You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: ["Variant", "Disease", "Species", "CellLine", "Chemical", "Gene"].

Please return the output as a JSON object of the format: {"CellLine": ["hRPTEC", ...], "Chemical": ["Glucose", ...], "Disease": ["Diabetes", ...], "Gene": ["HNF-6", ...], "Species": ["Patients", ...], "Variant": ["Pro75Ala", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].

Only output the JSON object and do not include any additional text.

Abstract:

Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment. Delta-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.
{"CellLine": [], "Chemical": [], "Disease": ["tumor", "tumors"], "Gene": ["VEGF-A", "Notch1", "Angpt2", "c-kit", "CSF2", "Delta-like 4", "IGFbp3", "VEGFR3", "DHH", "FGF1", "CD3", "CD105", "IGFbp2", "lectin", "SMA", "Notch", "CD11b", "Dll4", "VE-Cadherin", "CD31", "B220", "Akt", "Erk 1/2"], "Species": ["mice"], "Variant": []}