NEW_INSENT_TOKEN = "<t>"
ORD_A = 97

TEMPLATE_MLEE_Role_Name={
    'Cell_proliferation': {'Theme', 'AtLoc'},
    'Development': {'Theme'},
    'Blood_vessel_development': {'Theme'},
    'Growth': {'Theme'},
    'Death': {'Theme'},
    'Breakdown': {'Theme'},
    'Remodeling': {'Theme'},
    'Synthesis': {'Theme'},
    'Gene_expression': {'Theme'},
    'Transcription': {'Theme'},
    'Protein_processing': {'Theme'},
    'DNA_methylation': {'Theme'},
    'Metabolism': {'Theme'},
    'Catabolism': {'Theme'},
    'Phosphorylation': {'Theme', 'Site'},
    'Dephosphorylation': {'Theme', 'Site'},
    'Pathway': {'Theme'},
    'Localization': {'Theme', 'AtLoc', 'FROMLoc', 'TOLoc'},
    'Binding': {'Theme', 'Site'},
    'Regulation': {'Theme', 'Cause', 'Site'},
    'Positive_regulation': {'Theme', 'Cause', 'Site'},
    'Negative_regulation': {'Theme', 'Cause', 'Site'},
    'Planned_process': {'Theme', 'Instrument'},
}

TEMPLATE_MLEE_Event_Demo ={"Blood_vessel_development": "<eg> Given a document: M - CSF signals through the MAPK / ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as <t> angiogenesis <t> and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"AtLoc\": \"tumors\", \"Theme\": null} <eg>", "Positive_regulation": "<eg> Given a document: Nicked { beta } 2 - glycoprotein I binds angiostatin 4 . 5 ( plasminogen kringle 1 - 5 ) and attenuates its anti angiogenic property . Angiostatin was first discovered as a plasminogen fragment with anti tumor / anti angiogenic 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 <t> cleaved <t> by plasmin in its domain V ( nicked beta2GPI ) , resulting in binding to plasminogen . Anti angiogenic 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 anti angiogenic 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 anti angiogenic activity . \nYou need to output: {\"Cause\": \"plasmin\", \"Theme\": \"cleaved\", \"Site\": \"domain V\"} <eg>", "Regulation": "<eg> Given a document: Here we investigated the effects of small molecule inhibitors ( SMIs ) designed to disrupt integrin alpha2 I or beta1 I - like domain function on angiogenesis . In unchallenged endothelial cells , fibrillar collagen induced robust capillary morphogenesis . In contrast , tube formation was significantly reduced by SMI496 , a beta1 I - like domain inhibitor and by function - blocking anti - alpha2beta1 but not - alpha1beta1 antibodies . Endothelial cells bound fluorescein - labeled collagen I fibrils , an interaction specifically inhibited by SMI496 . Moreover , SMI496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound healing . SMI activities were examined in vivo by supplementing the growth medium of zebrafish embryos expressing green fluorescent protein under the <t> control <t> of the vascular endothelial growth factor receptor - 2 promoter . SMI496 , but not a control compound , interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels . We further characterized zebrafish alpha2 integrin and discovered that this integrin is highly conserved , especially the I domain . Notably , a similar vascular phenotype was induced by morpholino - mediated knockdown of the integrin alpha2 subunit . By live videomicroscopy , we confirmed that the vessels were largely nonfunctional in the absence of alpha2beta1 integrin . Collectively , our results provide strong biochemical and genetic evidence of a central role for alpha2beta1 integrin in experimental and developmental angiogenesis . \nYou need to output: {\"Cause\": \"vascular endothelial growth factor receptor - 2\", \"Site\": \"promoter\", \"Theme\": \"expressing\"} <eg>", "Pathway": "<eg> Given a document: M - CSF signals through the MAPK / ERK <t> pathway <t> via Sp1 to induce VEGF production and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"Participant\": \"MAPK, ERK\", \"Theme\": null} <eg>", "Gene_expression": "<eg> Given a document: M - CSF signals through the MAPK / ERK pathway via Sp1 to induce VEGF <t> production <t> and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"Theme\": \"VEGF\"} <eg>", "Localization": "<eg> Given a document: s - VEGF was also measured before , 4 and 8 weeks after nephrectomy in 11 patients . There were significant differences in s - VEGF between the RCC patients and the controls ( 207 . 3 + / - 32 . 9 vs . 71 . 5 + / - 9 . 1 pg / ml , mean + / - SE ) ( P less than 0 . 005 ) , between the tumor - bearing renal veins and the contralateral ones ( P less than 0 . 01 ) , between the pre - and post - nephrectomy situations ( P less than 0 . 01 ) and among the various parameters of tumor status such as tumor extent ( P less than 0 . 001 ) and existence of metastasis ( P less than 0 . 001 ) . s - VEGF significantly correlated with the tumor volume obtained by a three - dimensional measurement ( r = 0 . 802 , P less than 0 . 0001 ) . The sensitivity and specificity of s - VEGF at the cut - off level of 100 pg / ml , as determined by the receiver - operating - characteristics curve , were 80 . 0 % and 72 . 5 % , respectively . The results indicate that tumor tissue of RCC <t> liberates <t> VEGF into the systemic blood flow and that s - VEGF is a possible marker for RCC . \nYou need to output: {\"Theme\": \"VEGF\", \"ToLoc\": \"blood\", \"FromLoc\": \"tumor tissue\", \"FROMLoc\": null, \"AtLoc\": null, \"TOLoc\": null} <eg>", "Cell_proliferation": "<eg> Given a document: M - CSF signals through the MAPK / ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell <t> proliferation <t> and new blood vessel formation . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"Theme\": \"endothelial cell\", \"AtLoc\": null} <eg>", "Development": "<eg> Given a document: M - CSF signals through the MAPK / ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel <t> formation <t> . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"Theme\": \"blood vessel\"} <eg>", "Planned_process": "<eg> Given a document: Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - <t> treated <t> human monocytes . To evaluate the biological significance of M - CSF induced VEGF production , we used an in vivo angiogenesis model to illustrate the ability of M - CSF to recruit mononuclear phagocytes , increase VEGF levels , and enhance angiogenesis . Importantly , the addition of a neutralizing VEGF antibody abolished M - CSF - induced blood vessel formation . CONCLUSION : These data delineate an ERK - and Sp1 - dependent mechanism of M - CSF induced VEGF production and demonstrate for the first time the ability of M - CSF to induce angiogenesis via VEGF in vivo . \nYou need to output: {\"Instrument\": \"M - CSF\", \"Theme\": \"monocytes\"} <eg>", "Negative_regulation": "<eg> Given a document: Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK <t> decreased <t> VEGF promoter activity in M - CSF - treated human monocytes . To evaluate the biological significance of M - CSF induced VEGF production , we used an in vivo angiogenesis model to illustrate the ability of M - CSF to recruit mononuclear phagocytes , increase VEGF levels , and enhance angiogenesis . Importantly , the addition of a neutralizing VEGF antibody abolished M - CSF - induced blood vessel formation . CONCLUSION : These data delineate an ERK - and Sp1 - dependent mechanism of M - CSF induced VEGF production and demonstrate for the first time the ability of M - CSF to induce angiogenesis via VEGF in vivo . \nYou need to output: {\"Site\": \"promoter\", \"Theme\": \"VEGF\", \"Cause\": \"mutating\"} <eg>", "Binding": "<eg> Given a document: M - CSF signals through the MAPK / ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo . BACKGROUND : M - CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors . VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation . Previously , we reported that in vitro M - CSF induces the expression of biologically - active VEGF from human monocytes . METHODOLOGY AND RESULTS : In this study , we demonstrate the molecular mechanism of M - CSF - induced VEGF production . Using a construct containing the VEGF promoter linked to a luciferase reporter , we found that a mutation reducing HIF <t> binding <t> to the VEGF promoter had no significant effect on luciferase production induced by M - CSF stimulation . Further analysis revealed that M - CSF induced VEGF through the MAPK / ERK signaling pathway via the transcription factor , Sp1 . Thus , inhibition of either ERK or Sp1 suppressed M - CSF - induced VEGF at the mRNA and protein level . M - CSF also induced the nuclear localization of Sp1 , which was blocked by ERK inhibition . Finally , mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M - CSF - treated human monocytes . \nYou need to output: {\"Theme\": \"VEGF, HIF\", \"Site\": \"promoter\"} <eg>", "Growth": "<eg> Given a document: Current prospects for controlling cancer <t> growth <t> with non - cytotoxic agents - - nutrients , phytochemicals , herbal extracts , and available drugs . In animal or cell culture studies , the growth and spread of cancer can be slowed by many nutrients , food factors , herbal extracts , and well - tolerated , available drugs that are still rarely used in the clinical management of cancer , in part because they seem unlikely to constitute definitive therapies in themselves . However , it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and , when used as adjuvants , could improve the cure rates achievable with standard therapies . The therapeutic options available in this regard include measures that : down - regulate serum free IGF - I ; suppress the synthesis of mevalonic acid and / or certain derivatives thereof ; modulate arachidonate metabolism by inhibiting 5 - lipoxygenase , 12 - lipoxygenase , or COX - 2 ; antagonize the activation of AP - 1 transcription factors ; promote the activation of PPAR - gamma transcription factors ; and that suppress angiogenesis by additional mechanisms . Many of these measures appear suitable for use in cancer prevention . \nYou need to output: {\"Theme\": \"cancer\"} <eg>", "Synthesis": "<eg> Given a document: Current prospects for controlling cancer growth with non - cytotoxic agents - - nutrients , phytochemicals , herbal extracts , and available drugs . In animal or cell culture studies , the growth and spread of cancer can be slowed by many nutrients , food factors , herbal extracts , and well - tolerated , available drugs that are still rarely used in the clinical management of cancer , in part because they seem unlikely to constitute definitive therapies in themselves . However , it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and , when used as adjuvants , could improve the cure rates achievable with standard therapies . The therapeutic options available in this regard include measures that : down - regulate serum free IGF - I ; suppress the <t> synthesis <t> of mevalonic acid and / or certain derivatives thereof ; modulate arachidonate metabolism by inhibiting 5 - lipoxygenase , 12 - lipoxygenase , or COX - 2 ; antagonize the activation of AP - 1 transcription factors ; promote the activation of PPAR - gamma transcription factors ; and that suppress angiogenesis by additional mechanisms . Many of these measures appear suitable for use in cancer prevention . \nYou need to output: {\"Theme\": \"mevalonic acid\"} <eg>", "Metabolism": "<eg> Given a document: Current prospects for controlling cancer growth with non - cytotoxic agents - - nutrients , phytochemicals , herbal extracts , and available drugs . In animal or cell culture studies , the growth and spread of cancer can be slowed by many nutrients , food factors , herbal extracts , and well - tolerated , available drugs that are still rarely used in the clinical management of cancer , in part because they seem unlikely to constitute definitive therapies in themselves . However , it is reasonable to expect that mechanistically complementary combinations of these measures could have a worthwhile impact on survival times and , when used as adjuvants , could improve the cure rates achievable with standard therapies . The therapeutic options available in this regard include measures that : down - regulate serum free IGF - I ; suppress the synthesis of mevalonic acid and / or certain derivatives thereof ; modulate arachidonate <t> metabolism <t> by inhibiting 5 - lipoxygenase , 12 - lipoxygenase , or COX - 2 ; antagonize the activation of AP - 1 transcription factors ; promote the activation of PPAR - gamma transcription factors ; and that suppress angiogenesis by additional mechanisms . Many of these measures appear suitable for use in cancer prevention . \nYou need to output: {\"Theme\": \"arachidonate\"} <eg>", "Death": "<eg> Given a document: NF - kappaB and IKK as therapeutic targets in cancer . The transcription factor NF - kappaB and associated regulatory factors ( including IkappaB kinase subunits and the IkappaB family member Bcl - 3 ) are strongly implicated in a variety of hematologic and solid tumor malignancies . A role for NF - kappaB in cancer cells appears to involve regulation of cell proliferation , control of <t> apoptosis <t> , promotion of angiogenesis , and stimulation of invasion / metastasis . Consistent with a role for NF - kappaB in oncogenesis are observations that inhibition of NF - kappaB alone or in combination with cancer therapies leads to tumor cell death or growth inhibition . However , other experimental data indicate that NF - kappaB can play a tumor suppressor role in certain settings and that it can be important in promoting an apoptotic signal downstream of certain cancer therapy regimens . In order to appropriately move NF - kappaB inhibitors in the clinic , thorough approaches must be initiated to determine the molecular mechanisms that dictate the complexity of oncologic and therapeutic outcomes that are controlled by NF - kappaB . \nYou need to output: {\"Theme\": \"cancer cells\"} <eg>", "Transcription": "<eg> Given a document: VEGF165 expressed by a replication - deficient recombinant adenovirus vector induces angiogenesis in vivo . To evaluate the concept that localized delivery of angiogenic factors via virus - mediated gene transfer may be useful in the treatment of ischemic disorders , the replication - deficient adenovirus ( Ad ) vector AdCMV . VEGF165 ( where CMV is cytomegalovirus and VEGF is vascular endothelial growth factor ) containing the cDNA for human VEGF165 , a secreted endothelial cell - specific angiogenic growth factor , was constructed . Human umbilical vein endothelial cells ( HUVECs ) and rat aorta smooth muscle cells ( RASMCs ) infected with AdCMV . VEGF165 ( 5 and 20 plaque - forming units [ pfu ] per cell ) demonstrated VEGF mRNA <t> expression <t> and protein secretion into the supernatant . Furthermore , the conditioned medium from these cells enhanced vascular permeability in vivo . In contrast , neither VEGF mRNA nor secreted protein was found in uninfected HUVECs or RASMCs or in cells infected with the control vector AdCMV . beta gal ( where beta gal is beta - galactosidase ) . Assessment of starved HUVECs at 14 days demonstrated sixfold more cells for AdCMV . VEGF165 - infected HUVECs ( 20 pfu per cell ) than for either infected or uninfected control cells . RASMC proliferation was unaffected by infection with AdCMV . VEGF165 . \nYou need to output: {\"Theme\": \"VEGF\"} <eg>", "DNA_methylation": "<eg> Given a document: Involvement of PTEN promoter <t> methylation <t> in cerebral cavernous malformations . BACKGROUND AND PURPOSE : Cerebral cavernous malformations ( CCMs ) are prevalent cerebral vascular lesions involving aberrant angiogenesis . However , the underlying mechanism is poorly understood . Phosphatase and tension homolog deleted on chromosome 10 ( PTEN ) , a tumor suppressor , is frequently deficient in various pathologies due to mutation or epigenetic alterations . PTEN promoter hypermethylation is a major epigenetic silencing mechanism leading to activation of angiogenesis in tumors . The present study aimed to investigate whether PTEN promoter methylation was involved in CCMs . METHODS : PTEN promoter methylation was detected in surgical specimens of CCMs ( n = 69 ) by methylation - specific polymerase chain reaction . The methylation status was correlated to the clinical manifestations and to PTEN expression , which was analyzed by both Western blot and immunohistochemistry . To investigate the endothelial proliferation and the potential signaling pathways affected by PTEN methylation , proliferating cell nuclear antigen as well as phosphor - Akt and phosphor - Erk1 , 2 were detected by immunofluorescence and Western blot , respectively , in CCM specimens . RESULTS : Methylation - specific polymerase chain reaction revealed PTEN promoter methylation in 15 . 9 % CCMs . \nYou need to output: {\"Theme\": \"PTEN\", \"Site\": \"promoter\"} <eg>", "Catabolism": "<eg> Given a document: New functions of epidermal growth factor : stimulation of capillary endothelial cell migration and matrix dependent proliferation . The 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 <t> cleavage <t> 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 . \nYou need to output: {\"Theme\": \"EGF\"} <eg>", "Breakdown": "<eg> Given a document: Laser treatment of eccentric leaks in central serous chorioretinopathy resulting in disappearance of untreated juxtafoveal leaks . In 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 <t> detachment <t> , 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 . \nYou need to output: {\"Theme\": \"macular\"} <eg>", "Remodeling": "<eg> Given a document: Outcomes measures included transcutaneous blood gas levels , histology , total RNA content and analysis of alpha2 ( I ) collagen ( COL - I ) , type IV collagen ( COL - IV ) , alpha1 ( V ) collagen ( COL - V ) , and vascular endothelial growth factor ( VEGF ) expression using real - time quantitative PCR . All markers for stimulated wounds showed increased activity relative to non - stimulated control wounds between 7 and 14 days following injury , with peak activity at 14 days . By 21 days post - injury , all activity had returned to near baseline level . VEGF and COL - IV levels were found to be significantly higher for pattern A ( 110 mus pulse width ) compared to pattern B ( 5 mus pulse width ) at 14 days , implying that pattern A may be more effective at promoting angiogenesis . All wounds were fully re - epithelialized by 10 days post - injury . Both COL - I and COL - V showed statistically significant ( P less than 0 . 05 ) increased activity between day 7 and day 14 for pattern A , potentially indicating a continued effect on matrix <t> remodeling <t> . The early closure of all wounds implies that the rabbit ear model may not be valid for chronic wound studies . \nYou need to output: {\"Theme\": \"matrix\"} <eg>", "Phosphorylation": "<eg> Given a document: To evaluate the effect of EPOX on the endothelial signaling pathway , we did immunoblotting , immunoprecipitation , and immunofluorescence analysis . Intracellular glutathione levels were determined with the use of monochlorobimane , a glutathione - specific probe . RESULTS : EPOX induced endothelial cell apoptosis in association with proteasome - dependent Mcl - 1 degradation . Down - regulation of Mcl - 1 resulted in an increase in Mcl - 1 - free Bim , activation of Bax , and then signaling of mitochondria - mediated apoptosis . Additionally , glutathione depletion and extracellular signal - regulated kinase ( ERK ) inactivation was observed in EPOX - treated cells . Glutathione supplementation reversed the inhibitory effects of EPOX on ERK , which increases the <t> phosphorylation <t> of Mcl - 1 at T ( 163 . ) Overexpression of mitogen - activated protein / ERK kinase ( MEK ) partially reversed the effect of EPOX on Mcl - 1 dephosphorylation , ubiquitination , and degradation , further implicating ERK in the regulation of Mcl - 1 stability . CONCLUSIONS : This study provides evidence that EPOX induces glutathione depletion , ERK inactivation , and Mcl - 1 degradation on endothelial cells , which leads to inhibition of angiogenesis . Our results suggest that EPOX is a novel anti angiogenic agent , making it a promising lead compound for further development in the treatment of angiogenesis - related pathologies . \nYou need to output: {\"Site\": \"T ( 163\", \"Theme\": \"Mcl - 1\"} <eg>", "Dephosphorylation": "<eg> Given a document: Vascular 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 <t> dephosphorylates <t> 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 . \nYou need to output: {\"Theme\": \"VEGFR - 2\", \"Site\": \"Y951\"} <eg>", "Protein_processing": "<eg> Given a document: Nicked { beta } 2 - glycoprotein I binds angiostatin 4 . 5 ( plasminogen kringle 1 - 5 ) and attenuates its anti angiogenic property . Angiostatin was first discovered as a plasminogen fragment with anti tumor / anti angiogenic 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 <t> autoproteolysis <t> 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 . Anti angiogenic 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 anti angiogenic 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 anti angiogenic activity . \nYou need to output: {\"Theme\": \"angiostatin 4 . 5\"} <eg>"}

TEMPLATE_MLEE_Event_Full = {
    'Cell_proliferation':'Cell proliferate or accumulate',
    'Development':'Anatomical Entity develop or form',
    'Blood_vessel_development':'neovascularization or angiogenesis at Anatomical Location',
    'Growth':'growth of Anatomical Entity',
    'Death':'death of Anatomical Entity',
    'Breakdown':'Anatomical Entity degraded or damaged',
    'Remodeling':'Tissue remodeling or changes',
    'Synthesis':'synthesis of Drug/Compound',
    'Gene_expression':'expression of Gene and Gene ( and Gene )',
    'Transcription':'transcription of Gene',
    'Protein_processing':'processing of Gene product',
    'DNA_methylation':'methylation of Entity at Site',
    'Metabolism':'metabolism of Entity',
    'Catabolism':'catabolism of Entity',
    'Phosphorylation':'phosphorylation of Entity at Site',
    'Dephosphorylation':'dephosphorylation of Entity at Site',
    'Pathway':'Entity and Entity and Entity ( and Entity ) participate in signaling pathway or system',
    'Localization':'Entity At Location or To Location or From Location ',
    'Binding':'Site of Entity bind or interact with Site of Entity ( and Site of Entity )',
    'Regulation':'Something regulate Event/Entity at Site',
    'Positive_regulation':'Something positively regulate Event/Entity at Site',
    'Negative_regulation':'Something negatively regulate Event/Entity at Site',
    'Planned_process':'Something is treated with Entity and Entity ( and Entity )',
}