PubMed:23285048 JSON TXT

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LitCoin-entities-OrganismTaxon-PD

{"project":"LitCoin-entities-OrganismTaxon-PD","denotations":[{"id":"T1","span":{"begin":39,"end":44},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":99,"end":104},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":727,"end":731},"obj":"OrganismTaxon"},{"id":"T5","span":{"begin":1479,"end":1483},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"NCBItxid:998453"},{"id":"A2","pred":"db_id","subj":"T2","obj":"NCBItxid:998453"},{"id":"A3","pred":"db_id","subj":"T3","obj":"NCBItxid:10095"},{"id":"A4","pred":"db_id","subj":"T3","obj":"NCBItxid:10088"},{"id":"A5","pred":"db_id","subj":"T5","obj":"NCBItxid:10095"},{"id":"A6","pred":"db_id","subj":"T5","obj":"NCBItxid:10088"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-sentences

{"project":"LitCoin-sentences","denotations":[{"id":"T1","span":{"begin":0,"end":98},"obj":"Sentence"},{"id":"T2","span":{"begin":99,"end":311},"obj":"Sentence"},{"id":"T3","span":{"begin":312,"end":494},"obj":"Sentence"},{"id":"T4","span":{"begin":495,"end":609},"obj":"Sentence"},{"id":"T5","span":{"begin":610,"end":928},"obj":"Sentence"},{"id":"T6","span":{"begin":929,"end":1129},"obj":"Sentence"},{"id":"T7","span":{"begin":1130,"end":1273},"obj":"Sentence"},{"id":"T8","span":{"begin":1274,"end":1544},"obj":"Sentence"},{"id":"T9","span":{"begin":1545,"end":1677},"obj":"Sentence"},{"id":"T10","span":{"begin":1678,"end":1813},"obj":"Sentence"},{"id":"T11","span":{"begin":1814,"end":2039},"obj":"Sentence"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-entities

LitCoin_Mondo

{"project":"LitCoin_Mondo","denotations":[{"id":"T1","span":{"begin":331,"end":336},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":1152,"end":1163},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0043579"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0015292"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-GeneOrGeneProduct-v0

LitCoin-GeneOrGeneProduct-v2

LitCoin-Disease-MeSH

{"project":"LitCoin-Disease-MeSH","denotations":[{"id":"T1","span":{"begin":207,"end":212},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":303},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":487,"end":493},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"originalLabel","subj":"T1","obj":"D009369"},{"id":"A2","pred":"originalLabel","subj":"T2","obj":"D009369"},{"id":"A3","pred":"originalLabel","subj":"T3","obj":"D009369"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-GeneOrGeneProduct-v3

LitCoin_Mondo_095

{"project":"LitCoin_Mondo_095","denotations":[{"id":"T1","span":{"begin":207,"end":212},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":303},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":873,"end":876},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0005070"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0005070"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0019079"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-MeSH-Disease-2

{"project":"LitCoin-MeSH-Disease-2","denotations":[{"id":"T1","span":{"begin":207,"end":212},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":303},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":487,"end":493},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"ID:","subj":"T1","obj":"D009369"},{"id":"A2","pred":"ID:","subj":"T2","obj":"D009369"},{"id":"A3","pred":"ID:","subj":"T3","obj":"DISEASE"},{"id":"A4","pred":"ID:","subj":"T3","obj":"D009369"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-MONDO_bioort2019

{"project":"LitCoin-MONDO_bioort2019","denotations":[{"id":"T1","span":{"begin":207,"end":212},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":298,"end":303},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":487,"end":493},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"#label","subj":"T1","obj":"D009369"},{"id":"A2","pred":"#label","subj":"T2","obj":"D009369"},{"id":"A3","pred":"#label","subj":"T3","obj":"D009369"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-NCBITaxon-2

{"project":"LitCoin-NCBITaxon-2","denotations":[{"id":"T1","span":{"begin":39,"end":44},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":99,"end":104},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":727,"end":731},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":1479,"end":1483},"obj":"OrganismTaxon"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-Chemical-MeSH-CHEBI

{"project":"LitCoin-Chemical-MeSH-CHEBI","denotations":[{"id":"T1","span":{"begin":765,"end":776},"obj":"ChemicalEntity"},{"id":"T2","span":{"begin":1629,"end":1644},"obj":"ChemicalEntity"}],"attributes":[{"id":"A1","pred":"ID:","subj":"T1","obj":"C094954"},{"id":"A2","pred":"ID:","subj":"T2","obj":"D008747"},{"id":"A3","pred":"ID:","subj":"T2","obj":"http://purl.obolibrary.org/obo/CHEBI_53448"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

LitCoin-training-merged

Allie

{"project":"Allie","denotations":[{"id":"SS1_23285048_1_0","span":{"begin":99,"end":111},"obj":"expanded"},{"id":"SS2_23285048_1_0","span":{"begin":113,"end":117},"obj":"abbr"},{"id":"SS1_23285048_3_0","span":{"begin":575,"end":586},"obj":"expanded"},{"id":"SS2_23285048_3_0","span":{"begin":588,"end":590},"obj":"abbr"}],"relations":[{"id":"AE1_23285048_1_0","pred":"abbreviatedTo","subj":"SS1_23285048_1_0","obj":"SS2_23285048_1_0"},{"id":"AE1_23285048_3_0","pred":"abbreviatedTo","subj":"SS1_23285048_3_0","obj":"SS2_23285048_3_0"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

PubmedHPO

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":207,"end":212},"obj":"HP_0002664"},{"id":"T2","span":{"begin":298,"end":303},"obj":"HP_0002664"},{"id":"T3","span":{"begin":487,"end":493},"obj":"HP_0002664"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

biored-valid-deepseek-nr-ng

{"project":"biored-valid-deepseek-nr-ng","denotations":[{"id":"T1","span":{"begin":39,"end":51},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":113,"end":117},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":138,"end":143},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":315,"end":319},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":553,"end":557},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":628,"end":632},"obj":"GeneOrGeneProduct"},{"id":"T7","span":{"begin":756,"end":760},"obj":"GeneOrGeneProduct"},{"id":"T8","span":{"begin":765,"end":776},"obj":"GeneOrGeneProduct"},{"id":"T9","span":{"begin":784,"end":789},"obj":"GeneOrGeneProduct"},{"id":"T10","span":{"begin":852,"end":857},"obj":"GeneOrGeneProduct"},{"id":"T11","span":{"begin":862,"end":868},"obj":"GeneOrGeneProduct"},{"id":"T12","span":{"begin":873,"end":876},"obj":"GeneOrGeneProduct"},{"id":"T13","span":{"begin":990,"end":994},"obj":"GeneOrGeneProduct"},{"id":"T14","span":{"begin":1035,"end":1041},"obj":"GeneOrGeneProduct"},{"id":"T15","span":{"begin":1043,"end":1049},"obj":"GeneOrGeneProduct"},{"id":"T16","span":{"begin":1051,"end":1057},"obj":"GeneOrGeneProduct"},{"id":"T17","span":{"begin":1065,"end":1068},"obj":"GeneOrGeneProduct"},{"id":"T18","span":{"begin":1073,"end":1079},"obj":"GeneOrGeneProduct"},{"id":"T19","span":{"begin":1103,"end":1107},"obj":"GeneOrGeneProduct"},{"id":"T20","span":{"begin":1112,"end":1116},"obj":"GeneOrGeneProduct"},{"id":"T21","span":{"begin":1180,"end":1184},"obj":"GeneOrGeneProduct"},{"id":"T22","span":{"begin":1193,"end":1196},"obj":"GeneOrGeneProduct"},{"id":"T23","span":{"begin":1249,"end":1254},"obj":"GeneOrGeneProduct"},{"id":"T24","span":{"begin":1400,"end":1405},"obj":"GeneOrGeneProduct"},{"id":"T25","span":{"begin":1424,"end":1428},"obj":"GeneOrGeneProduct"},{"id":"T26","span":{"begin":1670,"end":1676},"obj":"GeneOrGeneProduct"}],"text":"Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.\nDelta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31(+), VE-Cadherin(+) and c-kit(+) vessel density, and also increased megakaryocytes, whereas CD105(+), VEGFR3(+), SMA(+) and lectin(+) vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b(+)), decreased B (B220(+)) and T (CD3(+)) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting."}

biored-valid

biored-valid-deepseek-nr-g

biored-valid-deepseek-r-ng

biored-valid-deepseek-r-g

biored-valid-gemini-nr-ng

biored-valid-gemini-r-ng

biored-valid-gemini-r-g

biored-valid-gpt-nr-ng

biored-valid-gpt-nr-g

biored-valid-gpt-r-ng

biored-valid-gpt-r-g

biored-valid-gemini-nr-g

biored-valid-gpt-r-m

biored-valid-gemini-r-m

biored-valid-deepseek-r-m