start": 237, "end": 239}, {"role": "Theme", "text": "metastasis", "start": 297, "end": 307}]}, {"trigger": {"text": "induced", "start": 447, "end": 454}, "arguments": [{"role": "Theme", "text": "apoptosis", "start": 455, "end": 464}]}, {"trigger": {"text": "activation", "start": 582, "end": 592}, "arguments": [{"role": "Theme", "text": "caspase 3", "start": 596, "end": 605}]}, {"trigger": {"text": "activation", "start": 880, "end": 890}, "arguments": [{"role": "Theme", "text": "caspase 3", "start": 870, "end": 879}]}, {"trigger": {"text": "induced", "start": 1025, "end": 1032}, "arguments": [{"role": "Cause", "text": "FVIIa", "start": 1019, "end": 1024}, {"role": "Theme", "text": "survival", "start": 1038, "end": 1046}]}, {"trigger": {"text": "activation", "start": 1067, "end": 1077}, "arguments": [{"role": "Theme", "text": "Akt", "start": 1081, "end": 1084}]}, {"trigger": {"text": "activation", "start": 1173, "end": 1183}, "arguments": [{"role": "Theme", "text": "p44/42 mitogen-activated protein kinase", "start": 1187, "end": 1226}]}, {"trigger": {"text": "promote", "start": 1353, "end": 1360}, "arguments": [{"role": "Cause", "text": "FVIIa", "start": 1344, "end": 1349}, {"role": "Theme", "text": "survival", "start": 1366, "end": 1374}]}, {"trigger": {"text": "activation", "start": 1505, "end": 1515}, "arguments": [{"role": "Theme", "text": "pathway", "start": 1534, "end": 1541}]}, {"trigger": {"text": "activation", "start": 1505, "end": 1515}, "arguments": [{"role": "Theme", "text": "pathway", "start": 1579, "end": 1586}]}]}}, "schema": []}
{"input": "Laser treatment of eccentric leaks in central serous chorioretinopathy resulting in disappearance of untreated juxtafoveal leaks.\n\nIn central serous chorioretinopathy (CSCR) laser treatment of leaking points close to the macular center should be avoided because of the possibility of producing juxtafoveal scotoma and stimulating choroidal neovascularization. Nine eyes of nine consecutive patients with CSCR had two or more leaking points within a macular detachment, one of which was foveal or near to the fovea. Photocoagulation with green argon laser was performed in all eyes, treating all the leaking points except for the central one. Visual symptoms regressed after treatment, and the serous detachment was resolved 10 days to 4 weeks after photocoagulation in all cases. Fluorescein angiography showed no leakage at either the central leakage point or the leakage point that had been treated. These results led us to believe that the central or dependent leak in our cases was not sufficient to maintain the serous detachment by itself. An alternative hypothesis is that the untreated leak did not represent real fluid movement but only diffusion of fluorescein molecules, or a false leak. In cases of CSCR with multiple leaks within a single macular detachment, we believe that a foveal leak may be a dependent or false leak and that direct treatment is not necessary.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 340, "end": 358}, "arguments": []}], "Breakdown": [{"trigger": {"text": "detachment", "start": 457, "end": 467}, "arguments": [{"role": "Theme", "text": "macular", "start": 449, "end": 456}]}, {"trigger": {"text": "detachment", "start": 1260, "end": 1270}, "arguments": [{"role": "Theme", "text": "macular", "start": 1252, "end": 1259}]}], "Positive_regulation": [{"trigger": {"text": "stimulating", "start": 318, "end": 329}, "arguments": [{"role": "Theme", "text": "neovascularization", "start": 340, "end": 358}]}]}}, "schema": []}
{"input": "Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure?\n\nAngiogenic factors, in particular vascular endothelial growth factor (VEGF) and the angiopoietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. The process of angiogenesis is also thought to occur in response to ischaemic conditions, which lie at the core of cardiovascular disease states such as coronary artery disease and congestive heart failure. However, current data do not conclusively show evidence of angiogenesis per se in these conditions, despite (for example) the presence of high levels of VEGF and Ang-2. High levels of these angiogenic factors in heart disease also have not translated into clinically significant new vessel formation, as in accelerated cancer growth or proliferative retinopathy. Indeed, we would hypothesize that these angiogenic markers--especially the angiopoietins--do not necessarily translate into new vessel formation in congestive heart failure (CHF), but may well reflect disturbances of endothelial integrity in CHF.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 35, "end": 47}, "arguments": []}, {"trigger": {"text": "Angiogenic", "start": 86, "end": 96}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 284, "end": 296}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 535, "end": 547}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 666, "end": 676}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 879, "end": 889}, "arguments": []}], "Breakdown": [{"trigger": {"text": "disturbances", "start": 1040, "end": 1052}, "arguments": [{"role": "Theme", "text": "endothelial", "start": 1056, "end": 1067}]}], "Development": [{"trigger": {"text": "formation", "start": 766, "end": 775}, "arguments": [{"role": "Theme", "text": "vessel", "start": 759, "end": 765}]}, {"trigger": {"text": "formation", "start": 974, "end": 983}, "arguments": [{"role": "Theme", "text": "vessel", "start": 967, "end": 973}]}], "Growth": [{"trigger": {"text": "growth", "start": 802, "end": 808}, "arguments": [{"role": "Theme", "text": "cancer", "start": 795, "end": 801}]}], "Localization": [{"trigger": {"text": "presence", "start": 602, "end": 610}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 629, "end": 633}]}, {"trigger": {"text": "presence", "start": 602, "end": 610}, "arguments": [{"role": "Theme", "text": "Ang-2", "start": 638, "end": 643}]}], "Positive_regulation": [{"trigger": {"text": "accelerated", "start": 783, "end": 794}, "arguments": [{"role": "Theme", "text": "growth", "start": 802, "end": 808}]}], "Regulation": [{"trigger": {"text": "translate", "start": 948, "end": 957}, "arguments": [{"role": "Cause", "text": "angiopoietins", "start": 914, "end": 927}, {"role": "Theme", "text": "formation", "start": 974, "end": 983}]}, {"trigger": {"text": "reflect", "start": 1032, "end": 1039}, "arguments": [{"role": "Cause", "text": "angiopoietins", "start": 914, "end": 927}, {"role": "Theme", "text": "disturbances", "start": 1040, "end": 1052}]}]}}, "schema": []}
{"input": "Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients.\n\nBACKGROUND: We suggest that surgical extirpation of primary breast cancer among other effects accelerates relapse for some premenopausal node-positive patients. These accelerated relapses occur within 10 months of surgery for untreated patients. The mechanism proposed is a stimulation of angiogenesis for distant dormant micrometastases. This has been suggested as one of the mechanisms to explain the mammography paradox for women aged 40-49 years. We could imagine that it also plays a role in adjuvant chemotherapy effectiveness since, perhaps not coincidentally, this is most beneficial for premenopausal node-positive patients. HYPOTHESIS: We speculate that there is a burst of angiogenesis of distant dormant micrometastases after surgery in approximately 20% of premenopausal node-positive patients. We also speculate that this synchronizes them into a temporal highly chemosensitive state and is the underlying reason why adjuvant chemotherapy works particularly well for that patient category. Furthermore, this may explain why cancer in younger patients is more often 'aggressive'. TESTING THE HYPOTHESIS: Stimulation of dormant micrometastases by primary tumor removal is known to occur in animal models. However, we need to determine whether it happens in breast cancer. Transient circulating levels of angioactive molecules and serial high-resolution imaging studies of focal angiogenesis might help. IMPLICATIONS: Short-course cytotoxic chemotherapy after surgery has probably reached its zenith, and other strategies, perhaps antiangiogenic methods, are needed to successfully treat more patients. In addition, the hypothesis predicts that early detection, which is designed to find more patients without involved lymph nodes, may not be a synergistic strategy with adjuvant chemotherapy, which works best with positive lymph node patients.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 20, "end": 32}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 490, "end": 502}, "arguments": [{"role": "AtLoc", "text": "distant dormant micrometastases", "start": 507, "end": 538}]}, {"trigger": {"text": "angiogenesis", "start": 885, "end": 897}, "arguments": [{"role": "AtLoc", "text": "distant dormant micrometastases", "start": 901, "end": 932}]}, {"trigger": {"text": "angioactive", "start": 1517, "end": 1528}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1591, "end": 1603}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1747, "end": 1757}, "arguments": []}], "Planned_process": [{"trigger": {"text": "surgery", "start": 39, "end": 46}, "arguments": [{"role": "Theme", "text": "patients", "start": 92, "end": 100}]}, {"trigger": {"text": "chemotherapy", "start": 143, "end": 155}, "arguments": [{"role": "Theme", "text": "patients", "start": 190, "end": 198}]}, {"trigger": {"text": "surgical extirpation", "start": 229, "end": 249}, "arguments": [{"role": "Theme", "text": "breast cancer", "start": 261, "end": 274}]}, {"trigger": {"text": "surgery", "start": 415, "end": 422}, "arguments": [{"role": "Theme", "text": "patients", "start": 437, "end": 445}]}, {"trigger": {"text": "untreated", "start": 427, "end": 436}, "arguments": [{"role": "Theme", "text": "patients", "start": 437, "end": 445}]}, {"trigger": {"text": "chemotherapy", "start": 707, "end": 719}, "arguments": [{"role": "Theme", "text": "patients", "start": 825, "end": 833}]}, {"trigger": {"text": "surgery", "start": 939, "end": 946}, "arguments": [{"role": "Theme", "text": "patients", "start": 999, "end": 1007}]}, {"trigger": {"text": "chemotherapy", "start": 1141, "end": 1153}, "arguments": [{"role": "Theme", "text": "patient", "start": 1187, "end": 1194}]}, {"trigger": {"text": "removal", "start": 1374, "end": 1381}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1368, "end": 1373}]}, {"trigger": {"text": "treat", "start": 1794, "end": 1799}, "arguments": [{"role": "Theme", "text": "patients", "start": 1805, "end": 1813}]}, {"trigger": {"text": "chemotherapy", "start": 1992, "end": 2004}, "arguments": [{"role": "Theme", "text": "patients", "start": 2048, "end": 2056}]}], "Positive_regulation": [{"trigger": {"text": "Induced", "start": 12, "end": 19}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 20, "end": 32}]}, {"trigger": {"text": "stimulation", "start": 475, "end": 486}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 490, "end": 502}]}, {"trigger": {"text": "burst", "start": 876, "end": 881}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 885, "end": 897}]}, {"trigger": {"text": "Stimulation", "start": 1318, "end": 1329}, "arguments": [{"role": "Theme", "text": "dormant micrometastases", "start": 1333, "end": 1356}, {"role": "Cause", "text": "removal", "start": 1374, "end": 1381}]}]}}, "schema": []}
{"input": "Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword.\n\nVascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, which can occur during cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown associated with these conditions. Given its recently-described role as an inflammatory mediator, VEGF could also contribute to the inflammatory responses observed in cerebral ischemia. After seizures, blood-brain barrier breakdown and inflammation is also observed in brain, albeit on a lower scale than that observed after stroke. Recent evidence has suggested a role for inflammation in seizure disorders. We have described striking increases in VEGF protein in both neurons and glia after pilocarpine-induced status epilepticus in the brain. Increases in VEGF could contribute to the blood-brain barrier breakdown and inflammation observed after seizures. However, VEGF has also been shown to be neuroprotective across several experimental paradigms, and hence could potentially protect vulnerable cells from damage associated with seizures. Therefore, the role of VEGF after seizures could be either protective or destructive. Although only further research will determine the exact nature of VEGF's role after seizures, preliminary data indicate that VEGF plays a protective role after seizures.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 162, "end": 174}, "arguments": []}], "Breakdown": [{"trigger": {"text": "breakdown", "start": 520, "end": 529}, "arguments": [{"role": "Theme", "text": "blood-brain barrier", "start": 500, "end": 519}]}, {"trigger": {"text": "breakdown", "start": 751, "end": 760}, "arguments": [{"role": "Theme", "text": "blood-brain barrier", "start": 731, "end": 750}]}, {"trigger": {"text": "breakdown", "start": 1137, "end": 1146}, "arguments": [{"role": "Theme", "text": "blood-brain barrier", "start": 1117, "end": 1136}]}, {"trigger": {"text": "damage", "start": 1342, "end": 1348}, "arguments": [{"role": "Theme", "text": "cells", "start": 1331, "end": 1336}]}], "Development": [{"trigger": {"text": "development", "start": 180, "end": 191}, "arguments": [{"role": "Theme", "text": "blood vessels", "start": 199, "end": 212}]}], "Negative_regulation": [{"trigger": {"text": "protect", "start": 1312, "end": 1319}, "arguments": [{"role": "Theme", "text": "damage", "start": 1342, "end": 1348}]}], "Positive_regulation": [{"trigger": {"text": "induces", "start": 154, "end": 161}, "arguments": [{"role": "Cause", "text": "Vascular endothelial growth factor", "start": 78, "end": 112}, {"role": "Theme", "text": "angiogenesis", "start": 162, "end": 174}]}, {"trigger": {"text": "upregulated", "start": 357, "end": 368}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 349, "end": 353}]}, {"trigger": {"text": "increases", "start": 965, "end": 974}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 978, "end": 982}]}, {"trigger": {"text": "Increases", "start": 1075, "end": 1084}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1088, "end": 1092}]}, {"trigger": {"text": "contribute", "start": 1099, "end": 1109}, "arguments": [{"role": "Cause", "text": "Increases", "start": 1075, "end": 1084}, {"role": "Theme", "text": "breakdown", "start": 1137, "end": 1146}]}]}}, "schema": []}
{"input": "Safety of verteporfin for treatment of subfoveal choroidal neovascular membranes associated with age-related macular degeneration.\n\nPhotodynamic therapy (PDT) is a novel treatment entity that exploits the photophysical properties of various photosensitive chemical entities which, upon light activation, results in targeted photooxidation and subsequent tissue destruction. The antiangiogenic properties of PDT have been adapted for treatment of subfoveal choroidal neovascular membranes due to disease states such as age-related macular degeneration (AMD). Historically, PDT has been limited by a lack of suitable photosensitive dyes. However, agents such as verteporfin, a second-generation benzoporphyrin derivative, appear to be free from the extensive phototoxicity that limited the success of previous agents. Verteporfin has a high affinity for choroidal neovascular membranes, typically found with exudative AMD, and upon photoactivation results in targeted microvascular damage and thrombus formation with resultant vessel occlusion. Scrutiny of diagnostic indicators for verteporfin administration, including critical angiographic evaluation of lesion size and visual acuity, is essential to treatment success. Large lesions with relatively good visual acuity (20/50 or better) may be at particular risk for marked vision loss following verteporfin administration. Lesion composition also appears to influence visual outcome with verteporfin use. The safety of verteporfin is directly dependent upon the appropriate integration of dosage, infusion and light activation required for a suitable pharmacotherapeutic outcome. When used appropriately, and with adequate patient education regarding photosensitivity, the risk-benefit of verteporfin for the medical treatment of neovascular AMD is favourable.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "affinity", "start": 839, "end": 847}, "arguments": [{"role": "Theme", "text": "Verteporfin", "start": 816, "end": 827}, {"role": "Theme", "text": "choroidal neovascular membranes", "start": 852, "end": 883}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenic", "start": 382, "end": 392}, "arguments": []}], "Breakdown": [{"trigger": {"text": "degeneration", "start": 117, "end": 129}, "arguments": [{"role": "Theme", "text": "macular", "start": 109, "end": 116}]}, {"trigger": {"text": "destruction", "start": 361, "end": 372}, "arguments": [{"role": "Theme", "text": "tissue", "start": 354, "end": 360}]}, {"trigger": {"text": "degeneration", "start": 538, "end": 550}, "arguments": [{"role": "Theme", "text": "macular", "start": 530, "end": 537}]}, {"trigger": {"text": "damage", "start": 980, "end": 986}, "arguments": [{"role": "Theme", "text": "microvascular", "start": 966, "end": 979}]}], "Development": [{"trigger": {"text": "formation", "start": 1000, "end": 1009}, "arguments": [{"role": "Theme", "text": "thrombus", "start": 991, "end": 999}]}], "Negative_regulation": [{"trigger": {"text": "properties", "start": 393, "end": 403}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 382, "end": 392}]}], "Planned_process": [{"trigger": {"text": "treatment", "start": 26, "end": 35}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 10, "end": 21}, {"role": "Theme", "text": "subfoveal choroidal neovascular membranes", "start": 39, "end": 80}]}, {"trigger": {"text": "treatment", "start": 433, "end": 442}, "arguments": [{"role": "Theme", "text": "subfoveal choroidal neovascular membranes", "start": 446, "end": 487}]}, {"trigger": {"text": "administration", "start": 1093, "end": 1107}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 1081, "end": 1092}]}, {"trigger": {"text": "administration", "start": 1359, "end": 1373}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 1347, "end": 1358}]}, {"trigger": {"text": "use", "start": 1452, "end": 1455}, "arguments": [{"role": "Theme", "text": "Lesion", "start": 1375, "end": 1381}, {"role": "Instrument", "text": "verteporfin", "start": 1440, "end": 1451}]}, {"trigger": {"text": "treatment", "start": 1769, "end": 1778}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 1741, "end": 1752}]}], "Positive_regulation": [{"trigger": {"text": "results", "start": 946, "end": 953}, "arguments": [{"role": "Theme", "text": "formation", "start": 1000, "end": 1009}]}, {"trigger": {"text": "results", "start": 946, "end": 953}, "arguments": [{"role": "Theme", "text": "damage", "start": 980, "end": 986}]}]}}, "schema": []}
{"input": "Retrospective case series of juxtafoveal choroidal neovascularization treated with photodynamic therapy with verteporfin.\n\nPURPOSE: To describe visual acuity and angiographic outcomes of juxtafoveal choroidal neovascularization (CNV) treated with photodynamic therapy and verteporfin (PDT). METHODS: Four hundred eighty-four consecutive eyes of 446 patients treated with PDT from January 1, 2001, to June 30, 2002, were identified from billing records. Fluorescein angiograms were reviewed retrospectively to identify juxtafoveal CNV. Eligible patients had CNV in which the central boundary of the lesion was between 1 and 199 microm from the geometric center of the foveal avascular zone (FAZ). Patient charts were reviewed for visual acuity of the treated eye before PDT and at 6- and 12-month follow-up examinations. Presence of subfoveal CNV at 6 and 12 months of follow-up was determined by review of fluorescein angiograms. A lesion was considered subfoveal if it extended underneath the geometric center of the FAZ. RESULTS: Twenty-one eyes had juxtafoveal CNV. Median change in visual acuity both 6 and 12 months after the initial PDT was 0 lines (n = 18 at 6 months, range -14 to + 8 lines; n = 17 at 12 months, range -18 to + 7 lines). Eleven lesions progressed to a subfoveal location by 12 months. Visual acuity in eyes with progressive lesions decreased a median of 4 lines of vision. CONCLUSIONS: Despite a small sample size and limited length of follow-up, this study shows that visual acuity on average can remain stable for at least 12 months after PDT of juxtafoveal lesions. Growth through the foveal center still can occur, however, and this can be associated with substantial visual loss.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 51, "end": 69}, "arguments": []}, {"trigger": {"text": "neovascularization", "start": 209, "end": 227}, "arguments": []}, {"trigger": {"text": "CNV", "start": 229, "end": 232}, "arguments": []}, {"trigger": {"text": "CNV", "start": 530, "end": 533}, "arguments": []}, {"trigger": {"text": "CNV", "start": 557, "end": 560}, "arguments": []}, {"trigger": {"text": "CNV", "start": 842, "end": 845}, "arguments": []}, {"trigger": {"text": "CNV", "start": 1064, "end": 1067}, "arguments": []}], "Development": [{"trigger": {"text": "progressed", "start": 1261, "end": 1271}, "arguments": [{"role": "Theme", "text": "lesions", "start": 1253, "end": 1260}]}], "Planned_process": [{"trigger": {"text": "treated", "start": 70, "end": 77}, "arguments": [{"role": "Theme", "text": "neovascularization", "start": 51, "end": 69}, {"role": "Instrument", "text": "verteporfin", "start": 109, "end": 120}]}, {"trigger": {"text": "treated", "start": 234, "end": 241}, "arguments": [{"role": "Theme", "text": "CNV", "start": 229, "end": 232}, {"role": "Instrument", "text": "verteporfin", "start": 272, "end": 283}]}, {"trigger": {"text": "treated", "start": 358, "end": 365}, "arguments": [{"role": "Theme", "text": "eyes", "start": 337, "end": 341}]}, {"trigger": {"text": "treated", "start": 750, "end": 757}, "arguments": [{"role": "Theme", "text": "eye", "start": 758, "end": 761}]}]}}, "schema": []}
{"input": "An evaluation of low molecular weight heparin and hyperbaric oxygen treatment in the prevention of intra-abdominal adhesions and wound healing.\n\nBACKGROUND: Abdominal surgery can lead to intra-abdominal adhesions with significant morbidity and mortality. To prevent adhesions, an experimental study was planned to designate the effects of low molecular weight (LMW) heparins and hyperbaric oxygen (HBO) therapy both on the formation of adhesions and wound healing. METHODS: Thirty-eight Wistar albino rats underwent laparotomy to cause intra-abdominal adhesions by mechanical abrasion of the cecum and ethanol application. The rats were divided into 4 groups. In the control group (group 1) no further management was undertaken. Group 2 was treated by Enoxaparine Na, group 3 received HBO therapy, and group 4 was given both enoxaparine Na and HBO treatment. RESULTS: There was a statistically significant difference between the control and enoxaparine Na groups regarding adhesions. Statistically significant differences were observed between groups 1 and 4 and between groups 1 and 3 regarding the hydroxyproline content of the abdominal wounds. In the pathologic analysis of the abdominal wounds, there was no statistically significant difference between any of the groups, including the control group, regarding inflammation. Statistically significant differences were observed regarding angiogenesis between the control group and groups 3 and 4. There was also a statistically significant difference regarding fibrosis between groups 1 and 4. CONCLUSIONS: Enoxaparine Na decreased intra-abdominal adhesions, and HBO therapy had no beneficial effect on adhesions. Enoxaparine Na had no harmful effects on wound healing, and HBO therapy increased the process of wound healing.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 1392, "end": 1404}, "arguments": []}], "Planned_process": [{"trigger": {"text": "treatment", "start": 68, "end": 77}, "arguments": [{"role": "Instrument", "text": "low molecular weight heparin", "start": 17, "end": 45}]}, {"trigger": {"text": "treatment", "start": 68, "end": 77}, "arguments": [{"role": "Instrument", "text": "hyperbaric oxygen", "start": 50, "end": 67}]}, {"trigger": {"text": "therapy", "start": 403, "end": 410}, "arguments": [{"role": "Instrument", "text": "low molecular weight (LMW) heparins", "start": 339, "end": 374}]}, {"trigger": {"text": "therapy", "start": 403, "end": 410}, "arguments": [{"role": "Instrument", "text": "hyperbaric oxygen", "start": 379, "end": 396}]}, {"trigger": {"text": "underwent", "start": 506, "end": 515}, "arguments": [{"role": "Theme", "text": "Wistar albino rats", "start": 487, "end": 505}]}, {"trigger": {"text": "abrasion", "start": 576, "end": 584}, "arguments": [{"role": "Theme", "text": "cecum", "start": 592, "end": 597}]}, {"trigger": {"text": "application", "start": 610, "end": 621}, "arguments": [{"role": "Instrument", "text": "ethanol", "start": 602, "end": 609}]}, {"trigger": {"text": "treated", "start": 741, "end": 748}, "arguments": [{"role": "Instrument", "text": "Enoxaparine Na", "start": 752, "end": 766}]}, {"trigger": {"text": "therapy", "start": 789, "end": 796}, "arguments": [{"role": "Instrument", "text": "HBO", "start": 785, "end": 788}]}, {"trigger": {"text": "treatment", "start": 848, "end": 857}, "arguments": [{"role": "Instrument", "text": "enoxaparine Na", "start": 825, "end": 839}, {"role": "Instrument", "text": "HBO", "start": 844, "end": 847}]}, {"trigger": {"text": "therapy", "start": 1621, "end": 1628}, "arguments": [{"role": "Instrument", "text": "HBO", "start": 1617, "end": 1620}]}, {"trigger": {"text": "therapy", "start": 1732, "end": 1739}, "arguments": [{"role": "Instrument", "text": "HBO", "start": 1728, "end": 1731}]}]}}, "schema": []}
{"input": "VEGF-targeted therapy: therapeutic potential and recent advances.\n\nAfter over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1-2 mm(3) in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 113, "end": 125}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 577, "end": 589}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 814, "end": 826}, "arguments": []}], "Cell_division": [{"trigger": {"text": "dividing", "start": 298, "end": 306}, "arguments": [{"role": "Theme", "text": "endothelial cells", "start": 280, "end": 297}]}], "Growth": [{"trigger": {"text": "growth", "start": 354, "end": 360}, "arguments": [{"role": "Theme", "text": "tumors", "start": 364, "end": 370}]}, {"trigger": {"text": "growth", "start": 398, "end": 404}, "arguments": [{"role": "Theme", "text": "vascular", "start": 389, "end": 397}]}, {"trigger": {"text": "grow", "start": 449, "end": 453}, "arguments": [{"role": "Theme", "text": "solid tumors", "start": 433, "end": 445}]}], "Planned_process": [{"trigger": {"text": "treatment", "start": 846, "end": 855}, "arguments": [{"role": "Theme", "text": "breast", "start": 859, "end": 865}]}, {"trigger": {"text": "treatment", "start": 846, "end": 855}, "arguments": [{"role": "Theme", "text": "lung", "start": 867, "end": 871}]}, {"trigger": {"text": "treatment", "start": 846, "end": 855}, "arguments": [{"role": "Theme", "text": "colorectal cancers", "start": 877, "end": 895}]}], "Positive_regulation": [{"trigger": {"text": "requires", "start": 371, "end": 379}, "arguments": [{"role": "Theme", "text": "growth", "start": 354, "end": 360}, {"role": "Cause", "text": "growth", "start": 398, "end": 404}]}, {"trigger": {"text": "requires", "start": 371, "end": 379}, "arguments": [{"role": "Theme", "text": "growth", "start": 354, "end": 360}, {"role": "Cause", "text": "remodeling", "start": 409, "end": 419}]}], "Remodeling": [{"trigger": {"text": "remodeling", "start": 409, "end": 419}, "arguments": [{"role": "Theme", "text": "vascular", "start": 389, "end": 397}]}]}}, "schema": []}
{"input": "Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model.\n\nThrombospondin is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. TSP interacts with a number of proteases and receptors and in this way inhibits stimulation of angiogenesis. An earlier study showed that thrombospondin is expressed in benign prostatic hyperplasia (BPH) and high-grade prostatic intraepithelial neoplasia (PIN) but is absent in prostate cancer. The present study was therefore designed to evaluate the expression of thrombospondin 1 and 2 (TSP-1, TSP-2), TSP receptors CD36 and CD47, and matrix-metalloproteases 2 and 9 (MMP-, MMP-9) in a rat prostate cancer model. By using immunohistochemistry, Western blot, and real-time PCR the expression patterns of TSP-1, TSP-2, CD36, CD47, MMP-2, and MMP-9 were investigated in normal rat prostate tissue and five malignant Dunning sublines tissue. TSP-1 mRNA levels were decreased in all tumours compared with normal prostate. However, there was no difference in expression of TSP-2 and CD36 mRNA in these samples. MMP-2 was increased with malignancy, but no expression of MMP-9 was seen. The CD47 receptor did slightly increase with malignancy except for H3327. The results showed that thrombospondin is expressed in normal prostate but not in prostate tumours in a rat model. Simultaneously, MMP-2 expression increases with malignancy.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "interacts", "start": 289, "end": 298}, "arguments": [{"role": "Theme", "text": "TSP", "start": 285, "end": 288}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 209, "end": 221}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 380, "end": 392}, "arguments": []}], "Gene_expression": [{"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "Thrombospondins", "start": 0, "end": 15}]}, {"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "metallo proteases", "start": 17, "end": 34}]}, {"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "thrombospondin receptors", "start": 39, "end": 63}]}, {"trigger": {"text": "expressed", "start": 441, "end": 450}, "arguments": [{"role": "Theme", "text": "thrombospondin", "start": 423, "end": 437}]}, {"trigger": {"text": "absent", "start": 553, "end": 559}, "arguments": [{"role": "Theme", "text": "thrombospondin", "start": 423, "end": 437}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "thrombospondin 1", "start": 651, "end": 667}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "2", "start": 672, "end": 673}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "CD36", "start": 704, "end": 708}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "CD47", "start": 713, "end": 717}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "matrix-metalloproteases 2", "start": 723, "end": 748}]}, {"trigger": {"text": "expression", "start": 637, "end": 647}, "arguments": [{"role": "Theme", "text": "9", "start": 753, "end": 754}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "TSP-1", "start": 891, "end": 896}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "TSP-2", "start": 898, "end": 903}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "CD36", "start": 905, "end": 909}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "CD47", "start": 911, "end": 915}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "MMP-2", "start": 917, "end": 922}]}, {"trigger": {"text": "expression", "start": 868, "end": 878}, "arguments": [{"role": "Theme", "text": "MMP-9", "start": 928, "end": 933}]}, {"trigger": {"text": "expression", "start": 1237, "end": 1247}, "arguments": [{"role": "Theme", "text": "MMP-9", "start": 1251, "end": 1256}]}, {"trigger": {"text": "expressed", "start": 1383, "end": 1392}, "arguments": [{"role": "Theme", "text": "thrombospondin", "start": 1365, "end": 1379}]}, {"trigger": {"text": "expression", "start": 1478, "end": 1488}, "arguments": [{"role": "Theme", "text": "MMP-2", "start": 1472, "end": 1477}]}], "Growth": [{"trigger": {"text": "growth", "start": 277, "end": 283}, "arguments": [{"role": "Theme", "text": "tumour", "start": 270, "end": 276}]}], "Negative_regulation": [{"trigger": {"text": "inhibits", "start": 356, "end": 364}, "arguments": [{"role": "Cause", "text": "TSP", "start": 285, "end": 288}, {"role": "Theme", "text": "stimulation", "start": 365, "end": 376}]}, {"trigger": {"text": "decreased", "start": 1049, "end": 1058}, "arguments": [{"role": "Theme", "text": "TSP-1", "start": 1026, "end": 1031}]}], "Positive_regulation": [{"trigger": {"text": "stimulation", "start": 365, "end": 376}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 380, "end": 392}]}, {"trigger": {"text": "increased", "start": 1203, "end": 1212}, "arguments": [{"role": "Theme", "text": "MMP-2", "start": 1193, "end": 1198}]}, {"trigger": {"text": "increase", "start": 1298, "end": 1306}, "arguments": [{"role": "Theme", "text": "CD47 receptor", "start": 1271, "end": 1284}]}, {"trigger": {"text": "increases", "start": 1489, "end": 1498}, "arguments": [{"role": "Theme", "text": "expression", "start": 1478, "end": 1488}]}], "Regulation": [{"trigger": {"text": "controlling", "start": 258, "end": 269}, "arguments": [{"role": "Cause", "text": "Thrombospondin", "start": 169, "end": 183}, {"role": "Theme", "text": "growth", "start": 277, "end": 283}]}], "Transcription": [{"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "Thrombospondins", "start": 0, "end": 15}]}, {"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "metallo proteases", "start": 17, "end": 34}]}, {"trigger": {"text": "expression", "start": 90, "end": 100}, "arguments": [{"role": "Theme", "text": "thrombospondin receptors", "start": 39, "end": 63}]}, {"trigger": {"text": "expression", "start": 1141, "end": 1151}, "arguments": [{"role": "Theme", "text": "TSP-2", "start": 1155, "end": 1160}]}, {"trigger": {"text": "expression", "start": 1141, "end": 1151}, "arguments": [{"role": "Theme", "text": "CD36", "start": 1165, "end": 1169}]}]}}, "schema": []}
{"input": "Minimal contribution of marrow-derived endothelial precursors to tumor vasculature.\n\nDuring embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only approximately 1 in 10(7) mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 349, "end": 367}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 343, "end": 348}]}], "Development": [{"trigger": {"text": "originate", "start": 138, "end": 147}, "arguments": [{"role": "Theme", "text": "vascular", "start": 107, "end": 115}]}, {"trigger": {"text": "originate", "start": 138, "end": 147}, "arguments": [{"role": "Theme", "text": "hemopoietic cells", "start": 120, "end": 137}]}, {"trigger": {"text": "transdifferentiation", "start": 725, "end": 745}, "arguments": [{"role": "Theme", "text": "marrow progenitors", "start": 749, "end": 767}]}, {"trigger": {"text": "fusion", "start": 788, "end": 794}, "arguments": [{"role": "Theme", "text": "cell", "start": 783, "end": 787}]}, {"trigger": {"text": "fusion", "start": 1475, "end": 1481}, "arguments": [{"role": "Theme", "text": "cell", "start": 1470, "end": 1474}]}, {"trigger": {"text": "differentiation", "start": 1555, "end": 1570}, "arguments": [{"role": "Theme", "text": "marrow stem cells", "start": 1574, "end": 1591}]}], "Localization": [{"trigger": {"text": "existence", "start": 221, "end": 230}, "arguments": [{"role": "Theme", "text": "endothelial precursors", "start": 234, "end": 256}]}, {"trigger": {"text": "secretion", "start": 1059, "end": 1068}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor (VEGF)-A", "start": 1015, "end": 1058}, {"role": "FromLoc", "text": "tumor cells", "start": 1072, "end": 1083}]}, {"trigger": {"text": "incorporation", "start": 1183, "end": 1196}, "arguments": [{"role": "Theme", "text": "marrow-derived endothelial progenitors", "start": 1200, "end": 1238}, {"role": "ToLoc", "text": "tumor vasculature", "start": 1244, "end": 1261}]}, {"trigger": {"text": "existence", "start": 1510, "end": 1519}, "arguments": [{"role": "Theme", "text": "hemangioblast", "start": 1532, "end": 1545}]}], "Planned_process": [{"trigger": {"text": "transplants", "start": 808, "end": 819}, "arguments": [{"role": "Theme", "text": "cell", "start": 803, "end": 807}]}], "Positive_regulation": [{"trigger": {"text": "increased", "start": 1005, "end": 1014}, "arguments": [{"role": "Theme", "text": "secretion", "start": 1059, "end": 1068}]}, {"trigger": {"text": "activation", "start": 1096, "end": 1106}, "arguments": [{"role": "Theme", "text": "VEGF receptor-2", "start": 1110, "end": 1125}]}, {"trigger": {"text": "stimulation", "start": 1684, "end": 1695}, "arguments": [{"role": "Cause", "text": "VEGF-A", "start": 1677, "end": 1683}, {"role": "Theme", "text": "hemopoietic cells", "start": 1699, "end": 1716}]}], "Regulation": [{"trigger": {"text": "contribution", "start": 8, "end": 20}, "arguments": [{"role": "Cause", "text": "marrow-derived endothelial precursors", "start": 24, "end": 61}, {"role": "Theme", "text": "tumor vasculature", "start": 65, "end": 82}]}, {"trigger": {"text": "have a role", "start": 328, "end": 339}, "arguments": [{"role": "Cause", "text": "endothelial precursors", "start": 234, "end": 256}, {"role": "Theme", "text": "neovascularization", "start": 349, "end": 367}]}, {"trigger": {"text": "contributes", "start": 851, "end": 862}, "arguments": [{"role": "Theme", "text": "hemopoietic", "start": 875, "end": 886}]}, {"trigger": {"text": "contributes", "start": 851, "end": 862}, "arguments": [{"role": "Theme", "text": "endothelial lineages", "start": 891, "end": 911}]}]}}, "schema": []}
{"input": "High-Dose celecoxib and metronomic \"low-dose\" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma.\n\nPURPOSE: Angiogenesis is increased in aggressive histology non-Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. EXPERIMENTAL DESIGN: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non-Hodgkin's lymphoma in a multicenter phase II prospective study. RESULTS: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index,  greater than or=2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted \"antiangiogenic\" levels. CONCLUSIONS: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non-Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "Angiogenesis", "start": 192, "end": 204}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 428, "end": 440}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1896, "end": 1906}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 2260, "end": 2272}, "arguments": []}], "Negative_regulation": [{"trigger": {"text": "inhibition", "start": 317, "end": 327}, "arguments": [{"role": "Theme", "text": "Angiogenesis", "start": 192, "end": 204}, {"role": "Cause", "text": "cyclooxygenase-2", "start": 300, "end": 316}]}, {"trigger": {"text": "decline", "start": 1787, "end": 1794}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 1741, "end": 1775}]}, {"trigger": {"text": "targeted", "start": 1882, "end": 1890}, "arguments": [{"role": "Cause", "text": "celecoxib", "start": 1856, "end": 1865}, {"role": "Theme", "text": "angiogenic", "start": 1896, "end": 1906}]}, {"trigger": {"text": "decline", "start": 2138, "end": 2145}, "arguments": [{"role": "Theme", "text": "endothelial cells", "start": 2161, "end": 2178}]}, {"trigger": {"text": "inhibiting", "start": 2249, "end": 2259}, "arguments": [{"role": "Cause", "text": "cyclophosphamide", "start": 1938, "end": 1954}, {"role": "Theme", "text": "angiogenesis", "start": 2260, "end": 2272}]}, {"trigger": {"text": "inhibiting", "start": 2249, "end": 2259}, "arguments": [{"role": "Cause", "text": "celecoxib", "start": 1969, "end": 1978}, {"role": "Theme", "text": "angiogenesis", "start": 2260, "end": 2272}]}], "Planned_process": [{"trigger": {"text": "therapy", "start": 88, "end": 95}, "arguments": [{"role": "Instrument", "text": "celecoxib", "start": 10, "end": 19}, {"role": "Theme", "text": "patients", "start": 99, "end": 107}]}, {"trigger": {"text": "therapy", "start": 88, "end": 95}, "arguments": [{"role": "Instrument", "text": "cyclophosphamide", "start": 46, "end": 62}, {"role": "Theme", "text": "patients", "start": 99, "end": 107}]}, {"trigger": {"text": "chemotherapy", "start": 343, "end": 355}, "arguments": [{"role": "Theme", "text": "non-Hodgkin's lymphoma", "start": 242, "end": 264}]}, {"trigger": {"text": "pretreated", "start": 825, "end": 835}, "arguments": [{"role": "Theme", "text": "Patients", "start": 744, "end": 752}]}, {"trigger": {"text": "transplant", "start": 983, "end": 993}, "arguments": [{"role": "Theme", "text": "Patients", "start": 744, "end": 752}, {"role": "Instrument", "text": "stem cell", "start": 973, "end": 982}]}, {"trigger": {"text": "pretreated", "start": 1505, "end": 1515}, "arguments": [{"role": "Theme", "text": "patients", "start": 1516, "end": 1524}]}, {"trigger": {"text": "treatment", "start": 1535, "end": 1544}, "arguments": [{"role": "Theme", "text": "patients", "start": 1516, "end": 1524}]}, {"trigger": {"text": "therapy", "start": 1625, "end": 1632}, "arguments": [{"role": "Theme", "text": "patients", "start": 1516, "end": 1524}]}, {"trigger": {"text": "pretreated", "start": 2011, "end": 2021}, "arguments": [{"role": "Instrument", "text": "cyclophosphamide", "start": 1938, "end": 1954}, {"role": "Theme", "text": "non-Hodgkin's lymphoma", "start": 2033, "end": 2055}]}, {"trigger": {"text": "pretreated", "start": 2011, "end": 2021}, "arguments": [{"role": "Instrument", "text": "celecoxib", "start": 1969, "end": 1978}, {"role": "Theme", "text": "non-Hodgkin's lymphoma", "start": 2033, "end": 2055}]}], "Positive_regulation": [{"trigger": {"text": "increased", "start": 208, "end": 217}, "arguments": [{"role": "Theme", "text": "Angiogenesis", "start": 192, "end": 204}]}, {"trigger": {"text": "increase", "start": 1822, "end": 1830}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 1741, "end": 1775}]}]}}, "schema": []}
{"input": "Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization secondary to pathologic myopia: long-term study.\n\nPURPOSE: To assess the safety and effectiveness of photodynamic therapy (PDT) with verteporfin for subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). METHODS: Sixty-two patients (62 eyes) with PM underwent PDT according to the guidelines of the Verteporfin in Photodynamic Therapy Study. Clinical evaluations performed at all study visits included measurement of best-corrected Snellen visual acuity, slit-lamp biomicroscopy, and fundus fluorescein angiography. Patients were followed up at 1 month and 3 months after treatment and thereafter at 3-month intervals. RESULTS: The final visual acuity of the study patients, after a median follow-up of 31 months, improved by  greater than or=1 Snellen lines in 8 patients (13%), deteriorated in 20 (32%), and remained stable in 34 (55%). The baseline visual acuity was similar in the various study groups. The final mean visual acuity in group A (55 years of age or younger) was 20/80 and significantly (P=0.006) better than that (20/138) in group B (older than 55 years of age). The mean final visual acuity in eyes with higher refractive error at baseline (greater than -17 diopters) was significantly better (P=0.014) than that in eyes with lower refractive error (-6 to -10 diopters). CNV size did not affect visual outcomes. CONCLUSION: PDT preserves vision in patients with CNV associated with PM. Younger patients and eyes with higher refractive error appear more likely to benefit from PDT with verteporfin.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 62, "end": 80}, "arguments": []}, {"trigger": {"text": "neovascularization", "start": 250, "end": 268}, "arguments": []}, {"trigger": {"text": "CNV", "start": 270, "end": 273}, "arguments": []}, {"trigger": {"text": "CNV", "start": 1398, "end": 1401}, "arguments": []}, {"trigger": {"text": "CNV", "start": 1489, "end": 1492}, "arguments": []}], "Planned_process": [{"trigger": {"text": "Photodynamic therapy", "start": 0, "end": 20}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 26, "end": 37}]}, {"trigger": {"text": "photodynamic therapy", "start": 182, "end": 202}, "arguments": [{"role": "Instrument", "text": "verteporfin", "start": 214, "end": 225}]}, {"trigger": {"text": "PDT", "start": 368, "end": 371}, "arguments": [{"role": "Theme", "text": "patients", "start": 331, "end": 339}]}, {"trigger": {"text": "Photodynamic Therapy", "start": 422, "end": 442}, "arguments": [{"role": "Theme", "text": "patients", "start": 331, "end": 339}, {"role": "Instrument", "text": "Verteporfin", "start": 407, "end": 418}]}, {"trigger": {"text": "angiography", "start": 611, "end": 622}, "arguments": [{"role": "Theme", "text": "fundus", "start": 592, "end": 598}, {"role": "Instrument", "text": "fluorescein", "start": 599, "end": 610}]}, {"trigger": {"text": "treatment", "start": 680, "end": 689}, "arguments": [{"role": "Theme", "text": "Patients", "start": 624, "end": 632}]}, {"trigger": {"text": "PDT", "start": 1451, "end": 1454}, "arguments": [{"role": "Theme", "text": "patients", "start": 1475, "end": 1483}]}, {"trigger": {"text": "PDT", "start": 1603, "end": 1606}, "arguments": [{"role": "Theme", "text": "patients", "start": 1521, "end": 1529}, {"role": "Instrument", "text": "verteporfin", "start": 1612, "end": 1623}]}, {"trigger": {"text": "PDT", "start": 1603, "end": 1606}, "arguments": [{"role": "Theme", "text": "eyes", "start": 1534, "end": 1538}, {"role": "Instrument", "text": "verteporfin", "start": 1612, "end": 1623}]}]}}, "schema": []}
{"input": "Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy.\n\nMaternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.\n", "output": {"json_structures": {"Breakdown": [{"trigger": {"text": "dysfunction", "start": 136, "end": 147}, "arguments": [{"role": "Theme", "text": "endothelial", "start": 124, "end": 135}]}], "Development": [{"trigger": {"text": "formation", "start": 1087, "end": 1096}, "arguments": [{"role": "Theme", "text": "tube", "start": 1082, "end": 1086}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 492, "end": 502}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 506, "end": 512}]}, {"trigger": {"text": "production", "start": 753, "end": 763}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 746, "end": 752}]}, {"trigger": {"text": "expression", "start": 1416, "end": 1426}, "arguments": [{"role": "Theme", "text": "Ang II", "start": 1399, "end": 1405}]}, {"trigger": {"text": "expression", "start": 1416, "end": 1426}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 1409, "end": 1415}]}], "Localization": [{"trigger": {"text": "release", "start": 58, "end": 65}, "arguments": [{"role": "Theme", "text": "fms-Like tyrosine kinase-1", "start": 31, "end": 57}]}, {"trigger": {"text": "circulating", "start": 240, "end": 251}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 266, "end": 300}]}, {"trigger": {"text": "circulating", "start": 240, "end": 251}, "arguments": [{"role": "Theme", "text": "placental growth factor", "start": 305, "end": 328}]}, {"trigger": {"text": "circulating", "start": 590, "end": 601}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 612, "end": 618}]}, {"trigger": {"text": "secretion", "start": 696, "end": 705}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 689, "end": 695}]}, {"trigger": {"text": "secretion", "start": 1002, "end": 1011}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 995, "end": 1001}]}, {"trigger": {"text": "migration", "start": 1059, "end": 1068}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 1042, "end": 1058}]}, {"trigger": {"text": "release", "start": 1240, "end": 1247}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 1233, "end": 1239}]}], "Negative_regulation": [{"trigger": {"text": "dysregulation", "start": 1532, "end": 1545}, "arguments": [{"role": "Theme", "text": "system", "start": 1577, "end": 1583}]}], "Pathway": [{"trigger": {"text": "calcineurin signaling pathway", "start": 70, "end": 99}, "arguments": []}, {"trigger": {"text": "calcineurin signaling", "start": 1294, "end": 1315}, "arguments": []}, {"trigger": {"text": "system", "start": 1577, "end": 1583}, "arguments": [{"role": "Participant", "text": "renin", "start": 1559, "end": 1564}, {"role": "Participant2", "text": "angiotensin", "start": 1565, "end": 1576}]}], "Planned_process": [{"trigger": {"text": "infusion", "start": 547, "end": 555}, "arguments": [{"role": "Theme", "text": "Ang II", "start": 559, "end": 565}]}], "Positive_regulation": [{"trigger": {"text": "induces", "start": 15, "end": 22}, "arguments": [{"role": "Cause", "text": "induces", "start": 15, "end": 22}, {"role": "Theme", "text": "release", "start": 58, "end": 65}]}, {"trigger": {"text": "increased", "start": 183, "end": 192}, "arguments": [{"role": "Theme", "text": "fms-like tyrosine kinase-1", "start": 201, "end": 227}]}, {"trigger": {"text": "increases", "start": 387, "end": 396}, "arguments": [{"role": "Theme", "text": "Angiotensin II", "start": 330, "end": 344}]}, {"trigger": {"text": "promote", "start": 480, "end": 487}, "arguments": [{"role": "Cause", "text": "Ang II", "start": 469, "end": 475}, {"role": "Theme", "text": "expression", "start": 492, "end": 502}]}, {"trigger": {"text": "increases", "start": 580, "end": 589}, "arguments": [{"role": "Cause", "text": "infusion", "start": 547, "end": 555}, {"role": "Theme", "text": "circulating", "start": 590, "end": 601}]}, {"trigger": {"text": "stimulated", "start": 735, "end": 745}, "arguments": [{"role": "Cause", "text": "Ang II", "start": 728, "end": 734}, {"role": "Theme", "text": "production", "start": 753, "end": 763}]}, {"trigger": {"text": "induced", "start": 987, "end": 994}, "arguments": [{"role": "Cause", "text": "Ang II", "start": 980, "end": 986}, {"role": "Theme", "text": "secretion", "start": 1002, "end": 1011}]}, {"trigger": {"text": "inhibition", "start": 1028, "end": 1038}, "arguments": [{"role": "Cause", "text": "induced", "start": 987, "end": 994}, {"role": "Theme", "text": "migration", "start": 1059, "end": 1068}]}, {"trigger": {"text": "inhibition", "start": 1028, "end": 1038}, "arguments": [{"role": "Cause", "text": "induced", "start": 987, "end": 994}, {"role": "Theme", "text": "formation", "start": 1087, "end": 1096}]}, {"trigger": {"text": "mediated", "start": 1224, "end": 1232}, "arguments": [{"role": "Theme", "text": "release", "start": 1240, "end": 1247}, {"role": "Cause", "text": "activation", "start": 1279, "end": 1289}]}, {"trigger": {"text": "activation", "start": 1279, "end": 1289}, "arguments": [{"role": "Theme", "text": "Ang II type 1 receptor", "start": 1256, "end": 1278}]}, {"trigger": {"text": "elevated", "start": 1474, "end": 1482}, "arguments": [{"role": "Theme", "text": "sFlt-1", "start": 1483, "end": 1489}]}, {"trigger": {"text": "caused", "start": 1520, "end": 1526}, "arguments": [{"role": "Theme", "text": "elevated", "start": 1474, "end": 1482}, {"role": "Cause", "text": "dysregulation", "start": 1532, "end": 1545}]}], "Regulation": [{"trigger": {"text": "induces", "start": 15, "end": 22}, "arguments": [{"role": "Cause", "text": "Angiotensin II", "start": 0, "end": 14}, {"role": "Theme", "text": "calcineurin signaling pathway", "start": 70, "end": 99}]}, {"trigger": {"text": "mediated", "start": 1224, "end": 1232}, "arguments": [{"role": "Cause", "text": "Ang II", "start": 1217, "end": 1223}, {"role": "Theme", "text": "activation", "start": 1279, "end": 1289}]}, {"trigger": {"text": "regulatory role", "start": 1379, "end": 1394}, "arguments": [{"role": "Theme", "text": "expression", "start": 1416, "end": 1426}]}]}}, "schema": []}
{"input": "Ectopic decorin expression up-regulates VEGF expression in mouse cerebral endothelial cells via activation of the transcription factors Sp1, HIF1alpha, and Stat3.\n\nWe demonstrate that a proteoglycan decorin (DCN) up-regulates the vascular endothelial growth factor (VEGF) expression with activation of VEGF regulating transcription factors Sp1, hypoxia-inducible factor 1alpha (HIF1alpha), and signal transducer and activator of transcription 3 (Stat3) via epidermal growth factor receptor (EGFR), mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) pathways in DCN transfected mouse cerebral endothelial (MCE) cells. Treatment with pharmacological inhibitors and small interfering RNAs reveal that induction and activation of Sp1, HIF1alpha, and Stat3 facilitate their nuclear localization and binding to their specific motifs of the VEGF promoter and induce VEGF expression via two independent pathways, DCN/EGFR/phosphoinositide-3 kinase/AKT and DCN/EGFR/ERK1/2, respectively, in DCN synthesizing MCE cells. The cell type specific glycosylation protects Sp1 and HIF1alpha from proteosome degradation and plays an important and novel role in the regulation of VEGF in DCN transfected MCE cells. Induction of gelatinases (matrix metalloproteinase 2 and 9), the serine protease tissue plasminogen activator and plasmin by DCN transfection in MCE cells leads to extracellular proteolysis and to release of matrix-bound VEGF and activation of angiogenesis. In this study, we demonstrate that two independent downstream signal pathways, DCN/EGFR/ERK1/2 and DCN/EGFR/phosphoinositide-3 kinase/AKT, mediate up-regulation and activation of transcription factors of VEGF such as HIF1alpha, Stat3, and Sp1 and increase VEGF transcription and angiogenesis in MCE cells.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "binding", "start": 855, "end": 862}, "arguments": [{"role": "Theme2", "text": "Sp1", "start": 787, "end": 790}, {"role": "Theme", "text": "VEGF", "start": 895, "end": 899}, {"role": "Site", "text": "promoter", "start": 900, "end": 908}]}, {"trigger": {"text": "binding", "start": 855, "end": 862}, "arguments": [{"role": "Theme2", "text": "HIF1alpha", "start": 792, "end": 801}, {"role": "Theme", "text": "VEGF", "start": 895, "end": 899}, {"role": "Site", "text": "promoter", "start": 900, "end": 908}]}, {"trigger": {"text": "binding", "start": 855, "end": 862}, "arguments": [{"role": "Theme2", "text": "Stat3", "start": 807, "end": 812}, {"role": "Theme", "text": "VEGF", "start": 895, "end": 899}, {"role": "Site", "text": "promoter", "start": 900, "end": 908}]}, {"trigger": {"text": "bound", "start": 1472, "end": 1477}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1478, "end": 1482}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 1501, "end": 1513}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1794, "end": 1806}, "arguments": []}], "Catabolism": [{"trigger": {"text": "degradation", "start": 1151, "end": 1162}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 1117, "end": 1120}]}, {"trigger": {"text": "degradation", "start": 1151, "end": 1162}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 1125, "end": 1134}]}], "Dissociation": [{"trigger": {"text": "release", "start": 1454, "end": 1461}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1478, "end": 1482}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 16, "end": 26}, "arguments": [{"role": "Theme", "text": "decorin", "start": 8, "end": 15}]}, {"trigger": {"text": "expression", "start": 45, "end": 55}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 40, "end": 44}]}, {"trigger": {"text": "expression", "start": 272, "end": 282}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 230, "end": 264}]}, {"trigger": {"text": "expression", "start": 925, "end": 935}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 920, "end": 924}]}, {"trigger": {"text": "synthesizing", "start": 1047, "end": 1059}, "arguments": [{"role": "Theme", "text": "DCN", "start": 1043, "end": 1046}]}], "Localization": [{"trigger": {"text": "localization", "start": 838, "end": 850}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 787, "end": 790}]}, {"trigger": {"text": "localization", "start": 838, "end": 850}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 792, "end": 801}]}, {"trigger": {"text": "localization", "start": 838, "end": 850}, "arguments": [{"role": "Theme", "text": "Stat3", "start": 807, "end": 812}]}], "Negative_regulation": [{"trigger": {"text": "protects", "start": 1108, "end": 1116}, "arguments": [{"role": "Theme", "text": "degradation", "start": 1151, "end": 1162}]}], "Pathway": [{"trigger": {"text": "pathways", "start": 610, "end": 618}, "arguments": [{"role": "Participant", "text": "epidermal growth factor receptor", "start": 457, "end": 489}]}, {"trigger": {"text": "pathways", "start": 610, "end": 618}, "arguments": [{"role": "Participant", "text": "mitogen-activated protein kinase extracellular signal-regulated kinase 1/2", "start": 498, "end": 572}]}, {"trigger": {"text": "pathways", "start": 610, "end": 618}, "arguments": [{"role": "Participant", "text": "protein kinase B", "start": 587, "end": 603}]}, {"trigger": {"text": "pathways", "start": 956, "end": 964}, "arguments": [{"role": "Participant", "text": "DCN", "start": 1009, "end": 1012}, {"role": "Participant2", "text": "EGFR", "start": 1013, "end": 1017}, {"role": "Participant3", "text": "ERK1/2", "start": 1018, "end": 1024}]}, {"trigger": {"text": "pathways", "start": 956, "end": 964}, "arguments": [{"role": "Participant", "text": "DCN", "start": 966, "end": 969}, {"role": "Participant2", "text": "EGFR", "start": 970, "end": 974}, {"role": "Participant3", "text": "phosphoinositide-3 kinase", "start": 975, "end": 1000}, {"role": "Participant4", "text": "AKT", "start": 1001, "end": 1004}]}, {"trigger": {"text": "signal pathways", "start": 1577, "end": 1592}, "arguments": [{"role": "Participant", "text": "DCN", "start": 1594, "end": 1597}, {"role": "Participant2", "text": "EGFR", "start": 1598, "end": 1602}, {"role": "Participant3", "text": "ERK1/2", "start": 1603, "end": 1609}]}, {"trigger": {"text": "signal pathways", "start": 1577, "end": 1592}, "arguments": [{"role": "Participant", "text": "DCN", "start": 1614, "end": 1617}, {"role": "Participant2", "text": "EGFR", "start": 1618, "end": 1622}, {"role": "Participant3", "text": "phosphoinositide-3 kinase", "start": 1623, "end": 1648}, {"role": "Participant4", "text": "AKT", "start": 1649, "end": 1652}]}], "Planned_process": [{"trigger": {"text": "transfected", "start": 626, "end": 637}, "arguments": [{"role": "Instrument", "text": "DCN", "start": 622, "end": 625}, {"role": "Theme", "text": "cerebral endothelial (MCE) cells", "start": 644, "end": 676}]}, {"trigger": {"text": "transfected", "start": 1234, "end": 1245}, "arguments": [{"role": "Instrument", "text": "DCN", "start": 1230, "end": 1233}, {"role": "Theme", "text": "MCE cells", "start": 1246, "end": 1255}]}, {"trigger": {"text": "transfection", "start": 1386, "end": 1398}, "arguments": [{"role": "Instrument", "text": "DCN", "start": 1382, "end": 1385}, {"role": "Theme", "text": "MCE cells", "start": 1402, "end": 1411}]}], "Positive_regulation": [{"trigger": {"text": "up-regulates", "start": 27, "end": 39}, "arguments": [{"role": "Theme", "text": "expression", "start": 45, "end": 55}, {"role": "Cause", "text": "activation", "start": 96, "end": 106}]}, {"trigger": {"text": "activation", "start": 96, "end": 106}, "arguments": [{"role": "Cause", "text": "expression", "start": 16, "end": 26}, {"role": "Theme", "text": "Sp1", "start": 136, "end": 139}]}, {"trigger": {"text": "activation", "start": 96, "end": 106}, "arguments": [{"role": "Cause", "text": "expression", "start": 16, "end": 26}, {"role": "Theme", "text": "HIF1alpha", "start": 141, "end": 150}]}, {"trigger": {"text": "activation", "start": 96, "end": 106}, "arguments": [{"role": "Cause", "text": "expression", "start": 16, "end": 26}, {"role": "Theme", "text": "Stat3", "start": 156, "end": 161}]}, {"trigger": {"text": "up-regulates", "start": 213, "end": 225}, "arguments": [{"role": "Theme", "text": "expression", "start": 272, "end": 282}, {"role": "Cause", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "activation", "start": 288, "end": 298}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 340, "end": 343}, {"role": "Cause", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "activation", "start": 288, "end": 298}, "arguments": [{"role": "Theme", "text": "hypoxia-inducible factor 1alpha", "start": 345, "end": 376}, {"role": "Cause", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "activation", "start": 288, "end": 298}, "arguments": [{"role": "Theme", "text": "signal transducer and activator of transcription 3", "start": 394, "end": 444}, {"role": "Cause", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "induction", "start": 759, "end": 768}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 787, "end": 790}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "induction", "start": 759, "end": 768}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 792, "end": 801}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "induction", "start": 759, "end": 768}, "arguments": [{"role": "Theme", "text": "Stat3", "start": 807, "end": 812}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "activation", "start": 773, "end": 783}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 787, "end": 790}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "activation", "start": 773, "end": 783}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 792, "end": 801}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "activation", "start": 773, "end": 783}, "arguments": [{"role": "Theme", "text": "Stat3", "start": 807, "end": 812}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "induce", "start": 913, "end": 919}, "arguments": [{"role": "Theme", "text": "expression", "start": 925, "end": 935}, {"role": "Cause", "text": "pathways", "start": 956, "end": 964}]}, {"trigger": {"text": "Induction", "start": 1257, "end": 1266}, "arguments": [{"role": "Theme", "text": "matrix metalloproteinase 2", "start": 1283, "end": 1309}, {"role": "Cause", "text": "transfection", "start": 1386, "end": 1398}]}, {"trigger": {"text": "Induction", "start": 1257, "end": 1266}, "arguments": [{"role": "Theme", "text": "9", "start": 1314, "end": 1315}, {"role": "Cause", "text": "transfection", "start": 1386, "end": 1398}]}, {"trigger": {"text": "Induction", "start": 1257, "end": 1266}, "arguments": [{"role": "Theme", "text": "tissue plasminogen activator", "start": 1338, "end": 1366}, {"role": "Cause", "text": "transfection", "start": 1386, "end": 1398}]}, {"trigger": {"text": "Induction", "start": 1257, "end": 1266}, "arguments": [{"role": "Theme", "text": "plasmin", "start": 1371, "end": 1378}, {"role": "Cause", "text": "transfection", "start": 1386, "end": 1398}]}, {"trigger": {"text": "leads", "start": 1412, "end": 1417}, "arguments": [{"role": "Cause", "text": "Induction", "start": 1257, "end": 1266}, {"role": "Theme", "text": "release", "start": 1454, "end": 1461}]}, {"trigger": {"text": "leads", "start": 1412, "end": 1417}, "arguments": [{"role": "Cause", "text": "Induction", "start": 1257, "end": 1266}, {"role": "Theme", "text": "activation", "start": 1487, "end": 1497}]}, {"trigger": {"text": "activation", "start": 1487, "end": 1497}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1501, "end": 1513}]}, {"trigger": {"text": "mediate", "start": 1654, "end": 1661}, "arguments": [{"role": "Cause", "text": "signal pathways", "start": 1577, "end": 1592}, {"role": "Theme", "text": "up-regulation", "start": 1662, "end": 1675}]}, {"trigger": {"text": "mediate", "start": 1654, "end": 1661}, "arguments": [{"role": "Cause", "text": "signal pathways", "start": 1577, "end": 1592}, {"role": "Theme", "text": "activation", "start": 1680, "end": 1690}]}, {"trigger": {"text": "mediate", "start": 1654, "end": 1661}, "arguments": [{"role": "Cause", "text": "signal pathways", "start": 1577, "end": 1592}, {"role": "Theme", "text": "increase", "start": 1762, "end": 1770}]}, {"trigger": {"text": "up-regulation", "start": 1662, "end": 1675}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 1732, "end": 1741}]}, {"trigger": {"text": "up-regulation", "start": 1662, "end": 1675}, "arguments": [{"role": "Theme", "text": "Stat3", "start": 1743, "end": 1748}]}, {"trigger": {"text": "up-regulation", "start": 1662, "end": 1675}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 1754, "end": 1757}]}, {"trigger": {"text": "activation", "start": 1680, "end": 1690}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 1732, "end": 1741}]}, {"trigger": {"text": "activation", "start": 1680, "end": 1690}, "arguments": [{"role": "Theme", "text": "Stat3", "start": 1743, "end": 1748}]}, {"trigger": {"text": "activation", "start": 1680, "end": 1690}, "arguments": [{"role": "Theme", "text": "Sp1", "start": 1754, "end": 1757}]}, {"trigger": {"text": "increase", "start": 1762, "end": 1770}, "arguments": [{"role": "Theme", "text": "transcription", "start": 1776, "end": 1789}]}, {"trigger": {"text": "increase", "start": 1762, "end": 1770}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1794, "end": 1806}]}], "Regulation": [{"trigger": {"text": "up-regulates", "start": 213, "end": 225}, "arguments": [{"role": "Cause", "text": "decorin", "start": 199, "end": 206}, {"role": "Theme", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "activation", "start": 288, "end": 298}, "arguments": [{"role": "Cause", "text": "decorin", "start": 199, "end": 206}, {"role": "Theme", "text": "pathways", "start": 610, "end": 618}]}, {"trigger": {"text": "regulating", "start": 307, "end": 317}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 302, "end": 306}, {"role": "Cause", "text": "Sp1", "start": 340, "end": 343}]}, {"trigger": {"text": "regulating", "start": 307, "end": 317}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 302, "end": 306}, {"role": "Cause", "text": "hypoxia-inducible factor 1alpha", "start": 345, "end": 376}]}, {"trigger": {"text": "regulating", "start": 307, "end": 317}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 302, "end": 306}, {"role": "Cause", "text": "signal transducer and activator of transcription 3", "start": 394, "end": 444}]}, {"trigger": {"text": "regulation", "start": 1208, "end": 1218}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1222, "end": 1226}]}], "Transcription": [{"trigger": {"text": "transcription", "start": 1776, "end": 1789}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1771, "end": 1775}]}]}}, "schema": []}
{"input": "Effects of spironolactone on corneal allograft survival in the rat.\n\nPURPOSE: Spironolactone has recently been shown to have suppressive effects on several immunoactive and proinflammatory cytokines. In this study, we investigated the effects of spironolactone on the prevention of corneal allograft rejection in a MHC class I/II mismatch rat corneal transplant model. METHODS: Grafted animals for corneal survival analysis were assigned to receive either spironolactone suspension (orally, 100 mg/kg/day, n = 7), phosphate-buffered saline (PBS, orally, same volume as spironolactone, n = 9) or remained untreated (n = 16). Additional grafted rats treated with spironolactone (n = 6) or PBS (n = 8) were sacrificed on day 12 for quantitative RT-PCR analysis for mechanistic studies. RESULTS: Mean (+/-SEM) graft survival was significantly prolonged in animals receiving spironolactone (14.9 +/- 2.0 days) compared with both PBS-treated (12.3 +/- 1.2 days, p = 0.007) and untreated controls (13.0 +/- 1.0 days, p = 0.01). We found a decrease in corneal neovascularization in spironolactone-treated rats compared with the PBS-treated group, although the difference was not statistically significant. Spironolactone affected both systemic (down-regulation of CD25+ cells in spleen) and local immune response (up-regulation of IL-10 in cornea). CONCLUSION: We present initial results demonstrating anti-inflammatory effects of spironolactone.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 1052, "end": 1070}, "arguments": [{"role": "AtLoc", "text": "corneal", "start": 1044, "end": 1051}]}], "Death": [{"trigger": {"text": "survival", "start": 47, "end": 55}, "arguments": [{"role": "Theme", "text": "corneal allograft", "start": 29, "end": 46}]}, {"trigger": {"text": "rejection", "start": 300, "end": 309}, "arguments": [{"role": "Theme", "text": "corneal allograft", "start": 282, "end": 299}]}, {"trigger": {"text": "survival", "start": 406, "end": 414}, "arguments": [{"role": "Theme", "text": "corneal", "start": 398, "end": 405}]}, {"trigger": {"text": "survival", "start": 812, "end": 820}, "arguments": [{"role": "Theme", "text": "graft", "start": 806, "end": 811}]}], "Negative_regulation": [{"trigger": {"text": "prevention", "start": 268, "end": 278}, "arguments": [{"role": "Theme", "text": "rejection", "start": 300, "end": 309}]}, {"trigger": {"text": "decrease", "start": 1032, "end": 1040}, "arguments": [{"role": "Theme", "text": "neovascularization", "start": 1052, "end": 1070}]}, {"trigger": {"text": "down-regulation", "start": 1237, "end": 1252}, "arguments": [{"role": "Theme", "text": "CD25+ cells", "start": 1256, "end": 1267}]}], "Planned_process": [{"trigger": {"text": "transplant", "start": 351, "end": 361}, "arguments": [{"role": "Theme", "text": "rat", "start": 339, "end": 342}, {"role": "Instrument", "text": "corneal", "start": 343, "end": 350}]}, {"trigger": {"text": "grafted", "start": 635, "end": 642}, "arguments": [{"role": "Theme", "text": "rats", "start": 643, "end": 647}]}, {"trigger": {"text": "treated", "start": 648, "end": 655}, "arguments": [{"role": "Theme", "text": "rats", "start": 643, "end": 647}, {"role": "Instrument", "text": "spironolactone", "start": 661, "end": 675}]}, {"trigger": {"text": "treated", "start": 648, "end": 655}, "arguments": [{"role": "Theme", "text": "rats", "start": 643, "end": 647}, {"role": "Instrument", "text": "PBS", "start": 687, "end": 690}]}, {"trigger": {"text": "sacrificed", "start": 704, "end": 714}, "arguments": [{"role": "Theme", "text": "rats", "start": 643, "end": 647}]}, {"trigger": {"text": "receiving", "start": 860, "end": 869}, "arguments": [{"role": "Instrument", "text": "spironolactone", "start": 870, "end": 884}]}, {"trigger": {"text": "treated", "start": 928, "end": 935}, "arguments": [{"role": "Theme", "text": "graft", "start": 806, "end": 811}, {"role": "Instrument", "text": "PBS", "start": 924, "end": 927}]}, {"trigger": {"text": "untreated", "start": 971, "end": 980}, "arguments": [{"role": "Theme", "text": "graft", "start": 806, "end": 811}]}, {"trigger": {"text": "treated", "start": 1089, "end": 1096}, "arguments": [{"role": "Instrument", "text": "spironolactone", "start": 1074, "end": 1088}, {"role": "Theme", "text": "rats", "start": 1097, "end": 1101}]}, {"trigger": {"text": "treated", "start": 1124, "end": 1131}, "arguments": [{"role": "Theme", "text": "rats", "start": 1097, "end": 1101}, {"role": "Instrument", "text": "PBS", "start": 1120, "end": 1123}]}], "Positive_regulation": [{"trigger": {"text": "prolonged", "start": 839, "end": 848}, "arguments": [{"role": "Theme", "text": "survival", "start": 812, "end": 820}, {"role": "Cause", "text": "receiving", "start": 860, "end": 869}]}, {"trigger": {"text": "up-regulation", "start": 1306, "end": 1319}, "arguments": [{"role": "Theme", "text": "IL-10", "start": 1323, "end": 1328}]}], "Regulation": [{"trigger": {"text": "Effects", "start": 0, "end": 7}, "arguments": [{"role": "Cause", "text": "spironolactone", "start": 11, "end": 25}, {"role": "Theme", "text": "survival", "start": 47, "end": 55}]}, {"trigger": {"text": "effects", "start": 235, "end": 242}, "arguments": [{"role": "Cause", "text": "spironolactone", "start": 246, "end": 260}, {"role": "Theme", "text": "prevention", "start": 268, "end": 278}]}, {"trigger": {"text": "affected", "start": 1213, "end": 1221}, "arguments": [{"role": "Cause", "text": "Spironolactone", "start": 1198, "end": 1212}, {"role": "Theme", "text": "down-regulation", "start": 1237, "end": 1252}]}, {"trigger": {"text": "affected", "start": 1213, "end": 1221}, "arguments": [{"role": "Cause", "text": "Spironolactone", "start": 1198, "end": 1212}, {"role": "Theme", "text": "up-regulation", "start": 1306, "end": 1319}]}]}}, "schema": []}
{"input": "A new autosomal dominant vascular retinopathy syndrome.\n\nWe describe a new syndrome with autosomal dominant transmission whose most striking feature is vascular retinopathy. The retinopathy is often associated with migraine, Raynaud's phenomenon and mental changes, mainly forgetfulness, aggression and depression. To define this syndrome we collected medical data on 110 family members. General ophthalmological examination and fluorescein angiography were performed in 61 persons. The retinopathy, as diagnosed in 22 persons, is characterized by central and peripheral microangiopathy, areas of capillary non-perfusion, haemorrhages, cotton wool spots and, in a more advanced stage, occlusion of large retinal vessels, which can induce a neovascular response. A vascular occlusive disorder may be the common aetiological factor of the various manifestation of this syndrome.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascular response", "start": 740, "end": 760}, "arguments": []}], "Planned_process": [{"trigger": {"text": "angiography", "start": 441, "end": 452}, "arguments": [{"role": "Instrument", "text": "fluorescein", "start": 429, "end": 440}, {"role": "Theme", "text": "persons", "start": 474, "end": 481}]}], "Positive_regulation": [{"trigger": {"text": "induce", "start": 731, "end": 737}, "arguments": [{"role": "Theme", "text": "neovascular response", "start": 740, "end": 760}]}]}}, "schema": []}
{"input": "The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis.\n\nSolid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of  less than /=1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S-induced and VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C-expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenic", "start": 318, "end": 328}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 727, "end": 739}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1539, "end": 1551}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1694, "end": 1706}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1988, "end": 2000}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 1408, "end": 1421}, "arguments": [{"role": "Theme", "text": "lymphatic", "start": 1450, "end": 1459}]}, {"trigger": {"text": "proliferation", "start": 1408, "end": 1421}, "arguments": [{"role": "Theme", "text": "blood vascular endothelial cells", "start": 1464, "end": 1496}]}], "Death": [{"trigger": {"text": "survival", "start": 1423, "end": 1431}, "arguments": [{"role": "Theme", "text": "lymphatic", "start": 1450, "end": 1459}]}, {"trigger": {"text": "survival", "start": 1423, "end": 1431}, "arguments": [{"role": "Theme", "text": "blood vascular endothelial cells", "start": 1464, "end": 1496}]}], "Development": [{"trigger": {"text": "progression", "start": 1931, "end": 1942}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1925, "end": 1930}]}], "Gene_expression": [{"trigger": {"text": "expressing", "start": 1592, "end": 1602}, "arguments": [{"role": "Theme", "text": "VEGF-E", "start": 1585, "end": 1591}]}, {"trigger": {"text": "expressing", "start": 1618, "end": 1628}, "arguments": [{"role": "Theme", "text": "VEGF-C156S", "start": 1607, "end": 1617}]}, {"trigger": {"text": "expressing", "start": 1753, "end": 1763}, "arguments": [{"role": "Theme", "text": "VEGF-A", "start": 1764, "end": 1770}]}, {"trigger": {"text": "expressing", "start": 1753, "end": 1763}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 1774, "end": 1780}]}, {"trigger": {"text": "expressing", "start": 1844, "end": 1854}, "arguments": [{"role": "Theme", "text": "VEGF-C", "start": 1837, "end": 1843}]}], "Growth": [{"trigger": {"text": "growth", "start": 504, "end": 510}, "arguments": [{"role": "Theme", "text": "tumor", "start": 498, "end": 503}]}, {"trigger": {"text": "growth", "start": 758, "end": 764}, "arguments": [{"role": "Theme", "text": "tumor", "start": 752, "end": 757}]}], "Localization": [{"trigger": {"text": "migration", "start": 1437, "end": 1446}, "arguments": [{"role": "Theme", "text": "lymphatic", "start": 1450, "end": 1459}]}, {"trigger": {"text": "migration", "start": 1437, "end": 1446}, "arguments": [{"role": "Theme", "text": "blood vascular endothelial cells", "start": 1464, "end": 1496}]}], "Negative_regulation": [{"trigger": {"text": "blocks", "start": 40, "end": 46}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 30, "end": 39}, {"role": "Theme", "text": "vascular endothelial growth factor receptor-3", "start": 62, "end": 107}]}, {"trigger": {"text": "impede", "start": 491, "end": 497}, "arguments": [{"role": "Cause", "text": "tyrosine kinase inhibitors", "start": 408, "end": 434}, {"role": "Theme", "text": "growth", "start": 504, "end": 510}]}, {"trigger": {"text": "prevent", "start": 704, "end": 711}, "arguments": [{"role": "Cause", "text": "Cediranib", "start": 594, "end": 603}, {"role": "Theme", "text": "angiogenesis", "start": 727, "end": 739}]}, {"trigger": {"text": "prevent", "start": 704, "end": 711}, "arguments": [{"role": "Cause", "text": "Cediranib", "start": 594, "end": 603}, {"role": "Theme", "text": "growth", "start": 758, "end": 764}]}, {"trigger": {"text": "inhibited", "start": 1134, "end": 1143}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1124, "end": 1133}, {"role": "Theme", "text": "phosphorylation", "start": 1159, "end": 1174}]}, {"trigger": {"text": "inhibited", "start": 1134, "end": 1143}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1124, "end": 1133}, {"role": "Theme", "text": "phosphorylation", "start": 1209, "end": 1224}]}, {"trigger": {"text": "blocked", "start": 1362, "end": 1369}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1352, "end": 1361}, {"role": "Theme", "text": "proliferation", "start": 1408, "end": 1421}]}, {"trigger": {"text": "blocked", "start": 1362, "end": 1369}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1352, "end": 1361}, {"role": "Theme", "text": "survival", "start": 1423, "end": 1431}]}, {"trigger": {"text": "blocked", "start": 1362, "end": 1369}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1352, "end": 1361}, {"role": "Theme", "text": "migration", "start": 1437, "end": 1446}]}, {"trigger": {"text": "prevented", "start": 1529, "end": 1538}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 1507, "end": 1516}, {"role": "Theme", "text": "angiogenesis", "start": 1539, "end": 1551}]}, {"trigger": {"text": "blocked", "start": 1686, "end": 1693}, "arguments": [{"role": "Cause", "text": "Cediranib", "start": 1657, "end": 1666}, {"role": "Theme", "text": "angiogenesis", "start": 1694, "end": 1706}]}, {"trigger": {"text": "preventing", "start": 1914, "end": 1924}, "arguments": [{"role": "Theme", "text": "progression", "start": 1931, "end": 1942}, {"role": "Cause", "text": "inhibiting", "start": 1956, "end": 1966}]}, {"trigger": {"text": "preventing", "start": 1914, "end": 1924}, "arguments": [{"role": "Theme", "text": "progression", "start": 1931, "end": 1942}, {"role": "Cause", "text": "inhibiting", "start": 2028, "end": 2038}]}, {"trigger": {"text": "inhibiting", "start": 1956, "end": 1966}, "arguments": [{"role": "Cause", "text": "Cediranib", "start": 1863, "end": 1872}, {"role": "Theme", "text": "VEGFR-2", "start": 1967, "end": 1974}]}, {"trigger": {"text": "inhibiting", "start": 1956, "end": 1966}, "arguments": [{"role": "Cause", "text": "Cediranib", "start": 1863, "end": 1872}, {"role": "Theme", "text": "angiogenesis", "start": 1988, "end": 2000}]}, {"trigger": {"text": "inhibiting", "start": 2028, "end": 2038}, "arguments": [{"role": "Theme", "text": "VEGFR-3", "start": 2039, "end": 2046}]}], "Pathway": [{"trigger": {"text": "signaling", "start": 648, "end": 657}, "arguments": [{"role": "Participant", "text": "VEGF", "start": 643, "end": 647}]}], "Phosphorylation": [{"trigger": {"text": "phosphorylation", "start": 1159, "end": 1174}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1178, "end": 1185}]}, {"trigger": {"text": "phosphorylation", "start": 1209, "end": 1224}, "arguments": [{"role": "Theme", "text": "VEGFR-3", "start": 1228, "end": 1235}]}], "Positive_regulation": [{"trigger": {"text": "induced", "start": 54, "end": 61}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor receptor-3", "start": 62, "end": 107}]}, {"trigger": {"text": "induced", "start": 719, "end": 726}, "arguments": [{"role": "Cause", "text": "VEGF-A", "start": 712, "end": 718}, {"role": "Theme", "text": "angiogenesis", "start": 727, "end": 739}]}, {"trigger": {"text": "induced", "start": 1151, "end": 1158}, "arguments": [{"role": "Cause", "text": "VEGF-E", "start": 1144, "end": 1150}, {"role": "Theme", "text": "phosphorylation", "start": 1159, "end": 1174}]}, {"trigger": {"text": "induced", "start": 1201, "end": 1208}, "arguments": [{"role": "Cause", "text": "VEGF-C156S", "start": 1190, "end": 1200}, {"role": "Theme", "text": "phosphorylation", "start": 1209, "end": 1224}]}, {"trigger": {"text": "induced", "start": 1381, "end": 1388}, "arguments": [{"role": "Cause", "text": "VEGF-C156S", "start": 1370, "end": 1380}, {"role": "Theme", "text": "proliferation", "start": 1408, "end": 1421}]}, {"trigger": {"text": "induced", "start": 1381, "end": 1388}, "arguments": [{"role": "Cause", "text": "VEGF-C156S", "start": 1370, "end": 1380}, {"role": "Theme", "text": "survival", "start": 1423, "end": 1431}]}, {"trigger": {"text": "induced", "start": 1381, "end": 1388}, "arguments": [{"role": "Cause", "text": "VEGF-C156S", "start": 1370, "end": 1380}, {"role": "Theme", "text": "migration", "start": 1437, "end": 1446}]}, {"trigger": {"text": "induced", "start": 1400, "end": 1407}, "arguments": [{"role": "Cause", "text": "VEGF-E", "start": 1393, "end": 1399}, {"role": "Theme", "text": "proliferation", "start": 1408, "end": 1421}]}, {"trigger": {"text": "induced", "start": 1400, "end": 1407}, "arguments": [{"role": "Cause", "text": "VEGF-E", "start": 1393, "end": 1399}, {"role": "Theme", "text": "survival", "start": 1423, "end": 1431}]}, {"trigger": {"text": "induced", "start": 1400, "end": 1407}, "arguments": [{"role": "Cause", "text": "VEGF-E", "start": 1393, "end": 1399}, {"role": "Theme", "text": "migration", "start": 1437, "end": 1446}]}, {"trigger": {"text": "induced", "start": 1574, "end": 1581}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1539, "end": 1551}, {"role": "Cause", "text": "adenoviruses", "start": 1629, "end": 1641}]}], "Regulation": [{"trigger": {"text": "effects", "start": 774, "end": 781}, "arguments": [{"role": "Cause", "text": "cediranib", "start": 785, "end": 794}, {"role": "Theme", "text": "endothelial cell", "start": 831, "end": 847}]}, {"trigger": {"text": "mediated", "start": 822, "end": 830}, "arguments": [{"role": "Cause", "text": "VEGF receptor (VEGFR)-3", "start": 798, "end": 821}, {"role": "Theme", "text": "endothelial cell", "start": 831, "end": 847}]}]}}, "schema": []}
{"input": "Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases.\n\nOBJECT: Endothelial proliferation has been recognized as a marker of high-grade or aggressive glioma. Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody to vascular endothelial growth factor that has been shown to have activity in malignant gliomas when combined with irinotecan. The authors report on a case series of 13 patients with recurrent heavily pretreated malignant glioma that was treated with the combination of bevacizumab and irinotecan. METHODS: Standard therapy with primary resection followed by adjuvant chemotherapy and radiation had failed in all patients. The median number of therapies applied, including initial surgery, was 5 (range 3-7 therapies). Nine patients were started on bevacizumab at a dose of 5 mg/m2 every 2 weeks. Four patients received bevacizumab at a dose of 10 mg/m2; irinotecan was given at a dose of 125 mg/m2 every week for 3 weeks. RESULTS: Of the 13 treated patients, 10 (77%) had a radiologically demonstrated partial response and 3 (23%) had stable disease. Six patients (46%) had a clinical response. The median time to disease progression while on treatment was 24 weeks. The median overall survival was 27 weeks. The disease progressed in 8 patients, despite an initial response. Five patients are still responding to therapy. Six of the 8 patients whose disease progressed have died. Bevacizumab was discontinued in 2 patients because of nonfatal intracranial bleeding. CONCLUSIONS: The combination of bevacizumab and irinotecan is safe and has excellent activity even in this relapsed, heavily pretreated population of patients with high-grade malignant glioma, most of whom would not be candidates for clinical trials.\n", "output": {"json_structures": {"Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 106, "end": 119}, "arguments": [{"role": "Theme", "text": "Endothelial", "start": 94, "end": 105}]}], "Death": [{"trigger": {"text": "died", "start": 1429, "end": 1433}, "arguments": [{"role": "Theme", "text": "patients", "start": 1390, "end": 1398}]}], "Planned_process": [{"trigger": {"text": "therapy", "start": 27, "end": 34}, "arguments": [{"role": "Instrument", "text": "Bevacizumab", "start": 0, "end": 11}, {"role": "Theme", "text": "glioblastoma multiforme", "start": 38, "end": 61}]}, {"trigger": {"text": "therapy", "start": 27, "end": 34}, "arguments": [{"role": "Instrument", "text": "irinotecan", "start": 16, "end": 26}, {"role": "Theme", "text": "glioblastoma multiforme", "start": 38, "end": 61}]}, {"trigger": {"text": "pretreated", "start": 454, "end": 464}, "arguments": [{"role": "Theme", "text": "patients", "start": 422, "end": 430}]}, {"trigger": {"text": "treated", "start": 491, "end": 498}, "arguments": [{"role": "Theme", "text": "glioma", "start": 475, "end": 481}, {"role": "Instrument", "text": "bevacizumab", "start": 523, "end": 534}, {"role": "Instrument", "text": "irinotecan", "start": 539, "end": 549}]}, {"trigger": {"text": "chemotherapy", "start": 621, "end": 633}, "arguments": [{"role": "Theme", "text": "patients", "start": 666, "end": 674}]}, {"trigger": {"text": "radiation", "start": 638, "end": 647}, "arguments": [{"role": "Theme", "text": "patients", "start": 666, "end": 674}]}, {"trigger": {"text": "started", "start": 791, "end": 798}, "arguments": [{"role": "Theme", "text": "patients", "start": 777, "end": 785}, {"role": "Instrument", "text": "bevacizumab", "start": 802, "end": 813}]}, {"trigger": {"text": "received", "start": 864, "end": 872}, "arguments": [{"role": "Theme", "text": "patients", "start": 855, "end": 863}, {"role": "Instrument", "text": "bevacizumab", "start": 873, "end": 884}]}, {"trigger": {"text": "given", "start": 923, "end": 928}, "arguments": [{"role": "Theme", "text": "patients", "start": 855, "end": 863}, {"role": "Instrument", "text": "irinotecan", "start": 908, "end": 918}]}, {"trigger": {"text": "treated", "start": 995, "end": 1002}, "arguments": [{"role": "Theme", "text": "patients", "start": 1003, "end": 1011}]}, {"trigger": {"text": "discontinued", "start": 1451, "end": 1463}, "arguments": [{"role": "Instrument", "text": "Bevacizumab", "start": 1435, "end": 1446}, {"role": "Theme", "text": "patients", "start": 1469, "end": 1477}]}, {"trigger": {"text": "pretreated", "start": 1646, "end": 1656}, "arguments": [{"role": "Theme", "text": "patients", "start": 1671, "end": 1679}]}], "Regulation": [{"trigger": {"text": "have activity", "start": 314, "end": 327}, "arguments": [{"role": "Cause", "text": "Bevacizumab", "start": 188, "end": 199}, {"role": "Theme", "text": "gliomas", "start": 341, "end": 348}]}]}}, "schema": []}
{"input": "Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization.\n\nThe formation of functional, mature blood vessels depends on the interaction between endothelial cells and pericytes. Commonality exists in the processes involved in vasculature development between tissues whether healthy or diseased. Endosialin/TEM 1 is a cell membrane protein that is expressed in blood vessels during embryogenesis and tumorigenesis but not in normal mature vessels. Antibodies developed to human endosialin were used to investigate endosialin expression and function in human prenatal brain pericytes and pericytes residing in tumors. Anti-endosialin was capable of preventing pericyte tube formation in culture and inhibited migration. Brain pericytes in culture had higher levels of endosialin/TEM 1 than TEMs-2, -3, -4, -5, -7, and -8. Immunocytochemistry revealed that endosialin was present in the cytoplasmic body and in the elongated extensions essential to pericyte function. Transgenic mice engineered to express human endosialin bred on an immunocompromised background allowed the growth of human tumor xenografts. In human colon carcinoma Colo205 and HT29 xenografts grown in human endosialin-transgenic mice, endosialin expression was largely confined to NG2-expressing perivascular cells and not CD31-positive endothelial cells. Similar methods applied to human ovarian and colon tumors confirmed endosialin expression by pericytes. The data indicate that endosialin is strongly expressed by pericytes during periods of active angiogenesis during embryonic and tumor development. Anti-endosialin antibodies may have value in identifying vasculature in malignant tissues. With the appropriate agent, targeting endosialin may interfere with blood vessel growth during tumor development.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "interaction", "start": 153, "end": 164}, "arguments": [{"role": "Theme", "text": "endothelial cells", "start": 173, "end": 190}, {"role": "Theme", "text": "pericytes", "start": 195, "end": 204}]}], "Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 67, "end": 85}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 61, "end": 66}]}, {"trigger": {"text": "angiogenesis", "start": 1549, "end": 1561}, "arguments": []}], "Development": [{"trigger": {"text": "formation", "start": 92, "end": 101}, "arguments": [{"role": "Theme", "text": "blood vessels", "start": 124, "end": 137}]}, {"trigger": {"text": "development", "start": 266, "end": 277}, "arguments": [{"role": "Theme", "text": "vasculature", "start": 254, "end": 265}]}, {"trigger": {"text": "formation", "start": 700, "end": 709}, "arguments": [{"role": "Theme", "text": "pericyte tube", "start": 686, "end": 699}]}, {"trigger": {"text": "development", "start": 1589, "end": 1600}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1583, "end": 1588}]}, {"trigger": {"text": "development", "start": 1794, "end": 1805}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1788, "end": 1793}]}], "Gene_expression": [{"trigger": {"text": "expressed", "start": 375, "end": 384}, "arguments": [{"role": "Theme", "text": "TEM 1", "start": 334, "end": 339}]}, {"trigger": {"text": "expression", "start": 552, "end": 562}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 541, "end": 551}]}, {"trigger": {"text": "express", "start": 1023, "end": 1030}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 1037, "end": 1047}]}, {"trigger": {"text": "expression", "start": 1241, "end": 1251}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 1230, "end": 1240}]}, {"trigger": {"text": "expressing", "start": 1280, "end": 1290}, "arguments": [{"role": "Theme", "text": "NG2", "start": 1276, "end": 1279}]}, {"trigger": {"text": "positive", "start": 1323, "end": 1331}, "arguments": [{"role": "Theme", "text": "CD31", "start": 1318, "end": 1322}]}, {"trigger": {"text": "expression", "start": 1430, "end": 1440}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 1419, "end": 1429}]}, {"trigger": {"text": "expressed", "start": 1501, "end": 1510}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 1478, "end": 1488}]}], "Growth": [{"trigger": {"text": "growth", "start": 1100, "end": 1106}, "arguments": [{"role": "Theme", "text": "tumor xenografts", "start": 1116, "end": 1132}]}, {"trigger": {"text": "grown", "start": 1187, "end": 1192}, "arguments": [{"role": "Theme", "text": "colon carcinoma Colo205", "start": 1143, "end": 1166}]}, {"trigger": {"text": "grown", "start": 1187, "end": 1192}, "arguments": [{"role": "Theme", "text": "HT29", "start": 1171, "end": 1175}]}, {"trigger": {"text": "growth", "start": 1774, "end": 1780}, "arguments": [{"role": "Theme", "text": "blood vessel", "start": 1761, "end": 1773}]}], "Localization": [{"trigger": {"text": "present", "start": 897, "end": 904}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 882, "end": 892}]}], "Negative_regulation": [{"trigger": {"text": "preventing", "start": 675, "end": 685}, "arguments": [{"role": "Cause", "text": "Anti-endosialin", "start": 644, "end": 659}, {"role": "Theme", "text": "formation", "start": 700, "end": 709}]}, {"trigger": {"text": "interfere", "start": 1746, "end": 1755}, "arguments": [{"role": "Cause", "text": "targeting", "start": 1721, "end": 1730}, {"role": "Theme", "text": "growth", "start": 1774, "end": 1780}]}], "Planned_process": [{"trigger": {"text": "Transgenic", "start": 993, "end": 1003}, "arguments": [{"role": "Theme", "text": "mice", "start": 1004, "end": 1008}, {"role": "Instrument", "text": "endosialin", "start": 1037, "end": 1047}]}, {"trigger": {"text": "transgenic", "start": 1213, "end": 1223}, "arguments": [{"role": "Instrument", "text": "endosialin", "start": 1202, "end": 1212}, {"role": "Theme", "text": "mice", "start": 1224, "end": 1228}]}, {"trigger": {"text": "targeting", "start": 1721, "end": 1730}, "arguments": [{"role": "Theme", "text": "endosialin", "start": 1731, "end": 1741}]}], "Positive_regulation": [{"trigger": {"text": "depends", "start": 138, "end": 145}, "arguments": [{"role": "Theme", "text": "formation", "start": 92, "end": 101}, {"role": "Cause", "text": "interaction", "start": 153, "end": 164}]}]}}, "schema": []}
{"input": "Efficient inhibition of ovarian cancer growth and prolonged survival by transfection with a novel pro-apoptotic gene, hPNAS-4, in a mouse model. In vivo and in vitro results.\n\nOBJECTIVE: We transfected ovarian cancer cells and administered recombinant plasmid encoding hPNAS-4 to nude mice bearing ovarian cancer, aiming to evaluate the effect of hPNAS-4 against ovarian cancer in vitro and in vivo. METHODS: Ovarian cancer SKOV3 cells were transfected with hPNAS-4-plasmid, and cell proliferation was evaluated by MTT assay; apoptosis was examined by DNA ladder, Hoechst33258 staining and flow-cytometric assays. Nude mice bearing ovarian cancers were treated with hPNAS-4-p/liposome. Tumor growth was determined and survival was recorded. TUNEL assay and microvessel density was assessed to evaluate apoptosis and angiogenesis. RESULTS: Both inhibition of proliferation (p < 0.05) and induction of apoptosis (p < 0.05) were observed in SKOV3 cells transfected with hPNAS-4-p in vitro. In hPNAS-4-p-treated tumor cells in vivo, tumor growth significantly decreased, while the survival time of tumor-bearing mice was prolonged compared with control groups (p < 0.05). Increased apoptosis of tumor cells and decreased angiogenesis in tumor tissue were also observed. CONCLUSIONS: Our promising results on the potential antitumor effects of hPNAS-4 on ovarian cancer in vitro and in vivo may be explained, in part, by the induction of apoptosis and inhibition of angiogenesis. Consequently, hPNAS-4 has potential as a new gene therapy for human ovarian cancer.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 816, "end": 828}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1217, "end": 1229}, "arguments": [{"role": "AtLoc", "text": "tumor tissue", "start": 1233, "end": 1245}]}, {"trigger": {"text": "angiogenesis", "start": 1461, "end": 1473}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 484, "end": 497}, "arguments": [{"role": "Theme", "text": "cell", "start": 479, "end": 483}]}, {"trigger": {"text": "proliferation", "start": 858, "end": 871}, "arguments": [{"role": "Theme", "text": "SKOV3 cells", "start": 938, "end": 949}]}], "Death": [{"trigger": {"text": "survival", "start": 60, "end": 68}, "arguments": [{"role": "Theme", "text": "mouse", "start": 132, "end": 137}]}, {"trigger": {"text": "apoptosis", "start": 526, "end": 535}, "arguments": [{"role": "Theme", "text": "Ovarian cancer SKOV3 cells", "start": 409, "end": 435}]}, {"trigger": {"text": "apoptosis", "start": 900, "end": 909}, "arguments": [{"role": "Theme", "text": "SKOV3 cells", "start": 938, "end": 949}]}, {"trigger": {"text": "survival", "start": 1077, "end": 1085}, "arguments": [{"role": "Theme", "text": "mice", "start": 1108, "end": 1112}]}, {"trigger": {"text": "apoptosis", "start": 1178, "end": 1187}, "arguments": [{"role": "Theme", "text": "tumor cells", "start": 1191, "end": 1202}]}, {"trigger": {"text": "apoptosis", "start": 1433, "end": 1442}, "arguments": [{"role": "Theme", "text": "ovarian cancer", "start": 1350, "end": 1364}]}], "Growth": [{"trigger": {"text": "growth", "start": 39, "end": 45}, "arguments": [{"role": "Theme", "text": "ovarian cancer", "start": 24, "end": 38}]}, {"trigger": {"text": "growth", "start": 692, "end": 698}, "arguments": [{"role": "Theme", "text": "Tumor", "start": 686, "end": 691}]}, {"trigger": {"text": "growth", "start": 1035, "end": 1041}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1029, "end": 1034}]}], "Negative_regulation": [{"trigger": {"text": "inhibition", "start": 10, "end": 20}, "arguments": [{"role": "Theme", "text": "growth", "start": 39, "end": 45}, {"role": "Cause", "text": "transfection", "start": 72, "end": 84}]}, {"trigger": {"text": "inhibition", "start": 10, "end": 20}, "arguments": [{"role": "Theme", "text": "survival", "start": 60, "end": 68}, {"role": "Cause", "text": "transfection", "start": 72, "end": 84}]}, {"trigger": {"text": "inhibition", "start": 844, "end": 854}, "arguments": [{"role": "Theme", "text": "proliferation", "start": 858, "end": 871}]}, {"trigger": {"text": "decreased", "start": 1056, "end": 1065}, "arguments": [{"role": "Theme", "text": "growth", "start": 1035, "end": 1041}]}, {"trigger": {"text": "decreased", "start": 1207, "end": 1216}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1217, "end": 1229}]}, {"trigger": {"text": "effects", "start": 1328, "end": 1335}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1322, "end": 1327}, {"role": "Cause", "text": "hPNAS-4", "start": 1339, "end": 1346}]}, {"trigger": {"text": "effects", "start": 1328, "end": 1335}, "arguments": [{"role": "Theme", "text": "ovarian cancer", "start": 1350, "end": 1364}, {"role": "Cause", "text": "induction", "start": 1420, "end": 1429}]}, {"trigger": {"text": "effects", "start": 1328, "end": 1335}, "arguments": [{"role": "Theme", "text": "ovarian cancer", "start": 1350, "end": 1364}, {"role": "Cause", "text": "inhibition", "start": 1447, "end": 1457}]}, {"trigger": {"text": "inhibition", "start": 1447, "end": 1457}, "arguments": [{"role": "Cause", "text": "hPNAS-4", "start": 1339, "end": 1346}, {"role": "Theme", "text": "angiogenesis", "start": 1461, "end": 1473}]}], "Planned_process": [{"trigger": {"text": "transfection", "start": 72, "end": 84}, "arguments": [{"role": "Instrument", "text": "hPNAS-4", "start": 118, "end": 125}]}, {"trigger": {"text": "transfected", "start": 190, "end": 201}, "arguments": [{"role": "Theme", "text": "ovarian cancer cells", "start": 202, "end": 222}, {"role": "Instrument", "text": "hPNAS-4", "start": 269, "end": 276}]}, {"trigger": {"text": "administered", "start": 227, "end": 239}, "arguments": [{"role": "Instrument", "text": "hPNAS-4", "start": 269, "end": 276}, {"role": "Theme", "text": "nude mice", "start": 280, "end": 289}]}, {"trigger": {"text": "transfected", "start": 441, "end": 452}, "arguments": [{"role": "Theme", "text": "Ovarian cancer SKOV3 cells", "start": 409, "end": 435}, {"role": "Instrument", "text": "hPNAS-4", "start": 458, "end": 465}]}, {"trigger": {"text": "treated", "start": 653, "end": 660}, "arguments": [{"role": "Theme", "text": "Nude mice", "start": 614, "end": 623}, {"role": "Instrument", "text": "hPNAS-4", "start": 666, "end": 673}, {"role": "Instrument", "text": "liposome", "start": 676, "end": 684}]}, {"trigger": {"text": "transfected", "start": 950, "end": 961}, "arguments": [{"role": "Theme", "text": "SKOV3 cells", "start": 938, "end": 949}, {"role": "Instrument", "text": "hPNAS-4", "start": 967, "end": 974}]}, {"trigger": {"text": "treated", "start": 1000, "end": 1007}, "arguments": [{"role": "Instrument", "text": "hPNAS-4", "start": 990, "end": 997}, {"role": "Theme", "text": "tumor cells", "start": 1008, "end": 1019}]}, {"trigger": {"text": "gene therapy", "start": 1520, "end": 1532}, "arguments": [{"role": "Instrument", "text": "hPNAS-4", "start": 1489, "end": 1496}, {"role": "Theme", "text": "ovarian cancer", "start": 1543, "end": 1557}]}], "Positive_regulation": [{"trigger": {"text": "induction", "start": 887, "end": 896}, "arguments": [{"role": "Theme", "text": "apoptosis", "start": 900, "end": 909}]}, {"trigger": {"text": "prolonged", "start": 1117, "end": 1126}, "arguments": [{"role": "Theme", "text": "survival", "start": 1077, "end": 1085}]}, {"trigger": {"text": "Increased", "start": 1168, "end": 1177}, "arguments": [{"role": "Theme", "text": "apoptosis", "start": 1178, "end": 1187}]}, {"trigger": {"text": "induction", "start": 1420, "end": 1429}, "arguments": [{"role": "Cause", "text": "hPNAS-4", "start": 1339, "end": 1346}, {"role": "Theme", "text": "apoptosis", "start": 1433, "end": 1442}]}], "Regulation": [{"trigger": {"text": "effect", "start": 337, "end": 343}, "arguments": [{"role": "Cause", "text": "hPNAS-4", "start": 347, "end": 354}, {"role": "Theme", "text": "ovarian cancer", "start": 363, "end": 377}]}]}}, "schema": []}
{"input": "The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer.\n\nThe steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg(-1) oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg(-1) dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 43, "end": 55}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 196, "end": 206}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 502, "end": 512}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 940, "end": 952}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1075, "end": 1085}, "arguments": []}], "Growth": [{"trigger": {"text": "growth", "start": 470, "end": 476}, "arguments": [{"role": "Theme", "text": "tumour", "start": 463, "end": 469}]}, {"trigger": {"text": "growth", "start": 648, "end": 654}, "arguments": [{"role": "Theme", "text": "MDA-MB-231 xenograft tumours", "start": 658, "end": 686}]}], "Negative_regulation": [{"trigger": {"text": "inhibition", "start": 477, "end": 487}, "arguments": [{"role": "Theme", "text": "growth", "start": 470, "end": 476}]}, {"trigger": {"text": "potential", "start": 513, "end": 522}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 502, "end": 512}, {"role": "Cause", "text": "STX243", "start": 547, "end": 553}]}, {"trigger": {"text": "retarding", "start": 634, "end": 643}, "arguments": [{"role": "Cause", "text": "STX243", "start": 600, "end": 606}, {"role": "Theme", "text": "growth", "start": 648, "end": 654}]}, {"trigger": {"text": "retarding", "start": 634, "end": 643}, "arguments": [{"role": "Cause", "text": "STX140", "start": 611, "end": 617}, {"role": "Theme", "text": "growth", "start": 648, "end": 654}]}, {"trigger": {"text": "inhibition", "start": 799, "end": 809}, "arguments": [{"role": "Theme", "text": "tumour", "start": 792, "end": 798}]}, {"trigger": {"text": "restricted", "start": 957, "end": 967}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 940, "end": 952}, {"role": "Cause", "text": "STX243", "start": 973, "end": 979}]}, {"trigger": {"text": "restricted", "start": 957, "end": 967}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 940, "end": 952}, {"role": "Cause", "text": "STX140", "start": 984, "end": 990}]}, {"trigger": {"text": "activity", "start": 1086, "end": 1094}, "arguments": [{"role": "Cause", "text": "STX243", "start": 973, "end": 979}, {"role": "Theme", "text": "angiogenic", "start": 1075, "end": 1085}]}, {"trigger": {"text": "activity", "start": 1086, "end": 1094}, "arguments": [{"role": "Cause", "text": "STX140", "start": 984, "end": 990}, {"role": "Theme", "text": "angiogenic", "start": 1075, "end": 1085}]}], "Planned_process": [{"trigger": {"text": "treated", "start": 762, "end": 769}, "arguments": [{"role": "Instrument", "text": "2-MeOE2", "start": 775, "end": 782}]}], "Regulation": [{"trigger": {"text": "active against", "start": 846, "end": 860}, "arguments": [{"role": "Cause", "text": "STX243", "start": 830, "end": 836}, {"role": "Theme", "text": "MCF-7 paclitaxel-resistant tumours", "start": 861, "end": 895}]}]}}, "schema": []}
{"input": "Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway.\n\nBlockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase-mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 28, "end": 40}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 140, "end": 152}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 305, "end": 317}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 367, "end": 379}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 795, "end": 807}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1288, "end": 1300}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 1282, "end": 1287}]}, {"trigger": {"text": "angiogenic", "start": 1593, "end": 1603}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1705, "end": 1715}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 1140, "end": 1153}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 1123, "end": 1139}]}], "Development": [{"trigger": {"text": "formation", "start": 1186, "end": 1195}, "arguments": [{"role": "Theme", "text": "sprout", "start": 1179, "end": 1185}]}], "Growth": [{"trigger": {"text": "growth", "start": 1271, "end": 1277}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1265, "end": 1270}]}], "Localization": [{"trigger": {"text": "migration", "start": 1158, "end": 1167}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 1123, "end": 1139}]}], "Negative_regulation": [{"trigger": {"text": "inhibits", "start": 19, "end": 27}, "arguments": [{"role": "Cause", "text": "Grape seed extract", "start": 0, "end": 18}, {"role": "Theme", "text": "angiogenesis", "start": 28, "end": 40}]}, {"trigger": {"text": "suppression", "start": 45, "end": 56}, "arguments": [{"role": "Cause", "text": "Grape seed extract", "start": 0, "end": 18}, {"role": "Theme", "text": "signaling pathway", "start": 108, "end": 125}]}, {"trigger": {"text": "Blockade", "start": 128, "end": 136}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 140, "end": 152}]}, {"trigger": {"text": "prevention", "start": 203, "end": 213}, "arguments": [{"role": "Theme", "text": "cancer", "start": 182, "end": 188}]}, {"trigger": {"text": "treatment", "start": 380, "end": 389}, "arguments": [{"role": "Cause", "text": "Vascular endothelial growth factor", "start": 215, "end": 249}, {"role": "Theme", "text": "angiogenesis", "start": 367, "end": 379}]}, {"trigger": {"text": "activity", "start": 712, "end": 720}, "arguments": [{"role": "Cause", "text": "Grape seed extract", "start": 625, "end": 643}, {"role": "Theme", "text": "tumor", "start": 706, "end": 711}]}, {"trigger": {"text": "inhibit", "start": 842, "end": 849}, "arguments": [{"role": "Cause", "text": "GSE", "start": 823, "end": 826}, {"role": "Theme", "text": "VEGF receptor 2", "start": 882, "end": 897}]}, {"trigger": {"text": "inhibit", "start": 971, "end": 978}, "arguments": [{"role": "Theme", "text": "signaling pathway", "start": 1039, "end": 1056}]}, {"trigger": {"text": "inhibit", "start": 1102, "end": 1109}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1092, "end": 1095}, {"role": "Theme", "text": "proliferation", "start": 1140, "end": 1153}]}, {"trigger": {"text": "inhibit", "start": 1102, "end": 1109}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1092, "end": 1095}, {"role": "Theme", "text": "migration", "start": 1158, "end": 1167}]}, {"trigger": {"text": "inhibit", "start": 1102, "end": 1109}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1092, "end": 1095}, {"role": "Theme", "text": "formation", "start": 1186, "end": 1195}]}, {"trigger": {"text": "inhibit", "start": 1257, "end": 1264}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1247, "end": 1250}, {"role": "Theme", "text": "growth", "start": 1271, "end": 1277}]}, {"trigger": {"text": "inhibit", "start": 1257, "end": 1264}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1247, "end": 1250}, {"role": "Theme", "text": "angiogenesis", "start": 1288, "end": 1300}]}, {"trigger": {"text": "reduction", "start": 1434, "end": 1443}, "arguments": [{"role": "Theme", "text": "blood vessel", "start": 1447, "end": 1459}]}, {"trigger": {"text": "Depletion", "start": 1525, "end": 1534}, "arguments": [{"role": "Theme", "text": "polyphenol", "start": 1538, "end": 1548}, {"role": "Cause", "text": "polyvinylpyrrolidone", "start": 1554, "end": 1574}]}, {"trigger": {"text": "abolished", "start": 1575, "end": 1584}, "arguments": [{"role": "Cause", "text": "Depletion", "start": 1525, "end": 1534}, {"role": "Theme", "text": "activity", "start": 1604, "end": 1612}]}, {"trigger": {"text": "activity", "start": 1604, "end": 1612}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 1593, "end": 1603}, {"role": "Cause", "text": "GSE", "start": 1616, "end": 1619}]}, {"trigger": {"text": "activity", "start": 1716, "end": 1724}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1674, "end": 1677}, {"role": "Theme", "text": "angiogenic", "start": 1705, "end": 1715}]}, {"trigger": {"text": "prevention", "start": 1873, "end": 1883}, "arguments": [{"role": "Cause", "text": "GSE", "start": 1768, "end": 1771}, {"role": "Theme", "text": "cancer", "start": 1866, "end": 1872}]}], "Pathway": [{"trigger": {"text": "signaling pathway", "start": 108, "end": 125}, "arguments": [{"role": "Participant", "text": "vascular endothelial growth factor receptor", "start": 64, "end": 107}]}, {"trigger": {"text": "signaling pathway", "start": 1039, "end": 1056}, "arguments": []}], "Phosphorylation": [{"trigger": {"text": "phosphorylation", "start": 1472, "end": 1487}, "arguments": [{"role": "Theme", "text": "mitogen-activated protein kinase", "start": 1491, "end": 1523}]}], "Planned_process": [{"trigger": {"text": "treatment", "start": 189, "end": 198}, "arguments": [{"role": "Theme", "text": "cancer", "start": 182, "end": 188}]}, {"trigger": {"text": "treatment", "start": 1383, "end": 1392}, "arguments": [{"role": "Instrument", "text": "GSE", "start": 1379, "end": 1382}, {"role": "Theme", "text": "mice", "start": 1410, "end": 1414}]}, {"trigger": {"text": "treatment", "start": 1887, "end": 1896}, "arguments": [{"role": "Instrument", "text": "GSE", "start": 1768, "end": 1771}, {"role": "Theme", "text": "cancer", "start": 1866, "end": 1872}]}], "Positive_regulation": [{"trigger": {"text": "induce", "start": 298, "end": 304}, "arguments": [{"role": "Cause", "text": "Vascular endothelial growth factor", "start": 215, "end": 249}, {"role": "Theme", "text": "angiogenesis", "start": 305, "end": 317}]}, {"trigger": {"text": "mediated", "start": 1030, "end": 1038}, "arguments": [{"role": "Cause", "text": "VEGF receptor", "start": 983, "end": 996}, {"role": "Theme", "text": "signaling pathway", "start": 1039, "end": 1056}]}, {"trigger": {"text": "mediated", "start": 1030, "end": 1038}, "arguments": [{"role": "Cause", "text": "mitogen-activated protein kinase", "start": 997, "end": 1029}, {"role": "Theme", "text": "signaling pathway", "start": 1039, "end": 1056}]}, {"trigger": {"text": "induced", "start": 1115, "end": 1122}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 1110, "end": 1114}, {"role": "Theme", "text": "proliferation", "start": 1140, "end": 1153}]}, {"trigger": {"text": "induced", "start": 1115, "end": 1122}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 1110, "end": 1114}, {"role": "Theme", "text": "migration", "start": 1158, "end": 1167}]}, {"trigger": {"text": "led", "start": 1415, "end": 1418}, "arguments": [{"role": "Cause", "text": "treatment", "start": 1383, "end": 1392}, {"role": "Theme", "text": "reduction", "start": 1434, "end": 1443}]}, {"trigger": {"text": "led", "start": 1415, "end": 1418}, "arguments": [{"role": "Cause", "text": "treatment", "start": 1383, "end": 1392}, {"role": "Theme", "text": "phosphorylation", "start": 1472, "end": 1487}]}, {"trigger": {"text": "responsible", "start": 1681, "end": 1692}, "arguments": [{"role": "Cause", "text": "polyphenol", "start": 1660, "end": 1670}, {"role": "Theme", "text": "activity", "start": 1716, "end": 1724}]}]}}, "schema": []}
{"input": "Role of the interferon-inducible IFI16 gene in the induction of ICAM-1 by TNF-alpha.\n\nThe Interferon-inducible gene IFI16, a member of the HIN200 family, is activated by oxidative stress and cell density, in addition to Interferons, and it is implicated in the regulation of endothelial cell proliferation and vessel formation in vitro. We have previously shown that IFI16 is required for proinflammatory gene stimulation by IFN-gamma through the NF-kappaB complex. To examine whether IFI16 induction might be extended to other proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, we used the strategy of the RNA interference to knock down IFI16 expression, and analyze the capability of TNF-alpha to stimulate intercellular adhesion molecule-1 (ICAM-1 or CD54) expression in the absence of functional IFI16. Our studies demonstrate that IFI16 mediates ICAM-1 stimulation by TNF-alpha through the NF-kappaB pathway, thus reinforcing the role of the IFI16 molecule in the inflammation process.\n", "output": {"json_structures": {"Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 292, "end": 305}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 275, "end": 291}]}], "Development": [{"trigger": {"text": "formation", "start": 317, "end": 326}, "arguments": [{"role": "Theme", "text": "vessel", "start": 310, "end": 316}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 662, "end": 672}, "arguments": [{"role": "Theme", "text": "IFI16", "start": 656, "end": 661}]}, {"trigger": {"text": "expression", "start": 778, "end": 788}, "arguments": [{"role": "Theme", "text": "ICAM-1", "start": 762, "end": 768}]}, {"trigger": {"text": "expression", "start": 778, "end": 788}, "arguments": [{"role": "Theme", "text": "CD54", "start": 772, "end": 776}]}], "Pathway": [{"trigger": {"text": "pathway", "start": 923, "end": 930}, "arguments": [{"role": "Participant", "text": "NF-kappaB", "start": 913, "end": 922}]}], "Planned_process": [{"trigger": {"text": "knock down", "start": 645, "end": 655}, "arguments": [{"role": "Theme", "text": "IFI16", "start": 656, "end": 661}]}], "Positive_regulation": [{"trigger": {"text": "inducible", "start": 23, "end": 32}, "arguments": [{"role": "Cause", "text": "interferon", "start": 12, "end": 22}, {"role": "Theme", "text": "IFI16", "start": 33, "end": 38}]}, {"trigger": {"text": "induction", "start": 51, "end": 60}, "arguments": [{"role": "Theme", "text": "ICAM-1", "start": 64, "end": 70}, {"role": "Cause", "text": "TNF-alpha", "start": 74, "end": 83}]}, {"trigger": {"text": "inducible", "start": 101, "end": 110}, "arguments": [{"role": "Cause", "text": "Interferon", "start": 90, "end": 100}, {"role": "Theme", "text": "IFI16", "start": 116, "end": 121}]}, {"trigger": {"text": "activated", "start": 157, "end": 166}, "arguments": [{"role": "Theme", "text": "IFI16", "start": 116, "end": 121}, {"role": "Cause", "text": "Interferons", "start": 220, "end": 231}]}, {"trigger": {"text": "induction", "start": 491, "end": 500}, "arguments": [{"role": "Theme", "text": "IFI16", "start": 485, "end": 490}]}, {"trigger": {"text": "extended", "start": 510, "end": 518}, "arguments": [{"role": "Cause", "text": "induction", "start": 491, "end": 500}, {"role": "Theme", "text": "tumor necrosis factor (TNF)-alpha", "start": 562, "end": 595}]}, {"trigger": {"text": "stimulate", "start": 717, "end": 726}, "arguments": [{"role": "Cause", "text": "TNF-alpha", "start": 704, "end": 713}, {"role": "Theme", "text": "expression", "start": 778, "end": 788}]}, {"trigger": {"text": "stimulation", "start": 876, "end": 887}, "arguments": [{"role": "Theme", "text": "ICAM-1", "start": 869, "end": 875}, {"role": "Cause", "text": "TNF-alpha", "start": 891, "end": 900}]}], "Regulation": [{"trigger": {"text": "Role", "start": 0, "end": 4}, "arguments": [{"role": "Cause", "text": "IFI16", "start": 33, "end": 38}, {"role": "Theme", "text": "induction", "start": 51, "end": 60}]}, {"trigger": {"text": "regulation", "start": 261, "end": 271}, "arguments": [{"role": "Cause", "text": "IFI16", "start": 116, "end": 121}, {"role": "Theme", "text": "proliferation", "start": 292, "end": 305}]}, {"trigger": {"text": "regulation", "start": 261, "end": 271}, "arguments": [{"role": "Cause", "text": "IFI16", "start": 116, "end": 121}, {"role": "Theme", "text": "formation", "start": 317, "end": 326}]}, {"trigger": {"text": "mediates", "start": 860, "end": 868}, "arguments": [{"role": "Cause", "text": "IFI16", "start": 854, "end": 859}, {"role": "Theme", "text": "pathway", "start": 923, "end": 930}]}, {"trigger": {"text": "mediates", "start": 860, "end": 868}, "arguments": [{"role": "Cause", "text": "mediates", "start": 860, "end": 868}, {"role": "Theme", "text": "stimulation", "start": 876, "end": 887}]}]}}, "schema": []}
{"input": "Impact of tumor cell VEGF expression on the in vivo efficacy of vandetanib (ZACTIMA; ZD6474).\n\nVEGF is the key player in tumor angiogenesis. In the current study, the impact of VEGF expression on the response of tumors to the VEGFR2 associated tyrosine kinase inhibitor vandetanib was evaluated. MATERIALS AND METHODS: Human colon carcinoma (HT29) and murine squamous carcinoma (SCCVII) clonal cell lines expressing varying levels of VEGF were established and their response to vandetanib was assessed in tissue culture and as solid tumors. RESULTS: Vandetanib treatment had no effect on tumor cell clonogenic cell survival in vitro but doses >or=10 nM significantly reduced endothelial cell migration. In vivo, tumors derived from cell clones expressing high levels of VEGF displayed significantly enhanced angiogenesis and more aggressive growth. An intradermal angiogenesis assay was used to demonstrate that a 4-day treatment with vandetanib (50 mg/kg/day) was able to significantly inhibit blood vessel growth induced by both parental and high VEGF-expressing tumor cell clones. In the HT29 tumor model, treatment response to vandetanib (50 mg/kg/day, Monday-Friday for 2 weeks) was greatest in xenografts derived from the highest VEGF-expressing cell clones. A similar trend was noted in the SCCVII tumor model. The present findings indicate that vandetanib therapy effectively counteracted the aggressive feature of tumor growth resulting from VEGF over-expressing tumor cells and suggest that such tumors may be particularly well suited for anti-VEGF interventions.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "associated", "start": 233, "end": 243}, "arguments": [{"role": "Theme", "text": "VEGFR2", "start": 226, "end": 232}, {"role": "Theme", "text": "vandetanib", "start": 270, "end": 280}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 127, "end": 139}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 121, "end": 126}]}, {"trigger": {"text": "angiogenesis", "start": 808, "end": 820}, "arguments": [{"role": "AtLoc", "text": "tumors", "start": 712, "end": 718}]}, {"trigger": {"text": "angiogenesis", "start": 864, "end": 876}, "arguments": [{"role": "AtLoc", "text": "intradermal", "start": 852, "end": 863}]}], "Death": [{"trigger": {"text": "survival", "start": 615, "end": 623}, "arguments": [{"role": "Theme", "text": "cell", "start": 610, "end": 614}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 26, "end": 36}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 21, "end": 25}]}, {"trigger": {"text": "expression", "start": 182, "end": 192}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 177, "end": 181}]}, {"trigger": {"text": "expressing", "start": 405, "end": 415}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 434, "end": 438}]}, {"trigger": {"text": "expressing", "start": 744, "end": 754}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 770, "end": 774}]}, {"trigger": {"text": "expressing", "start": 1054, "end": 1064}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1049, "end": 1053}]}, {"trigger": {"text": "expressing", "start": 1241, "end": 1251}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1236, "end": 1240}]}, {"trigger": {"text": "over-expressing", "start": 1456, "end": 1471}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1451, "end": 1455}]}], "Growth": [{"trigger": {"text": "growth", "start": 841, "end": 847}, "arguments": [{"role": "Theme", "text": "tumors", "start": 712, "end": 718}]}, {"trigger": {"text": "growth", "start": 1008, "end": 1014}, "arguments": [{"role": "Theme", "text": "blood vessel", "start": 995, "end": 1007}]}, {"trigger": {"text": "growth", "start": 1429, "end": 1435}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1423, "end": 1428}]}], "Localization": [{"trigger": {"text": "migration", "start": 692, "end": 701}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 675, "end": 691}]}], "Negative_regulation": [{"trigger": {"text": "reduced", "start": 667, "end": 674}, "arguments": [{"role": "Cause", "text": "treatment", "start": 561, "end": 570}, {"role": "Theme", "text": "migration", "start": 692, "end": 701}]}, {"trigger": {"text": "inhibit", "start": 987, "end": 994}, "arguments": [{"role": "Cause", "text": "treatment", "start": 920, "end": 929}, {"role": "Theme", "text": "growth", "start": 1008, "end": 1014}]}, {"trigger": {"text": "counteracted", "start": 1384, "end": 1396}, "arguments": [{"role": "Cause", "text": "therapy", "start": 1364, "end": 1371}, {"role": "Theme", "text": "growth", "start": 1429, "end": 1435}]}, {"trigger": {"text": "interventions", "start": 1559, "end": 1572}, "arguments": [{"role": "Theme", "text": "VEGF", "start": 1554, "end": 1558}]}], "Planned_process": [{"trigger": {"text": "treatment", "start": 561, "end": 570}, "arguments": [{"role": "Instrument", "text": "Vandetanib", "start": 550, "end": 560}, {"role": "Theme", "text": "tumor cell", "start": 588, "end": 598}]}, {"trigger": {"text": "treatment", "start": 920, "end": 929}, "arguments": [{"role": "Instrument", "text": "vandetanib", "start": 935, "end": 945}]}, {"trigger": {"text": "treatment", "start": 1109, "end": 1118}, "arguments": [{"role": "Theme", "text": "HT29 tumor", "start": 1091, "end": 1101}]}, {"trigger": {"text": "therapy", "start": 1364, "end": 1371}, "arguments": [{"role": "Instrument", "text": "vandetanib", "start": 1353, "end": 1363}]}], "Positive_regulation": [{"trigger": {"text": "enhanced", "start": 799, "end": 807}, "arguments": [{"role": "Cause", "text": "tumors", "start": 712, "end": 718}, {"role": "Theme", "text": "angiogenesis", "start": 808, "end": 820}]}, {"trigger": {"text": "enhanced", "start": 799, "end": 807}, "arguments": [{"role": "Cause", "text": "tumors", "start": 712, "end": 718}, {"role": "Theme", "text": "growth", "start": 841, "end": 847}]}, {"trigger": {"text": "induced", "start": 1015, "end": 1022}, "arguments": [{"role": "Theme", "text": "growth", "start": 1008, "end": 1014}, {"role": "Cause", "text": "tumor cell", "start": 1065, "end": 1075}]}], "Regulation": [{"trigger": {"text": "response", "start": 200, "end": 208}, "arguments": [{"role": "Theme", "text": "tumors", "start": 212, "end": 218}, {"role": "Cause", "text": "vandetanib", "start": 270, "end": 280}]}, {"trigger": {"text": "response", "start": 466, "end": 474}, "arguments": [{"role": "Theme", "text": "expressing", "start": 405, "end": 415}, {"role": "Cause", "text": "vandetanib", "start": 478, "end": 488}]}, {"trigger": {"text": "effect", "start": 578, "end": 584}, "arguments": [{"role": "Cause", "text": "treatment", "start": 561, "end": 570}, {"role": "Theme", "text": "survival", "start": 615, "end": 623}]}, {"trigger": {"text": "response", "start": 1119, "end": 1127}, "arguments": [{"role": "Theme", "text": "HT29 tumor", "start": 1091, "end": 1101}, {"role": "Cause", "text": "vandetanib", "start": 1131, "end": 1141}]}]}}, "schema": []}
{"input": "The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice.\n\nDown syndrome critical region gene 1 (DSCR-1) short variant (DSCR-1s) is an inhibitor of calcineurin/NFAT signaling encoded by exons 4-7 of DSCR1. We previously reported that VEGF induces DSCR-1s expression in endothelial cells, which in turn negatively feeds back to attenuate endothelial cell activation. Here, in order to characterize the role of the promoter that drives DSCR-1s expression in mediating inducible expression in vivo and to determine the functional relevance of DSCR-1s in inflammation, we targeted a DNA construct containing 1.7 kb of the human DSCR1s promoter coupled to the lacZ reporter to the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus of mice. We determined that lacZ was uniformly expressed in the endothelium of transgenic embryos but was markedly downregulated postnatally. Systemic administration of VEGF or LPS in adult mice resulted in cyclosporine A-sensitive reactivation of the DSCR1s promoter and endogenous gene expression in a subset of organs, including the heart and brain. The DSCR1s promoter was similarly induced in the endothelium of tumor xenografts. In a mouse model of endotoxemia, DSCR-1s-deficient mice demonstrated increased sepsis mortality, whereas adenovirus-mediated DSCR-1s overexpression protected against LPS-induced lethality. Collectively, these data suggest that the DSCR1s promoter directs vascular bed-specific expression in activated endothelium and that DSCR-1s serves to dampen the host response to infection.\n", "output": {"json_structures": {"Gene_expression": [{"trigger": {"text": "expression", "start": 336, "end": 346}, "arguments": [{"role": "Theme", "text": "DSCR-1s", "start": 328, "end": 335}]}, {"trigger": {"text": "expression", "start": 523, "end": 533}, "arguments": [{"role": "Theme", "text": "DSCR-1s", "start": 515, "end": 522}]}, {"trigger": {"text": "expressed", "start": 865, "end": 874}, "arguments": [{"role": "Theme", "text": "lacZ", "start": 846, "end": 850}]}, {"trigger": {"text": "deficient", "start": 1294, "end": 1303}, "arguments": [{"role": "Theme", "text": "DSCR-1s", "start": 1286, "end": 1293}]}, {"trigger": {"text": "overexpression", "start": 1386, "end": 1400}, "arguments": [{"role": "Theme", "text": "DSCR-1s", "start": 1378, "end": 1385}]}, {"trigger": {"text": "expression", "start": 1530, "end": 1540}, "arguments": [{"role": "Theme", "text": "DSCR1", "start": 1484, "end": 1489}]}], "Negative_regulation": [{"trigger": {"text": "attenuate", "start": 408, "end": 417}, "arguments": [{"role": "Cause", "text": "induces", "start": 320, "end": 327}, {"role": "Theme", "text": "activation", "start": 435, "end": 445}]}, {"trigger": {"text": "downregulated", "start": 933, "end": 946}, "arguments": [{"role": "Theme", "text": "expressed", "start": 865, "end": 874}]}], "Pathway": [{"trigger": {"text": "signaling", "start": 246, "end": 255}, "arguments": [{"role": "Participant", "text": "calcineurin", "start": 229, "end": 240}, {"role": "Participant2", "text": "NFAT", "start": 241, "end": 245}]}], "Planned_process": [{"trigger": {"text": "targeted", "start": 649, "end": 657}, "arguments": [{"role": "Instrument", "text": "DSCR1s", "start": 705, "end": 711}, {"role": "Instrument", "text": "lacZ", "start": 736, "end": 740}, {"role": "Theme", "text": "mice", "start": 821, "end": 825}]}, {"trigger": {"text": "coupled", "start": 721, "end": 728}, "arguments": [{"role": "Instrument", "text": "DSCR1s", "start": 705, "end": 711}, {"role": "Instrument", "text": "lacZ", "start": 736, "end": 740}]}, {"trigger": {"text": "administration", "start": 969, "end": 983}, "arguments": [{"role": "Instrument", "text": "VEGF", "start": 987, "end": 991}, {"role": "Theme", "text": "mice", "start": 1008, "end": 1012}]}, {"trigger": {"text": "administration", "start": 969, "end": 983}, "arguments": [{"role": "Instrument", "text": "LPS", "start": 995, "end": 998}, {"role": "Theme", "text": "mice", "start": 1008, "end": 1012}]}], "Positive_regulation": [{"trigger": {"text": "induces", "start": 320, "end": 327}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 315, "end": 319}, {"role": "Theme", "text": "expression", "start": 336, "end": 346}]}, {"trigger": {"text": "activation", "start": 435, "end": 445}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 418, "end": 434}]}, {"trigger": {"text": "resulted", "start": 1013, "end": 1021}, "arguments": [{"role": "Cause", "text": "administration", "start": 969, "end": 983}, {"role": "Theme", "text": "reactivation", "start": 1050, "end": 1062}]}, {"trigger": {"text": "reactivation", "start": 1050, "end": 1062}, "arguments": [{"role": "Theme", "text": "DSCR1s", "start": 1070, "end": 1076}, {"role": "Site", "text": "promoter", "start": 1077, "end": 1085}]}, {"trigger": {"text": "induced", "start": 1205, "end": 1212}, "arguments": [{"role": "Theme", "text": "DSCR1s", "start": 1175, "end": 1181}, {"role": "Site", "text": "promoter", "start": 1182, "end": 1190}]}, {"trigger": {"text": "mediated", "start": 1369, "end": 1377}, "arguments": [{"role": "Cause", "text": "adenovirus", "start": 1358, "end": 1368}, {"role": "Theme", "text": "overexpression", "start": 1386, "end": 1400}]}, {"trigger": {"text": "activated", "start": 1544, "end": 1553}, "arguments": [{"role": "Theme", "text": "endothelium", "start": 1554, "end": 1565}]}], "Regulation": [{"trigger": {"text": "sensitive", "start": 1040, "end": 1049}, "arguments": [{"role": "Cause", "text": "cyclosporine A", "start": 1025, "end": 1039}, {"role": "Theme", "text": "reactivation", "start": 1050, "end": 1062}]}]}}, "schema": []}
{"input": "Nicked {beta}2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property.\n\nAngiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. beta2-glycoprotein I (beta2GPI) is proteolytically cleaved by plasmin in its domain V (nicked beta2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked beta2GPI as well as in intact beta2GPI at higher concentrations. In the present study, we found significant binding of nicked beta2GPI to AS4.5 (K(D) = 3.27 x 10(6) M(-1)). Via this binding, nicked beta2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact beta2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked beta2GPI exerts dual effects on angiogenesis, that is, nicked beta2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked beta2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked beta2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "binds", "start": 30, "end": 35}, "arguments": [{"role": "Theme", "text": "Nicked {beta}2-glycoprotein I", "start": 0, "end": 29}, {"role": "Theme", "text": "angiostatin 4.5", "start": 36, "end": 51}]}, {"trigger": {"text": "binding", "start": 538, "end": 545}, "arguments": [{"role": "Theme", "text": "nicked beta2GPI", "start": 507, "end": 522}, {"role": "Theme", "text": "plasminogen", "start": 549, "end": 560}]}, {"trigger": {"text": "binding", "start": 734, "end": 741}, "arguments": [{"role": "Theme", "text": "nicked beta2GPI", "start": 745, "end": 760}, {"role": "Theme", "text": "AS4.5", "start": 764, "end": 769}]}, {"trigger": {"text": "binding", "start": 808, "end": 815}, "arguments": [{"role": "Theme", "text": "nicked beta2GPI", "start": 817, "end": 832}, {"role": "Theme", "text": "AS4.5", "start": 876, "end": 881}]}, {"trigger": {"text": "bind", "start": 1094, "end": 1098}, "arguments": [{"role": "Theme", "text": "beta2GPI", "start": 1076, "end": 1084}, {"role": "Theme", "text": "AS4.5", "start": 1102, "end": 1107}]}, {"trigger": {"text": "interacting", "start": 1448, "end": 1459}, "arguments": [{"role": "Theme", "text": "plasmin-nicked beta2GPI", "start": 1399, "end": 1422}, {"role": "Theme", "text": "plasmin-generated AS4.5", "start": 1465, "end": 1488}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenic", "start": 101, "end": 111}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 201, "end": 211}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 566, "end": 576}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 852, "end": 862}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1042, "end": 1054}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1127, "end": 1137}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1193, "end": 1205}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1241, "end": 1253}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1313, "end": 1325}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1432, "end": 1444}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 889, "end": 902}, "arguments": [{"role": "Theme", "text": "arterial", "start": 906, "end": 914}]}, {"trigger": {"text": "proliferation", "start": 889, "end": 902}, "arguments": [{"role": "Theme", "text": "venous endothelial cells", "start": 915, "end": 939}]}], "Development": [{"trigger": {"text": "formation", "start": 991, "end": 1000}, "arguments": [{"role": "Theme", "text": "tube", "start": 986, "end": 990}]}], "Localization": [{"trigger": {"text": "invasion", "start": 969, "end": 977}, "arguments": [{"role": "Theme", "text": "arterial", "start": 906, "end": 914}, {"role": "ToLoc", "text": "extracellular matrix", "start": 948, "end": 968}]}, {"trigger": {"text": "invasion", "start": 969, "end": 977}, "arguments": [{"role": "Theme", "text": "venous endothelial cells", "start": 915, "end": 939}, {"role": "ToLoc", "text": "extracellular matrix", "start": 948, "end": 968}]}], "Negative_regulation": [{"trigger": {"text": "attenuates", "start": 82, "end": 92}, "arguments": [{"role": "Cause", "text": "Nicked {beta}2-glycoprotein I", "start": 0, "end": 29}, {"role": "Theme", "text": "property", "start": 112, "end": 120}]}, {"trigger": {"text": "property", "start": 112, "end": 120}, "arguments": [{"role": "Cause", "text": "Nicked {beta}2-glycoprotein I", "start": 0, "end": 29}, {"role": "Theme", "text": "angiogenic", "start": 101, "end": 111}]}, {"trigger": {"text": "property", "start": 212, "end": 220}, "arguments": [{"role": "Cause", "text": "plasminogen fragment", "start": 161, "end": 181}, {"role": "Theme", "text": "tumor", "start": 191, "end": 196}]}, {"trigger": {"text": "property", "start": 212, "end": 220}, "arguments": [{"role": "Cause", "text": "plasminogen fragment", "start": 161, "end": 181}, {"role": "Theme", "text": "angiogenic", "start": 201, "end": 211}]}, {"trigger": {"text": "properties", "start": 577, "end": 587}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 566, "end": 576}, {"role": "Cause", "text": "nicked beta2GPI", "start": 619, "end": 634}]}, {"trigger": {"text": "properties", "start": 577, "end": 587}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 566, "end": 576}, {"role": "Cause", "text": "beta2GPI", "start": 656, "end": 664}]}, {"trigger": {"text": "attenuates", "start": 833, "end": 843}, "arguments": [{"role": "Cause", "text": "nicked beta2GPI", "start": 817, "end": 832}, {"role": "Theme", "text": "functions", "start": 863, "end": 872}]}, {"trigger": {"text": "functions", "start": 863, "end": 872}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 852, "end": 862}, {"role": "Cause", "text": "AS4.5", "start": 876, "end": 881}]}, {"trigger": {"text": "inhibit", "start": 1111, "end": 1118}, "arguments": [{"role": "Cause", "text": "beta2GPI", "start": 1076, "end": 1084}, {"role": "Theme", "text": "activity", "start": 1138, "end": 1146}]}, {"trigger": {"text": "activity", "start": 1138, "end": 1146}, "arguments": [{"role": "Cause", "text": "AS4.5", "start": 1102, "end": 1107}, {"role": "Theme", "text": "angiogenic", "start": 1127, "end": 1137}]}, {"trigger": {"text": "inhibits", "start": 1304, "end": 1312}, "arguments": [{"role": "Cause", "text": "nicked beta2GPI", "start": 1288, "end": 1303}, {"role": "Theme", "text": "angiogenesis", "start": 1313, "end": 1325}]}], "Positive_regulation": [{"trigger": {"text": "cleaved", "start": 471, "end": 478}, "arguments": [{"role": "Theme", "text": "cleaved", "start": 471, "end": 478}, {"role": "Cause", "text": "plasmin", "start": 482, "end": 489}, {"role": "Site", "text": "domain V", "start": 497, "end": 505}]}, {"trigger": {"text": "resulting", "start": 525, "end": 534}, "arguments": [{"role": "Cause", "text": "cleaved", "start": 471, "end": 478}, {"role": "Theme", "text": "binding", "start": 538, "end": 545}]}, {"trigger": {"text": "promotes", "start": 1232, "end": 1240}, "arguments": [{"role": "Cause", "text": "nicked beta2GPI", "start": 1216, "end": 1231}, {"role": "Theme", "text": "angiogenesis", "start": 1241, "end": 1253}]}], "Protein_processing": [{"trigger": {"text": "autoproteolysis", "start": 375, "end": 390}, "arguments": [{"role": "Theme", "text": "angiostatin 4.5", "start": 264, "end": 279}]}, {"trigger": {"text": "cleaved", "start": 471, "end": 478}, "arguments": [{"role": "Theme", "text": "beta2-glycoprotein I", "start": 420, "end": 440}]}], "Regulation": [{"trigger": {"text": "promotes", "start": 1423, "end": 1431}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1432, "end": 1444}, {"role": "Cause", "text": "interacting", "start": 1448, "end": 1459}]}]}}, "schema": []}
{"input": "[An experimental study on angiogenesis of non-vascularized autogenous bone graft with vascular bundle implantation]\n\nOBJECTIVE: To investigate the effect of vascular bundle implantation in autogenous bone graft on angiogenesis. METHODS: Thirty-six New Zealand white rabbits were evaluated in this study. A portion of bilateral radial bones of a rabbit were removed as free bone grafts, whose periostea were peeled off. In test group, the external maxillary artery bundle was passed through the marrow cavity of the bone. In control group, there was no vascular bundle implantation. Each bone was placed in masseter muscle separately. The rabbits were sacrificed and the specimens were procured at 3 days, 1, 2, 3, 4 and 6 weeks after surgery for histological observation, Chinese ink perfusion and CD34 immunohistochemistry. Microvessel density (MVD) was assessed in order to evaluate angiogenesis of autogenous bone grafts. RESULTS: The bone grafts were found revascularization in 3 days after surgery in the test group, whereas at 2 weeks in the control group. In 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks after surgery, the MVD of test group was significantly higher than that of control group. In 4 weeks after surgery, angiogenesis of test group reached to peak. CONCLUSION: Vascular bundle implantation improved angiogenesis in non-vascularized autogenous bone graft in this study.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 26, "end": 38}, "arguments": [{"role": "AtLoc", "text": "autogenous bone graft", "start": 59, "end": 80}]}, {"trigger": {"text": "vascularized", "start": 46, "end": 58}, "arguments": [{"role": "AtLoc", "text": "autogenous bone graft", "start": 59, "end": 80}]}, {"trigger": {"text": "angiogenesis", "start": 214, "end": 226}, "arguments": [{"role": "AtLoc", "text": "autogenous bone graft", "start": 189, "end": 210}]}, {"trigger": {"text": "angiogenesis", "start": 885, "end": 897}, "arguments": [{"role": "Theme", "text": "Microvessel", "start": 825, "end": 836}, {"role": "AtLoc", "text": "autogenous bone grafts", "start": 901, "end": 923}]}, {"trigger": {"text": "revascularization", "start": 961, "end": 978}, "arguments": [{"role": "AtLoc", "text": "bone grafts", "start": 938, "end": 949}]}, {"trigger": {"text": "angiogenesis", "start": 1227, "end": 1239}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1321, "end": 1333}, "arguments": [{"role": "AtLoc", "text": "autogenous bone graft", "start": 1354, "end": 1375}]}, {"trigger": {"text": "vascularized", "start": 1341, "end": 1353}, "arguments": [{"role": "AtLoc", "text": "autogenous bone graft", "start": 1354, "end": 1375}]}], "Planned_process": [{"trigger": {"text": "implantation", "start": 102, "end": 114}, "arguments": [{"role": "Theme", "text": "autogenous bone graft", "start": 59, "end": 80}, {"role": "Instrument", "text": "vascular bundle", "start": 86, "end": 101}]}, {"trigger": {"text": "implantation", "start": 173, "end": 185}, "arguments": [{"role": "Instrument", "text": "vascular bundle", "start": 157, "end": 172}]}, {"trigger": {"text": "removed", "start": 357, "end": 364}, "arguments": [{"role": "Theme", "text": "bilateral radial bones", "start": 317, "end": 339}]}, {"trigger": {"text": "peeled off", "start": 407, "end": 417}, "arguments": [{"role": "Theme", "text": "periostea", "start": 392, "end": 401}]}, {"trigger": {"text": "implantation", "start": 568, "end": 580}, "arguments": [{"role": "Instrument", "text": "vascular bundle", "start": 552, "end": 567}]}, {"trigger": {"text": "placed", "start": 596, "end": 602}, "arguments": [{"role": "Instrument", "text": "bone", "start": 587, "end": 591}, {"role": "Theme", "text": "masseter muscle", "start": 606, "end": 621}]}, {"trigger": {"text": "sacrificed", "start": 651, "end": 661}, "arguments": [{"role": "Theme", "text": "rabbits", "start": 638, "end": 645}]}, {"trigger": {"text": "implantation", "start": 1299, "end": 1311}, "arguments": [{"role": "Instrument", "text": "Vascular bundle", "start": 1283, "end": 1298}]}], "Positive_regulation": [{"trigger": {"text": "improved", "start": 1312, "end": 1320}, "arguments": [{"role": "Cause", "text": "implantation", "start": 1299, "end": 1311}, {"role": "Theme", "text": "angiogenesis", "start": 1321, "end": 1333}]}], "Regulation": [{"trigger": {"text": "effect", "start": 147, "end": 153}, "arguments": [{"role": "Cause", "text": "implantation", "start": 173, "end": 185}, {"role": "Theme", "text": "angiogenesis", "start": 214, "end": 226}]}]}}, "schema": []}
{"input": "Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2.\n\nVascular endothelial growth factor (VEGF)-induced receptor phosphorylation is the crucial step for initiating downstream signaling pathways that lead to angiogenesis or related pathophysiological outcomes. Our previous studies have shown that the neurotransmitter dopamine could inhibit VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), endothelial cell proliferation, migration, microvascular permeability, and thus, angiogenesis. In this study, we address the mechanism by which VEGFR-2 phosphorylation is regulated by dopamine. Here, we demonstrate that D2 dopamine receptor (D2DR) colocalizes with VEGFR-2 at the cell surface. Dopamine pretreatment increases the translocation and colocalization of Src-homology-2-domain-containing protein tyrosine phosphatase (SHP-2) with D2DR at the cell surface. Dopamine administration leads to increased VEGF-induced phosphorylation of SHP-2 and this increased phosphorylation parallels the increased phosphatase activity of SHP-2. Active SHP-2 then dephosphorylates VEGFR-2 at Y951, Y996 and Y1059, but not Y1175. We also observe that SHP-2 knockdown impairs the dopamine-regulated inhibition of VEGF-induced phosphorylation of VEGFR-2 and, subsequently, Src phosphorylation and migration. Our data establish a novel role for SHP-2 phosphatase in the dopamine-mediated regulation of VEGFR-2 phosphorylation.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 285, "end": 297}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 559, "end": 571}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 495, "end": 508}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 478, "end": 494}]}], "Dephosphorylation": [{"trigger": {"text": "dephosphorylates", "start": 1134, "end": 1150}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1151, "end": 1158}, {"role": "Site", "text": "Y951", "start": 1162, "end": 1166}]}, {"trigger": {"text": "dephosphorylates", "start": 1134, "end": 1150}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1151, "end": 1158}, {"role": "Site", "text": "Y996", "start": 1168, "end": 1172}]}, {"trigger": {"text": "dephosphorylates", "start": 1134, "end": 1150}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1151, "end": 1158}, {"role": "Site", "text": "Y1059", "start": 1177, "end": 1182}]}, {"trigger": {"text": "dephosphorylates", "start": 1134, "end": 1150}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1151, "end": 1158}, {"role": "Site", "text": "Y1175", "start": 1192, "end": 1197}]}], "Localization": [{"trigger": {"text": "migration", "start": 510, "end": 519}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 478, "end": 494}]}, {"trigger": {"text": "colocalizes", "start": 726, "end": 737}, "arguments": [{"role": "Theme", "text": "D2 dopamine receptor", "start": 698, "end": 718}, {"role": "Theme", "text": "VEGFR-2", "start": 743, "end": 750}, {"role": "AtLoc", "text": "cell surface", "start": 758, "end": 770}]}, {"trigger": {"text": "translocation", "start": 808, "end": 821}, "arguments": [{"role": "Theme", "text": "Src-homology-2-domain-containing protein tyrosine phosphatase", "start": 844, "end": 905}]}, {"trigger": {"text": "colocalization", "start": 826, "end": 840}, "arguments": [{"role": "Theme", "text": "Src-homology-2-domain-containing protein tyrosine phosphatase", "start": 844, "end": 905}, {"role": "Theme", "text": "D2DR", "start": 919, "end": 923}, {"role": "AtLoc", "text": "cell surface", "start": 931, "end": 943}]}, {"trigger": {"text": "migration", "start": 1364, "end": 1373}, "arguments": [{"role": "Theme", "text": "Src", "start": 1340, "end": 1343}]}], "Negative_regulation": [{"trigger": {"text": "inhibit", "start": 411, "end": 418}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 396, "end": 404}, {"role": "Theme", "text": "phosphorylation", "start": 432, "end": 447}]}, {"trigger": {"text": "inhibit", "start": 411, "end": 418}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 396, "end": 404}, {"role": "Theme", "text": "proliferation", "start": 495, "end": 508}]}, {"trigger": {"text": "inhibit", "start": 411, "end": 418}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 396, "end": 404}, {"role": "Theme", "text": "migration", "start": 510, "end": 519}]}, {"trigger": {"text": "inhibit", "start": 411, "end": 418}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 396, "end": 404}, {"role": "Theme", "text": "microvascular", "start": 521, "end": 534}]}, {"trigger": {"text": "inhibit", "start": 411, "end": 418}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 396, "end": 404}, {"role": "Theme", "text": "angiogenesis", "start": 559, "end": 571}]}, {"trigger": {"text": "impairs", "start": 1236, "end": 1243}, "arguments": [{"role": "Cause", "text": "knockdown", "start": 1226, "end": 1235}, {"role": "Theme", "text": "inhibition", "start": 1267, "end": 1277}]}, {"trigger": {"text": "impairs", "start": 1236, "end": 1243}, "arguments": [{"role": "Cause", "text": "knockdown", "start": 1226, "end": 1235}, {"role": "Theme", "text": "phosphorylation", "start": 1344, "end": 1359}]}, {"trigger": {"text": "impairs", "start": 1236, "end": 1243}, "arguments": [{"role": "Cause", "text": "knockdown", "start": 1226, "end": 1235}, {"role": "Theme", "text": "migration", "start": 1364, "end": 1373}]}, {"trigger": {"text": "inhibition", "start": 1267, "end": 1277}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 1248, "end": 1256}, {"role": "Theme", "text": "phosphorylation", "start": 1294, "end": 1309}]}], "Phosphorylation": [{"trigger": {"text": "phosphorylation", "start": 19, "end": 34}, "arguments": [{"role": "Theme", "text": "VEGF receptor 2", "start": 38, "end": 53}]}, {"trigger": {"text": "phosphorylation", "start": 432, "end": 447}, "arguments": [{"role": "Theme", "text": "VEGF receptor 2", "start": 451, "end": 466}]}, {"trigger": {"text": "phosphorylation", "start": 630, "end": 645}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 622, "end": 629}]}, {"trigger": {"text": "phosphorylation", "start": 1001, "end": 1016}, "arguments": [{"role": "Theme", "text": "SHP-2", "start": 1020, "end": 1025}]}, {"trigger": {"text": "phosphorylation", "start": 1045, "end": 1060}, "arguments": [{"role": "Theme", "text": "SHP-2", "start": 1020, "end": 1025}]}, {"trigger": {"text": "phosphorylation", "start": 1294, "end": 1309}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1313, "end": 1320}]}, {"trigger": {"text": "phosphorylation", "start": 1344, "end": 1359}, "arguments": [{"role": "Theme", "text": "Src", "start": 1340, "end": 1343}]}, {"trigger": {"text": "phosphorylation", "start": 1476, "end": 1491}, "arguments": [{"role": "Theme", "text": "VEGFR-2", "start": 1468, "end": 1475}]}], "Planned_process": [{"trigger": {"text": "pretreatment", "start": 781, "end": 793}, "arguments": [{"role": "Instrument", "text": "Dopamine", "start": 772, "end": 780}]}, {"trigger": {"text": "administration", "start": 954, "end": 968}, "arguments": [{"role": "Instrument", "text": "Dopamine", "start": 945, "end": 953}]}, {"trigger": {"text": "knockdown", "start": 1226, "end": 1235}, "arguments": [{"role": "Theme", "text": "SHP-2", "start": 1220, "end": 1225}]}], "Positive_regulation": [{"trigger": {"text": "lead", "start": 277, "end": 281}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 285, "end": 297}]}, {"trigger": {"text": "induced", "start": 424, "end": 431}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 419, "end": 423}, {"role": "Theme", "text": "phosphorylation", "start": 432, "end": 447}]}, {"trigger": {"text": "increases", "start": 794, "end": 803}, "arguments": [{"role": "Cause", "text": "pretreatment", "start": 781, "end": 793}, {"role": "Theme", "text": "translocation", "start": 808, "end": 821}]}, {"trigger": {"text": "increases", "start": 794, "end": 803}, "arguments": [{"role": "Cause", "text": "pretreatment", "start": 781, "end": 793}, {"role": "Theme", "text": "colocalization", "start": 826, "end": 840}]}, {"trigger": {"text": "leads", "start": 969, "end": 974}, "arguments": [{"role": "Cause", "text": "administration", "start": 954, "end": 968}, {"role": "Theme", "text": "increased", "start": 978, "end": 987}]}, {"trigger": {"text": "increased", "start": 978, "end": 987}, "arguments": [{"role": "Theme", "text": "phosphorylation", "start": 1001, "end": 1016}]}, {"trigger": {"text": "induced", "start": 993, "end": 1000}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 988, "end": 992}, {"role": "Theme", "text": "phosphorylation", "start": 1001, "end": 1016}]}, {"trigger": {"text": "increased", "start": 1035, "end": 1044}, "arguments": [{"role": "Theme", "text": "phosphorylation", "start": 1045, "end": 1060}]}, {"trigger": {"text": "increased", "start": 1075, "end": 1084}, "arguments": [{"role": "Theme", "text": "SHP-2", "start": 1109, "end": 1114}]}, {"trigger": {"text": "dephosphorylates", "start": 1134, "end": 1150}, "arguments": [{"role": "Cause", "text": "SHP-2", "start": 1123, "end": 1128}, {"role": "Theme", "text": "dephosphorylates", "start": 1134, "end": 1150}]}, {"trigger": {"text": "induced", "start": 1286, "end": 1293}, "arguments": [{"role": "Cause", "text": "VEGF", "start": 1281, "end": 1285}, {"role": "Theme", "text": "phosphorylation", "start": 1294, "end": 1309}]}], "Regulation": [{"trigger": {"text": "regulates", "start": 9, "end": 18}, "arguments": [{"role": "Theme", "text": "phosphorylation", "start": 19, "end": 34}, {"role": "Cause", "text": "engaging", "start": 57, "end": 65}]}, {"trigger": {"text": "engaging", "start": 57, "end": 65}, "arguments": [{"role": "Cause", "text": "Dopamine", "start": 0, "end": 8}, {"role": "Theme", "text": "Src-homology-2-domain-containing protein tyrosine phosphatase 2", "start": 66, "end": 129}]}, {"trigger": {"text": "regulated", "start": 649, "end": 658}, "arguments": [{"role": "Theme", "text": "phosphorylation", "start": 630, "end": 645}, {"role": "Cause", "text": "dopamine", "start": 662, "end": 670}]}, {"trigger": {"text": "role", "start": 1402, "end": 1406}, "arguments": [{"role": "Cause", "text": "SHP-2 phosphatase", "start": 1411, "end": 1428}, {"role": "Theme", "text": "regulation", "start": 1454, "end": 1464}]}, {"trigger": {"text": "regulation", "start": 1454, "end": 1464}, "arguments": [{"role": "Cause", "text": "dopamine", "start": 1436, "end": 1444}, {"role": "Theme", "text": "phosphorylation", "start": 1476, "end": 1491}]}]}}, "schema": []}
{"input": "Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.\n\nCancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 43, "end": 55}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 37, "end": 42}]}, {"trigger": {"text": "vasculogenesis", "start": 60, "end": 74}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 37, "end": 42}]}, {"trigger": {"text": "angiogenesis", "start": 402, "end": 414}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 396, "end": 401}]}, {"trigger": {"text": "angiogenic", "start": 1046, "end": 1056}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 1194, "end": 1206}, "arguments": [{"role": "AtLoc", "text": "tumors", "start": 1241, "end": 1247}]}, {"trigger": {"text": "angiogenesis", "start": 1500, "end": 1512}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 1494, "end": 1499}]}, {"trigger": {"text": "angiogenic", "start": 1576, "end": 1586}, "arguments": []}], "Cell_proliferation": [{"trigger": {"text": "proliferative", "start": 276, "end": 289}, "arguments": [{"role": "Theme", "text": "Cancer stem cells", "start": 145, "end": 162}]}, {"trigger": {"text": "proliferation", "start": 901, "end": 914}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 884, "end": 900}]}], "Development": [{"trigger": {"text": "progression", "start": 215, "end": 226}, "arguments": [{"role": "Theme", "text": "tumor", "start": 209, "end": 214}]}, {"trigger": {"text": "progression", "start": 371, "end": 382}, "arguments": [{"role": "Theme", "text": "tumor", "start": 365, "end": 370}]}, {"trigger": {"text": "development", "start": 468, "end": 479}, "arguments": [{"role": "Theme", "text": "vascular", "start": 459, "end": 467}]}, {"trigger": {"text": "organization", "start": 926, "end": 938}, "arguments": [{"role": "Theme", "text": "tubule", "start": 919, "end": 925}]}], "Gene_expression": [{"trigger": {"text": "expressed", "start": 1009, "end": 1018}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 1065, "end": 1099}]}, {"trigger": {"text": "expressed", "start": 1009, "end": 1018}, "arguments": [{"role": "Theme", "text": "stromal-derived factor 1", "start": 1104, "end": 1128}]}], "Localization": [{"trigger": {"text": "mobilization", "start": 734, "end": 746}, "arguments": [{"role": "Theme", "text": "endothelial progenitor cells", "start": 792, "end": 820}]}, {"trigger": {"text": "recruitment", "start": 757, "end": 768}, "arguments": [{"role": "ToLoc", "text": "tumor", "start": 751, "end": 756}, {"role": "Theme", "text": "endothelial progenitor cells", "start": 792, "end": 820}]}, {"trigger": {"text": "mobilization/recruitment", "start": 1295, "end": 1319}, "arguments": [{"role": "Theme", "text": "EPC", "start": 1291, "end": 1294}]}], "Negative_regulation": [{"trigger": {"text": "blocked", "start": 1170, "end": 1177}, "arguments": [{"role": "Theme", "text": "vascular endothelial growth factor", "start": 1065, "end": 1099}]}, {"trigger": {"text": "blocked", "start": 1170, "end": 1177}, "arguments": [{"role": "Theme", "text": "stromal-derived factor 1", "start": 1104, "end": 1128}]}, {"trigger": {"text": "reduced", "start": 1372, "end": 1379}, "arguments": [{"role": "Cause", "text": "blocked", "start": 1170, "end": 1177}, {"role": "Theme", "text": "microvessel", "start": 1259, "end": 1270}]}, {"trigger": {"text": "reduced", "start": 1372, "end": 1379}, "arguments": [{"role": "Cause", "text": "blocked", "start": 1170, "end": 1177}, {"role": "Theme", "text": "mobilization/recruitment", "start": 1295, "end": 1319}]}, {"trigger": {"text": "reduced", "start": 1372, "end": 1379}, "arguments": [{"role": "Cause", "text": "blocked", "start": 1170, "end": 1177}, {"role": "Theme", "text": "stimulation", "start": 1325, "end": 1336}]}], "Positive_regulation": [{"trigger": {"text": "promote", "start": 29, "end": 36}, "arguments": [{"role": "Cause", "text": "promote", "start": 29, "end": 36}, {"role": "Theme", "text": "angiogenesis", "start": 43, "end": 55}]}, {"trigger": {"text": "promote", "start": 29, "end": 36}, "arguments": [{"role": "Cause", "text": "promote", "start": 29, "end": 36}, {"role": "Theme", "text": "vasculogenesis", "start": 60, "end": 74}]}, {"trigger": {"text": "support", "start": 357, "end": 364}, "arguments": [{"role": "Theme", "text": "progression", "start": 371, "end": 382}, {"role": "Cause", "text": "promoting", "start": 386, "end": 395}]}, {"trigger": {"text": "promoting", "start": 386, "end": 395}, "arguments": [{"role": "Cause", "text": "CSC", "start": 344, "end": 347}, {"role": "Theme", "text": "angiogenesis", "start": 402, "end": 414}]}, {"trigger": {"text": "increased", "start": 662, "end": 671}, "arguments": [{"role": "Cause", "text": "CSC-low tumors", "start": 620, "end": 634}, {"role": "Theme", "text": "microvessel", "start": 672, "end": 683}]}, {"trigger": {"text": "increased", "start": 662, "end": 671}, "arguments": [{"role": "Cause", "text": "CSC-high tumors", "start": 636, "end": 651}, {"role": "Theme", "text": "microvessel", "start": 672, "end": 683}]}, {"trigger": {"text": "induced", "start": 716, "end": 723}, "arguments": [{"role": "Cause", "text": "CSC-low tumors", "start": 620, "end": 634}, {"role": "Theme", "text": "mobilization", "start": 734, "end": 746}]}, {"trigger": {"text": "induced", "start": 716, "end": 723}, "arguments": [{"role": "Cause", "text": "CSC-low tumors", "start": 620, "end": 634}, {"role": "Theme", "text": "recruitment", "start": 757, "end": 768}]}, {"trigger": {"text": "induced", "start": 716, "end": 723}, "arguments": [{"role": "Cause", "text": "CSC-high tumors", "start": 636, "end": 651}, {"role": "Theme", "text": "mobilization", "start": 734, "end": 746}]}, {"trigger": {"text": "induced", "start": 716, "end": 723}, "arguments": [{"role": "Cause", "text": "CSC-high tumors", "start": 636, "end": 651}, {"role": "Theme", "text": "recruitment", "start": 757, "end": 768}]}, {"trigger": {"text": "induced", "start": 859, "end": 866}, "arguments": [{"role": "Cause", "text": "CSC-high C6 cell cultures", "start": 828, "end": 853}, {"role": "Theme", "text": "proliferation", "start": 901, "end": 914}]}, {"trigger": {"text": "induced", "start": 859, "end": 866}, "arguments": [{"role": "Cause", "text": "CSC-high C6 cell cultures", "start": 828, "end": 853}, {"role": "Theme", "text": "organization", "start": 926, "end": 938}]}, {"trigger": {"text": "increased", "start": 1019, "end": 1028}, "arguments": [{"role": "Theme", "text": "expressed", "start": 1009, "end": 1018}]}, {"trigger": {"text": "stimulation", "start": 1325, "end": 1336}, "arguments": [{"role": "Theme", "text": "endothelial cell", "start": 1340, "end": 1356}]}, {"trigger": {"text": "promoting", "start": 1516, "end": 1525}, "arguments": [{"role": "Cause", "text": "CSC", "start": 1476, "end": 1479}, {"role": "Theme", "text": "endothelial cell", "start": 1537, "end": 1553}]}, {"trigger": {"text": "promoting", "start": 1516, "end": 1525}, "arguments": [{"role": "Cause", "text": "CSC", "start": 1476, "end": 1479}, {"role": "Theme", "text": "angiogenic", "start": 1576, "end": 1586}]}, {"trigger": {"text": "dependent", "start": 1671, "end": 1680}, "arguments": [{"role": "Theme", "text": "contribute", "start": 1480, "end": 1490}, {"role": "Cause", "text": "vascular endothelial growth factor", "start": 1636, "end": 1670}]}, {"trigger": {"text": "dependent", "start": 1710, "end": 1719}, "arguments": [{"role": "Theme", "text": "contribute", "start": 1480, "end": 1490}, {"role": "Cause", "text": "stromal-derived factor 1", "start": 1685, "end": 1709}]}], "Regulation": [{"trigger": {"text": "promote", "start": 29, "end": 36}, "arguments": [{"role": "Cause", "text": "Glioma tumor stem-like cells", "start": 0, "end": 28}, {"role": "Theme", "text": "stromal-derived factor 1", "start": 118, "end": 142}]}, {"trigger": {"text": "promote", "start": 29, "end": 36}, "arguments": [{"role": "Cause", "text": "Glioma tumor stem-like cells", "start": 0, "end": 28}, {"role": "Theme", "text": "vascular endothelial growth factor", "start": 79, "end": 113}]}, {"trigger": {"text": "contribute", "start": 439, "end": 449}, "arguments": [{"role": "Cause", "text": "CSC", "start": 435, "end": 438}, {"role": "Theme", "text": "development", "start": 468, "end": 479}]}, {"trigger": {"text": "contribute", "start": 1480, "end": 1490}, "arguments": [{"role": "Theme", "text": "angiogenesis", "start": 1500, "end": 1512}, {"role": "Cause", "text": "promoting", "start": 1516, "end": 1525}]}]}}, "schema": []}
{"input": "Inducible nitric oxide synthase modulates angiogenesis in ischemic hindlimb of rat.\n\nBACKGROUND: Angiogenesis plays an important role in maintaining adequate oxygen delivery, and nitric oxide (NO) is a potential regulator of angiogenesis. NO is synthesized through three isoforms of NO synthase (NOS). It is hypothesized that the NO derived from inducible NOS (iNOS) may promote survival of ischemic tissue through angiogenesis. To test this hypothesis, we investigated the effect of iNOS deficiency (by L-NIL) on angiogenesis in a hindlimb ischemia model. METHODS: Thirty-two male wistar rats randomly divided into four groups. In groups 1 & 2, hindlimb ischemia was induced by ligation of femoral artery and they received L-NIL and saline respectively. The animals in groups 3 and 4 also received L-NIL and saline respectively without surgical procedure. After 21 days, the serum concentration of nitrite, capillary density and expression of HIF1alpha were determined. RESULTS: Serum nitrite levels were significantly lower in L-NIL groups (p<0.05). The capillary density in group 1 (ischemia+L-NIL) was significantly different from group 2 (ischemia+saline); group 1: 360.33+/-77.02, group 2: 549+/-81.85 /mm2, p<0.05) .In addition, expression of HIF1alpha was significantly increased in ischemic groups (p<0.05). CONCLUSION: Selective inhibition of iNOS by L-NIL inhibits angiogenesis in a hindlimb ischemic rat model. In addition, ischemia induces expression of HIF1alpha in hypoxic tissue.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 42, "end": 54}, "arguments": []}, {"trigger": {"text": "Angiogenesis", "start": 97, "end": 109}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 225, "end": 237}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 415, "end": 427}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 514, "end": 526}, "arguments": [{"role": "AtLoc", "text": "hindlimb", "start": 532, "end": 540}]}, {"trigger": {"text": "angiogenesis", "start": 1376, "end": 1388}, "arguments": [{"role": "AtLoc", "text": "hindlimb", "start": 1394, "end": 1402}]}], "Death": [{"trigger": {"text": "survival", "start": 379, "end": 387}, "arguments": [{"role": "Theme", "text": "ischemic tissue", "start": 391, "end": 406}]}], "Gene_expression": [{"trigger": {"text": "expression", "start": 930, "end": 940}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 944, "end": 953}]}, {"trigger": {"text": "expression", "start": 1236, "end": 1246}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 1250, "end": 1259}]}, {"trigger": {"text": "expression", "start": 1453, "end": 1463}, "arguments": [{"role": "Theme", "text": "HIF1alpha", "start": 1467, "end": 1476}]}], "Localization": [{"trigger": {"text": "delivery", "start": 165, "end": 173}, "arguments": [{"role": "Theme", "text": "oxygen", "start": 158, "end": 164}]}], "Negative_regulation": [{"trigger": {"text": "inhibition", "start": 1339, "end": 1349}, "arguments": [{"role": "Theme", "text": "iNOS", "start": 1353, "end": 1357}, {"role": "Cause", "text": "L-NIL", "start": 1361, "end": 1366}]}, {"trigger": {"text": "inhibits", "start": 1367, "end": 1375}, "arguments": [{"role": "Cause", "text": "inhibition", "start": 1339, "end": 1349}, {"role": "Theme", "text": "angiogenesis", "start": 1376, "end": 1388}]}], "Planned_process": [{"trigger": {"text": "ligation", "start": 679, "end": 687}, "arguments": [{"role": "Theme", "text": "femoral artery", "start": 691, "end": 705}]}, {"trigger": {"text": "received", "start": 715, "end": 723}, "arguments": [{"role": "Instrument", "text": "L-NIL", "start": 724, "end": 729}]}, {"trigger": {"text": "received", "start": 715, "end": 723}, "arguments": [{"role": "Instrument", "text": "saline", "start": 734, "end": 740}]}, {"trigger": {"text": "received", "start": 790, "end": 798}, "arguments": [{"role": "Instrument", "text": "L-NIL", "start": 799, "end": 804}]}, {"trigger": {"text": "received", "start": 790, "end": 798}, "arguments": [{"role": "Instrument", "text": "saline", "start": 809, "end": 815}]}], "Positive_regulation": [{"trigger": {"text": "promote", "start": 371, "end": 378}, "arguments": [{"role": "Cause", "text": "promote", "start": 371, "end": 378}, {"role": "Theme", "text": "survival", "start": 379, "end": 387}]}, {"trigger": {"text": "increased", "start": 1278, "end": 1287}, "arguments": [{"role": "Theme", "text": "expression", "start": 1236, "end": 1246}]}, {"trigger": {"text": "induces", "start": 1445, "end": 1452}, "arguments": [{"role": "Theme", "text": "expression", "start": 1453, "end": 1463}]}], "Regulation": [{"trigger": {"text": "modulates", "start": 32, "end": 41}, "arguments": [{"role": "Cause", "text": "Inducible nitric oxide synthase", "start": 0, "end": 31}, {"role": "Theme", "text": "angiogenesis", "start": 42, "end": 54}]}, {"trigger": {"text": "plays an important role", "start": 110, "end": 133}, "arguments": [{"role": "Cause", "text": "Angiogenesis", "start": 97, "end": 109}, {"role": "Theme", "text": "maintaining", "start": 137, "end": 148}]}, {"trigger": {"text": "maintaining", "start": 137, "end": 148}, "arguments": [{"role": "Theme", "text": "delivery", "start": 165, "end": 173}]}, {"trigger": {"text": "promote", "start": 371, "end": 378}, "arguments": [{"role": "Cause", "text": "NO", "start": 330, "end": 332}, {"role": "Theme", "text": "angiogenesis", "start": 415, "end": 427}]}], "Synthesis": [{"trigger": {"text": "synthesized", "start": 245, "end": 256}, "arguments": [{"role": "Theme", "text": "NO", "start": 239, "end": 241}]}]}}, "schema": []}
{"input": "[Intraepithelial neoplasm of the uterine cervix and angiogenesis: morphologic study]\n\nThirty uterine cervix specimens sampled following conization or total hysterectomy were studied using histology, histoenzymology (vessel phosphatase alkaline activity), and immunohistochemistry (demonstration of laminin and type IV collagen in epithelium and vessel basement membranes). Pathologic conditions included dystrophia, moderate dysplasia, severe dysplasia, and intraepithelial carcinoma. Results were compared to findings in a control group. We found that the severity of vascular abnormalities correlated positively with the severity of histologic epithelial lesions; this finding is consistent with colposcopic results. Anarchic angiogenesis with large, moniliform, tortuous vessels was seen in severe dysplasias and carcinomas. The vascular anomalies seem to precede the development of histologic lesions in some instances. Histogenesis of the abnormal vessels may involve production of an angiogenic factor by the cancerized epithelia.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 52, "end": 64}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 728, "end": 740}, "arguments": [{"role": "Theme", "text": "vessels", "start": 774, "end": 781}, {"role": "AtLoc", "text": "carcinomas", "start": 816, "end": 826}]}, {"trigger": {"text": "angiogenic", "start": 990, "end": 1000}, "arguments": []}], "Development": [{"trigger": {"text": "Histogenesis", "start": 924, "end": 936}, "arguments": [{"role": "Theme", "text": "abnormal vessels", "start": 944, "end": 960}]}], "Planned_process": [{"trigger": {"text": "conization", "start": 136, "end": 146}, "arguments": [{"role": "Theme", "text": "uterine cervix", "start": 93, "end": 107}]}, {"trigger": {"text": "hysterectomy", "start": 156, "end": 168}, "arguments": [{"role": "Theme", "text": "uterine cervix", "start": 93, "end": 107}]}]}}, "schema": []}
{"input": "Conjunctival hypoxia in diabetes mellitus.\n\nA frequently cited theory for the pathogenesis of neovascularization in diabetic retinopathy is that retinal hypoxia and/or ischemia release a factor which stimulates neovascularization. To the authors' knowledge, there is no direct in vivo evidence in the human proving this theory. One hundred and twenty-two diabetic subjects were studied to see whether worsening retinopathy was associated with changes in conjunctival oxygen tension (pO2). Diabetics without retinopathy had a conjunctival pO2 which was similar to an age-matched normal population. Diabetics with only background retinopathy had a significantly lower conjunctival pO2 than those without retinopathy (P less than 0.01). Diabetics with proliferative retinopathy showed a conjunctival pO2 that was significantly lower than either of the first two groups (P less than 0.05). The lowest value of all was found in patients with rubeosis iridis. Duration of diabetes alone did not correlate significantly to conjunctival pO2. These findings support the hypoxic theory of diabetic neovascular retinopathy.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 94, "end": 112}, "arguments": []}, {"trigger": {"text": "neovascularization", "start": 211, "end": 229}, "arguments": []}, {"trigger": {"text": "neovascular", "start": 1088, "end": 1099}, "arguments": []}], "Positive_regulation": [{"trigger": {"text": "stimulates", "start": 200, "end": 210}, "arguments": [{"role": "Theme", "text": "neovascularization", "start": 211, "end": 229}]}], "Regulation": [{"trigger": {"text": "changes", "start": 443, "end": 450}, "arguments": [{"role": "Theme", "text": "conjunctival", "start": 454, "end": 466}]}]}}, "schema": []}
{"input": "New functions of epidermal growth factor: stimulation of capillary endothelial cell migration and matrix dependent proliferation.\n\nThe proliferative response of bovine retinal capillary endothelial cells to EGF is dependent upon attaching the cells to a matrix of fibronectin. Bovine capillary endothelial cells are also stimulated to actively migrate when exposed to EGF in vitro. These activities provide an explanation for the angiogenic properties of EGF in vivo. Capillary cell migration and proliferation are proposed as sensitive quantifiable bioassays to explore the functional domains of the EGF molecule. Studies on the inactivation of these properties of EGF by specific cleavage of the molecule with CNBr or proteases suggest that an intact loop composed in part by amino acid residues 20 to 31 is essential for at least some functions.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "attaching", "start": 229, "end": 238}, "arguments": [{"role": "Theme", "text": "retinal capillary endothelial cells", "start": 168, "end": 203}, {"role": "Theme", "text": "cells", "start": 243, "end": 248}, {"role": "Theme", "text": "matrix", "start": 254, "end": 260}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenic", "start": 430, "end": 440}, "arguments": []}], "Catabolism": [{"trigger": {"text": "cleavage", "start": 682, "end": 690}, "arguments": [{"role": "Theme", "text": "EGF", "start": 666, "end": 669}]}], "Cell_proliferation": [{"trigger": {"text": "proliferation", "start": 115, "end": 128}, "arguments": [{"role": "Theme", "text": "capillary endothelial cell", "start": 57, "end": 83}]}, {"trigger": {"text": "proliferative", "start": 135, "end": 148}, "arguments": [{"role": "Theme", "text": "retinal capillary endothelial cells", "start": 168, "end": 203}]}, {"trigger": {"text": "proliferation", "start": 497, "end": 510}, "arguments": [{"role": "Theme", "text": "Capillary cell", "start": 468, "end": 482}]}], "Localization": [{"trigger": {"text": "migration", "start": 84, "end": 93}, "arguments": [{"role": "Theme", "text": "capillary endothelial cell", "start": 57, "end": 83}]}, {"trigger": {"text": "migrate", "start": 344, "end": 351}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 284, "end": 311}]}, {"trigger": {"text": "migration", "start": 483, "end": 492}, "arguments": [{"role": "Theme", "text": "Capillary cell", "start": 468, "end": 482}]}], "Negative_regulation": [{"trigger": {"text": "inactivation", "start": 630, "end": 642}, "arguments": [{"role": "Theme", "text": "EGF", "start": 666, "end": 669}, {"role": "Cause", "text": "cleavage", "start": 682, "end": 690}]}], "Planned_process": [{"trigger": {"text": "exposed", "start": 357, "end": 364}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 284, "end": 311}, {"role": "Instrument", "text": "EGF", "start": 368, "end": 371}]}], "Positive_regulation": [{"trigger": {"text": "stimulation", "start": 42, "end": 53}, "arguments": [{"role": "Cause", "text": "epidermal growth factor", "start": 17, "end": 40}, {"role": "Theme", "text": "proliferation", "start": 115, "end": 128}]}, {"trigger": {"text": "stimulation", "start": 42, "end": 53}, "arguments": [{"role": "Cause", "text": "epidermal growth factor", "start": 17, "end": 40}, {"role": "Theme", "text": "migration", "start": 84, "end": 93}]}, {"trigger": {"text": "dependent", "start": 105, "end": 114}, "arguments": [{"role": "Cause", "text": "matrix", "start": 98, "end": 104}, {"role": "Theme", "text": "proliferation", "start": 115, "end": 128}]}, {"trigger": {"text": "dependent", "start": 214, "end": 223}, "arguments": [{"role": "Theme", "text": "response", "start": 149, "end": 157}, {"role": "Cause", "text": "attaching", "start": 229, "end": 238}]}, {"trigger": {"text": "stimulated", "start": 321, "end": 331}, "arguments": [{"role": "Theme", "text": "migrate", "start": 344, "end": 351}, {"role": "Cause", "text": "exposed", "start": 357, "end": 364}]}, {"trigger": {"text": "cleavage", "start": 682, "end": 690}, "arguments": [{"role": "Theme", "text": "cleavage", "start": 682, "end": 690}, {"role": "Cause", "text": "CNBr", "start": 712, "end": 716}]}], "Regulation": [{"trigger": {"text": "response", "start": 149, "end": 157}, "arguments": [{"role": "Theme", "text": "proliferative", "start": 135, "end": 148}, {"role": "Cause", "text": "EGF", "start": 207, "end": 210}]}]}}, "schema": []}
{"input": "Angiogenesis: initiation and control.\n\nFrom in vivo experiments using new methods such as the rabbit cornea, it is now becoming clear that the growth of a capillary involves an ordered sequence of events that includes lysis of the basement membrane of a parent venule, directional migration of capillary endothelial cells toward the angiogenic stimulus, lumen formation, development of branches, and anastomosis of the tip of one tube with another to form a loop. It is also clear that diffusible angiogenic stimuli can be released not only from most solid tumors, but also from at least three non-neoplastic cells. These include activated macrophages, sensitized lymphocytes, and adipocytes. Other normal tissues can also stimulate angiogenesis, but the type of cell giving rise to the angiogenic stimulus is unknown, and the period of angiogenic stimulation is brief. With the recent ability to clone capillary endothelial cells and to carry them in long-term culture, it has been possible to further delineate the mechanism of capillary growth. In vitro studies have shown that the mast cell seems to behave as a helper cell for capillary endothelial cells, in some way speeding up their rate of directional migration. At this writing, heparin appears to be the principal mast cell factor responsible for this effect on capillary endothelial cells. One theoretical possibility is that mast cells may prepare the matrix, perhaps by slow release of heparin, so that capillary sprouts can more easily move through it toward their angiogenic target. While the study of angiogenesis as a phenomenon is still in an early phase, it has become possible, by using a combination of in vitro and in vivo techniques, to more thoroughly understand the initiation and control of capillary growth.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "Angiogenesis", "start": 0, "end": 12}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 333, "end": 343}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 497, "end": 507}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 733, "end": 745}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 787, "end": 797}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 837, "end": 847}, "arguments": []}, {"trigger": {"text": "angiogenic", "start": 1530, "end": 1540}, "arguments": [{"role": "Theme", "text": "capillary sprouts", "start": 1467, "end": 1484}]}, {"trigger": {"text": "angiogenesis", "start": 1568, "end": 1580}, "arguments": []}], "Breakdown": [{"trigger": {"text": "lysis", "start": 218, "end": 223}, "arguments": [{"role": "Theme", "text": "basement membrane", "start": 231, "end": 248}]}], "Development": [{"trigger": {"text": "formation", "start": 360, "end": 369}, "arguments": [{"role": "Theme", "text": "lumen", "start": 354, "end": 359}]}, {"trigger": {"text": "development", "start": 371, "end": 382}, "arguments": [{"role": "Theme", "text": "branches", "start": 386, "end": 394}]}, {"trigger": {"text": "anastomosis", "start": 400, "end": 411}, "arguments": [{"role": "Theme", "text": "tube", "start": 430, "end": 434}]}, {"trigger": {"text": "prepare", "start": 1403, "end": 1410}, "arguments": [{"role": "Theme", "text": "matrix", "start": 1415, "end": 1421}]}], "Growth": [{"trigger": {"text": "growth", "start": 143, "end": 149}, "arguments": [{"role": "Theme", "text": "capillary", "start": 155, "end": 164}]}, {"trigger": {"text": "growth", "start": 1040, "end": 1046}, "arguments": [{"role": "Theme", "text": "capillary", "start": 1030, "end": 1039}]}, {"trigger": {"text": "growth", "start": 1778, "end": 1784}, "arguments": [{"role": "Theme", "text": "capillary", "start": 1768, "end": 1777}]}], "Localization": [{"trigger": {"text": "migration", "start": 281, "end": 290}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 294, "end": 321}]}, {"trigger": {"text": "migration", "start": 1211, "end": 1220}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 1132, "end": 1159}]}, {"trigger": {"text": "release", "start": 1439, "end": 1446}, "arguments": [{"role": "FromLoc", "text": "mast cells", "start": 1388, "end": 1398}, {"role": "Theme", "text": "heparin", "start": 1450, "end": 1457}]}, {"trigger": {"text": "move", "start": 1501, "end": 1505}, "arguments": [{"role": "Theme", "text": "capillary sprouts", "start": 1467, "end": 1484}]}], "Planned_process": [{"trigger": {"text": "clone", "start": 897, "end": 902}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 903, "end": 930}]}, {"trigger": {"text": "culture", "start": 962, "end": 969}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 903, "end": 930}]}], "Positive_regulation": [{"trigger": {"text": "initiation", "start": 14, "end": 24}, "arguments": [{"role": "Theme", "text": "Angiogenesis", "start": 0, "end": 12}]}, {"trigger": {"text": "activated", "start": 630, "end": 639}, "arguments": [{"role": "Theme", "text": "macrophages", "start": 640, "end": 651}]}, {"trigger": {"text": "stimulate", "start": 723, "end": 732}, "arguments": [{"role": "Cause", "text": "normal tissues", "start": 699, "end": 713}, {"role": "Theme", "text": "angiogenesis", "start": 733, "end": 745}]}, {"trigger": {"text": "stimulation", "start": 848, "end": 859}, "arguments": [{"role": "Theme", "text": "angiogenic", "start": 837, "end": 847}]}, {"trigger": {"text": "speeding up", "start": 1173, "end": 1184}, "arguments": [{"role": "Cause", "text": "mast cell", "start": 1085, "end": 1094}, {"role": "Theme", "text": "migration", "start": 1211, "end": 1220}]}, {"trigger": {"text": "initiation", "start": 1742, "end": 1752}, "arguments": [{"role": "Theme", "text": "growth", "start": 1778, "end": 1784}]}], "Regulation": [{"trigger": {"text": "control", "start": 29, "end": 36}, "arguments": [{"role": "Theme", "text": "Angiogenesis", "start": 0, "end": 12}]}, {"trigger": {"text": "involves", "start": 165, "end": 173}, "arguments": [{"role": "Cause", "text": "growth", "start": 143, "end": 149}, {"role": "Theme", "text": "lysis", "start": 218, "end": 223}]}, {"trigger": {"text": "involves", "start": 165, "end": 173}, "arguments": [{"role": "Cause", "text": "growth", "start": 143, "end": 149}, {"role": "Theme", "text": "migration", "start": 281, "end": 290}]}, {"trigger": {"text": "involves", "start": 165, "end": 173}, "arguments": [{"role": "Cause", "text": "growth", "start": 143, "end": 149}, {"role": "Theme", "text": "formation", "start": 360, "end": 369}]}, {"trigger": {"text": "involves", "start": 165, "end": 173}, "arguments": [{"role": "Cause", "text": "growth", "start": 143, "end": 149}, {"role": "Theme", "text": "development", "start": 371, "end": 382}]}, {"trigger": {"text": "involves", "start": 165, "end": 173}, "arguments": [{"role": "Cause", "text": "growth", "start": 143, "end": 149}, {"role": "Theme", "text": "anastomosis", "start": 400, "end": 411}]}, {"trigger": {"text": "effect", "start": 1313, "end": 1319}, "arguments": [{"role": "Theme", "text": "capillary endothelial cells", "start": 1323, "end": 1350}]}, {"trigger": {"text": "control", "start": 1757, "end": 1764}, "arguments": [{"role": "Theme", "text": "growth", "start": 1778, "end": 1784}]}]}}, "schema": []}
{"input": "Protection from experimental ocular herpetic keratitis by a heat-killed virus vaccine.\n\nNew Zealand white rabbits were given limbal inoculations of a heat-killed suspension of herpes simplex virus (HSV) in a lysate of human embryonic kidney cells. At intervals of four to 14 days, the animals were challenged by intrastromal inoculation with 10,000 plaque-forming units of viable HSV. Epithelial keratitis, disciform edema, and necrotizing keratitis with neovascularization of the cornea developed in control animals. Epithelial keratitis and corneal edema also developed in the immunized animals during the first week after virus challenge, but these symptoms rapidly resolved during the following weeks. The absence of iritis, neovascularization, and necrotizing keratitis in the corneas of the immunized animals was particularly striking.\n", "output": {"json_structures": {"Blood_vessel_development": [{"trigger": {"text": "neovascularization", "start": 455, "end": 473}, "arguments": [{"role": "AtLoc", "text": "cornea", "start": 481, "end": 487}]}, {"trigger": {"text": "neovascularization", "start": 729, "end": 747}, "arguments": [{"role": "AtLoc", "text": "corneas", "start": 782, "end": 789}]}], "Development": [{"trigger": {"text": "developed", "start": 488, "end": 497}, "arguments": [{"role": "Theme", "text": "cornea", "start": 481, "end": 487}]}, {"trigger": {"text": "developed", "start": 562, "end": 571}, "arguments": [{"role": "Theme", "text": "corneal edema", "start": 543, "end": 556}]}], "Planned_process": [{"trigger": {"text": "inoculations", "start": 132, "end": 144}, "arguments": [{"role": "Theme", "text": "New Zealand white rabbits", "start": 88, "end": 113}, {"role": "Instrument", "text": "herpes simplex virus", "start": 176, "end": 196}]}, {"trigger": {"text": "inoculation", "start": 325, "end": 336}, "arguments": [{"role": "Instrument", "text": "HSV", "start": 380, "end": 383}]}]}}, "schema": []}
{"input": "Molecular mediators of interactions with extracellular matrix components in metastasis and angiogenesis.\n\nMetastasis and tumor angiogenesis are invasive phenomena and share many common properties at the physiological level and some similarities at the molecular level. Each consists of repetitive cycles of interaction with adjacent extracellular matrix components by mediating cellular adhesion, matrix dissolution, and cellular motility to achieve metastasis of cancer cells or neovascularization of tumors. Molecular factors which implement this triad of events are reviewed, as are several signal transduction components which may regulate them. Some potentially promising prognostic, diagnostic, and therapeutic modalities for tumor angiogenesis and metastatic disease are also discussed.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "interactions", "start": 23, "end": 35}, "arguments": [{"role": "Theme", "text": "extracellular matrix components", "start": 41, "end": 72}]}, {"trigger": {"text": "interaction", "start": 307, "end": 318}, "arguments": [{"role": "Theme", "text": "extracellular matrix components", "start": 333, "end": 364}]}, {"trigger": {"text": "adhesion", "start": 387, "end": 395}, "arguments": [{"role": "Theme", "text": "cellular", "start": 378, "end": 386}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 91, "end": 103}, "arguments": []}, {"trigger": {"text": "angiogenesis", "start": 127, "end": 139}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 121, "end": 126}]}, {"trigger": {"text": "neovascularization", "start": 480, "end": 498}, "arguments": [{"role": "AtLoc", "text": "tumors", "start": 502, "end": 508}]}, {"trigger": {"text": "angiogenesis", "start": 738, "end": 750}, "arguments": [{"role": "AtLoc", "text": "tumor", "start": 732, "end": 737}]}], "Breakdown": [{"trigger": {"text": "matrix dissolution", "start": 397, "end": 415}, "arguments": [{"role": "Theme", "text": "matrix", "start": 397, "end": 403}]}], "Localization": [{"trigger": {"text": "motility", "start": 430, "end": 438}, "arguments": [{"role": "Theme", "text": "cellular", "start": 421, "end": 429}]}, {"trigger": {"text": "metastasis", "start": 450, "end": 460}, "arguments": [{"role": "Theme", "text": "cancer cells", "start": 464, "end": 476}]}], "Regulation": [{"trigger": {"text": "mediating", "start": 368, "end": 377}, "arguments": [{"role": "Theme", "text": "adhesion", "start": 387, "end": 395}]}, {"trigger": {"text": "mediating", "start": 368, "end": 377}, "arguments": [{"role": "Theme", "text": "matrix dissolution", "start": 397, "end": 415}]}, {"trigger": {"text": "mediating", "start": 368, "end": 377}, "arguments": [{"role": "Theme", "text": "motility", "start": 430, "end": 438}]}, {"trigger": {"text": "mediating", "start": 368, "end": 377}, "arguments": [{"role": "Theme", "text": "neovascularization", "start": 480, "end": 498}]}]}}, "schema": []}
{"input": "High density of somatostatin receptors in veins surrounding human cancer tissue: role in tumor-host interaction?\n\nSomatostatin receptors were detected in peritumoral veins of various human cancer tissue specimens. Vascular and neoplastic tissue from 14 colonic adenocarcinomas, 13 carcinoids, 6 renal-cell carcinomas and 7 malignant lymphomas were analyzed for somatostatin receptors by use of quantitative receptor autoradiography. In colonic carcinoma specimens, the peritumoral vessels expressed a high density of somatostatin receptors, whereas the neoplastic tissue itself was receptor-negative in many cases. In contrast, the incidence and density of somatostatin receptors in peritumoral vessels was low in well-differentiated gastrointestinal and bronchial carcinoids, in contrast to the high density of such receptors in the carcinoid tumor tissue. Autochthonous vessels surrounding other tumors such as renal-cell carcinomas or malignant lymphomas also frequently expressed somatostatin receptors. In all cases, the somatostatin receptors were localized in veins, particularly in the smooth-muscle cell layer. They exhibited specific and high-affinity binding of somatostatin-14, somatostatin-28 and octreotide, suggesting a preferential expression of the SSTR2 receptor subtype. Since the vessels of normal non-neoplastic human tissues, e.g. of intestine or lymphatic organs, have few somatostatin receptors, the increased somatostatin receptor expression in peritumoral vessels observed in this study may be linked to the neoplastic process itself. The results suggest that somatostatin and somatostatin receptors may play a regulatory role for hemodynamic tumor-host interactions, possibly involving tumor stroma generation, tumor environment, angiogenesis and, particularly, vascular drainage of poorly differentiated neoplasms.\n", "output": {"json_structures": {"Binding": [{"trigger": {"text": "interaction", "start": 100, "end": 111}, "arguments": [{"role": "Theme", "text": "tumor", "start": 89, "end": 94}]}, {"trigger": {"text": "binding", "start": 1162, "end": 1169}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 1026, "end": 1048}, {"role": "Theme", "text": "somatostatin-14", "start": 1173, "end": 1188}]}, {"trigger": {"text": "binding", "start": 1162, "end": 1169}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 1026, "end": 1048}, {"role": "Theme", "text": "somatostatin-28", "start": 1190, "end": 1205}]}, {"trigger": {"text": "binding", "start": 1162, "end": 1169}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 1026, "end": 1048}, {"role": "Theme", "text": "octreotide", "start": 1210, "end": 1220}]}, {"trigger": {"text": "interactions", "start": 1680, "end": 1692}, "arguments": [{"role": "Theme", "text": "tumor", "start": 1669, "end": 1674}]}], "Blood_vessel_development": [{"trigger": {"text": "angiogenesis", "start": 1757, "end": 1769}, "arguments": []}], "Development": [{"trigger": {"text": "differentiated", "start": 719, "end": 733}, "arguments": [{"role": "Theme", "text": "gastrointestinal", "start": 734, "end": 750}]}, {"trigger": {"text": "differentiated", "start": 719, "end": 733}, "arguments": [{"role": "Theme", "text": "bronchial carcinoids", "start": 755, "end": 775}]}, {"trigger": {"text": "generation", "start": 1726, "end": 1736}, "arguments": [{"role": "Theme", "text": "tumor stroma", "start": 1713, "end": 1725}]}, {"trigger": {"text": "differentiated", "start": 1817, "end": 1831}, "arguments": [{"role": "Theme", "text": "neoplasms", "start": 1832, "end": 1841}]}], "Gene_expression": [{"trigger": {"text": "expressed", "start": 489, "end": 498}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 517, "end": 539}]}, {"trigger": {"text": "negative", "start": 591, "end": 599}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 517, "end": 539}]}, {"trigger": {"text": "expressed", "start": 974, "end": 983}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 984, "end": 1006}]}, {"trigger": {"text": "expression", "start": 1248, "end": 1258}, "arguments": [{"role": "Theme", "text": "SSTR2 receptor", "start": 1266, "end": 1280}]}, {"trigger": {"text": "expression", "start": 1456, "end": 1466}, "arguments": [{"role": "Theme", "text": "somatostatin receptor", "start": 1434, "end": 1455}]}], "Localization": [{"trigger": {"text": "detected", "start": 142, "end": 150}, "arguments": [{"role": "Theme", "text": "Somatostatin receptors", "start": 114, "end": 136}, {"role": "AtLoc", "text": "veins", "start": 166, "end": 171}]}, {"trigger": {"text": "localized", "start": 1054, "end": 1063}, "arguments": [{"role": "Theme", "text": "somatostatin receptors", "start": 1026, "end": 1048}, {"role": "AtLoc", "text": "smooth-muscle cell", "start": 1094, "end": 1112}]}], "Positive_regulation": [{"trigger": {"text": "increased", "start": 1424, "end": 1433}, "arguments": [{"role": "Theme", "text": "expression", "start": 1456, "end": 1466}]}], "Regulation": [{"trigger": {"text": "role", "start": 81, "end": 85}, "arguments": [{"role": "Cause", "text": "somatostatin receptors", "start": 16, "end": 38}, {"role": "Theme", "text": "interaction", "start": 100, "end": 111}]}, {"trigger": {"text": "play a regulatory role", "start": 1630, "end": 1652}, "arguments": [{"role": "Cause", "text": "somatostatin", "start": 1586, "end": 1598}, {"role": "Theme", "text": "interactions", "start": 1680, "end": 1692}]}, {"trigger": {"text": "play a regulatory role", "start": 1630, "end": 1652}, "arguments": [{"role": "Cause", "text": "somatostatin receptors", "start": 1603, "end": 1625}, {"role": "Theme", "text": "interactions", "start": 1680, "end": 1692}]}, {"trigger": {"text": "involving", "start": 1703, "end": 1712}, "arguments": [{"role": "Cause", "text": "somatostatin", "start": 1586, "end": 1598}, {"role": "Theme", "text": "generation", "start": 1726, "end": 1736}]}, {"trigger": {"text": "involving", "start": 1703, "end": 1712}, "arguments": [{"role": "Cause", "text": "somatostatin", "start": 1586, "end": 1598}, {"role": "Theme", "text": "angiogenesis", "start": 1757, "end": 1769}]}, {"trigger": {"text": "involving", "start": 1703, "end": 1712}, "arguments": [{"role": "Cause", "text": "somatostatin receptors", "start": 1603, "end": 1625}, {"role": "Theme", "text": "generation", "start": 1726, "end": 1736}]}, {"trigger": {"text": "involving", "start": 1703, "end": 1712}, "arguments": [{"role": "Cause", "text": "somatostatin receptors", "start": 1603, "end": 1625}, {"role": "Theme", "text": "angiogenesis", "start": 1757, "end": 1769}]}]}}, "schema": []}