bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired CD163 Mediated Hemoglobin-Scavenging and Hemolytic Crisis in Patients Treated with CD33 Targeted Chemotherapy (Gemtuzumab Ozogamicin, Mylotarg™).
Authors: Maniecki Maciej B. , Hasle Henrik , Friis-Hansen Lennart , Lausen Birgitte , Nielsen Ove J. , Bendix Knud , Moestrup Soren K. , Moller Holger J. 
Published: April 2020

Abstract
Hemoglobin liberated to plasma during intravascular hemolyses is rapidly bound to haptoglobin. The hemoglobin-haptoglobin complexes undergo endocytosis through the monocyte/macrophage specific scavenger receptor for hemoglobin (CD163). This mechanism protects against oxidative and NO-scavenging adverse effects of free hemoglobin. In this study, we describe a novel syndrome of severe intravascular hemolysis and serious hemolytic crisis due to impaired hemoglobin scavenging in three acute myeloid leukemia patients following CD33-directed therapy with the immunotoxin gemtuzumab ozogamicin (GO, Mylotarg™). A synchronous high free hemoglobin, haptoglobin, and low bilirubin after septicemia-induced intravascular hemolysis indicated abrogated clearance of haptoglobin-hemoglobin complexes. This was further supported by low levels of plasma soluble CD163 and a concordant low number of CD163-expressing monocytes. We show that CD163 positive monocytes and bone marrow macrophages coexpress CD33 thus suggesting that the GO-induced cellular cytotoxicity of CD33 positive cells eradicates a significant part of the CD163 positive monocytes and macrophages. The patients had severe inflammation and serious organ failure symptoms that may be a direct effect of the persistent high level of free hemoglobin. One of the patients had a fatal outcome whereas, the other two recovered from the hemolytic episode, and the peripheral blood CD163 expression returned to normal. The risk of a serious hemolytic crisis should be considered following CD33-targeted chemotherapy. Furthermore, the cases provide circumstantial evidence of a key role of CD163 plasma hemoglobin clearance in vivo.
Heritability of Commonly Measured Blood Cell Phenotypes in the San Antonio Family Heart Study.
Authors: Viel Kevin R. , Howard Tom , Curran Joanne E. , Almasy Laura , Moses Eric K. , Glahn David C. , Ameri Afshin , John Blangero 
Published: April 2020

Abstract
Heritability (h2) indicates the extent to which genes contribute to the observed inter-individual variation in a phenotype. Traits that have a high h2 may be fruitful targets of a subsequent genome screen to identify quantitative trait loci (QTL) and the genetic variants underlying them. We have estimated the heritabilities of measurements that commonly comprise a complete blood cell count (CBC) for members of the San Antonio Family Heart Study (table). The number of white blood cells per μL of blood (WBC) was not under genetic influence (h2 = 0.160, p = 0.253), however, the individual components of the differential (lymphocyte, monocyte, and granulocyte percentage) did appear to be. Red blood cell count (RBC) had the highest heritability (h2 = 0.638, p &lt; 0.001) with both the mean corpuscular volume (MCV) and the red cell distribution width (RDW) demonstrating moderate heritability. The platelet count (Plt) and the mean platelet volume (MPV) had a mild genetic influence that was nominally significant. Currently, the fourth longitudinal examination of this cohort is in progress and to date we have measurements for 154 Mexican American subjects in 16 nuclear families. If prior recruitment rate is maintained, bivariate analyses assessing pleiotropy between traits may be available for presentation. Some of these traits have been investigated previously, but for many these are the first reported h2 estimates to our knowledge. This investigation is a necessary first step to understanding the contributions of genes to these important clinical measurements and to the elucidation of the biological pathways involved in their regulation, which may lead to improved diagnostics and therapies to treat blood cell-related disorders.
Heritabilities of commonly measured blood cell phenotypes Phenotype h2 (p-value) 1 Inverse normal transformed value WBC 0.163 (0.253) LY (%) 0.599 (&lt;0.001) MO (%) 0.603 (0.011) GR (%) 0.500 (0.004) RBC 0.638 (&lt;0.001) Hgb 0.283 (0.094) Hct 0.432 (0.023) MCV 0.476 (0.005) MCH 0.429 (0.011) MCHC1 0.249 (0.139) RDW1 0.422 (0.014) Plt 0.290 (0.013) MPV 0.298 (0.006)
Treatment Decisions for Young Women with Supra-Diaphragmatic, Limited-Stage Hodgkin Lymphoma: Exploration of Options Using a Markov Decision Analysis.
Authors: Hicks Lisa , Dent Rebecca , Meyer Ralph M. , Naimark David 
Published: April 2020

Abstract
Background: Treatment decisions for patients with limited-stage Hodgkin lymphoma (HL) involve trade-offs between combined modality therapy (CMT), which includes involved field radiation therapy (IFRT), versus ABVD alone. While CMT is associated with superior disease control, these gains must be balanced against late-effects associated with radiation, including a long-term increased risk of solid cancers. This balance may be particularly important for young women in whom IFRT would include portions of the breast, and in whom substantially increased relative risks (RR) of breast cancer have been reported. The use of a Markov decision model (MDM) may assist in evaluating the principles of this trade-off.
Methods: We developed a MDM to explore which strategy, CMT or ABVD alone, maximizes life expectancy among young women with limited-stage HL involving supraclavicular, axillary, and/or mediastinal adenopathy and whose IFRT would therefore include portions of the breast. Three base cases assessing women ages 20, 30 and 40 years at the time of HL diagnosis were evaluated. Published data on the RR of breast and other cancers following HL treatment, the risk of HL relapse with CMT and ABVD alone, expected survival with breast and other cancers, the risk of relapse following salvage HL therapy, the risk of leukemia after salvage HL therapy, and expected survival with secondary leukemia were used to populate the model. The RR of breast and other solid cancers was assumed to be negligible for the first 10 years after treatment and constant thereafter. The risk of HL relapse was assumed to be constant during the first five years post-treatment, and substantially lower thereafter. Uncertainty in critical variables was explored with deterministic sensitivity analysis.
Results: In our model, women age 20, 30, and 40 years at the time of HL diagnosis have a life expectancy of 56.1, 64.1, and 70.1 years with CMT, and 62.5, 66.1, and 69.9 years with chemotherapy alone. For women age 40 years at HL diagnosis, CMT was the favored strategy at all time points. For younger women, ABVD alone maximized life expectancy, but this benefit was manifest only &gt; 20 years after HL diagnosis. Our model was robust in one-way sensitivity analyses across a plausible range of critical variables. In two-way analyses, the model was sensitive to extreme values for the relative risk of breast cancer post-CMT, the relative risk of other cancer post-CMT, and the risk of HL relapse following ABVD alone.
Conclusions: The optimum treatment strategy for young women with limited-stage, supra-diaphragmatic HL is likely influenced by age at diagnosis. Use of a MDM may assist in evaluating the trade-offs associated with current treatment options.
Clincial Evidence That Very Small Embryonic Like (VSEL) Stem Cells Are Mobilizaed into Peripheral Blood in Patents after Stroke.
Authors: Kucia Magda , Paczkowska Edyta , Koziarska Dorota , Halasa Maciej , Safranow Krzysztof , Karbicka Anna , Nowik Marta , Nowacki Przemyslaw , Ratajczak Mariusz Z. , Machalinski Boguslaw 
Published: April 2020

Abstract
Murine bone marrow (BM) contains a mobile population of CXCR4+SSEA-1+Sca-1+lin−CD45− very small embryonic like (VSEL) stem cells (Leukemia2006:20; 857) that are mobilized into peripheral blood (PB) in SDF-1 dependent manner e.g., after pharmacological mobilization with G-CSF or in murine model of stroke (Leukemia2006:20;18). We proposed that VSEL could be potentially employed in regeneration of damaged brain or spinal cord. Since a similar population of CXCR4+CD133+CD34+SSEA-4+Oct-4+lin−CD45− cells resides also in human BM (Leukemia2007:21;297), we asked whether in humans, similarly as in mice, the stroke-related stress may trigger mobilization of these cells from BM into PB. To address this question, we evaluated a number of VSEL in 60 stroke patients and similar number of age-matched controls. The PB samples were harvested during first 24 h, day +3 and day + 7 after stroke, and compared to normal controls. The circulating VSEL in PB were evaluated by employing
RQ-PCR, FACS and direct immunofluorescence analysis.
To perform these studies, first the mRNA was extracted from circulating PB mononuclear cells (MNC) and the expression of pluripotent (e.g., Oct-4, Nanog) and neural specific markers (GFAP, Nestin, β-III-tubulin, Olig1, Olig) was evaluated by RQ-PCR. Next, the circulating PB MNC were analyzed by FACS for the presence of cells that express CXCR4+, CD133+ and CD34+ antigens. Finally, we measured the serum concentration of SDF-1 by ELISA. We found in stroke patients
an increase in total number of circulating CXCR4+D133+CD34+ cells, ∼ × 8 increase in expression of mRNA for Oct-4 and Nanog in circulating PB MNC that was subsequently confirmed by immunofluorescence staining for a presence of CXCR4+Oct-4+ cells, and increase in serum concentration of SDF-1.
Additionally, we found a positive correlation between the extensiveness of a stroke and the number of CXCR4+ VSEL circulating in PB. We conclude that the stroke triggers the mobilization of CXCR4+ VSEL. We hypothesize that these cells could have a prognostic value in stroke patients as well as use for regeneration of neural tissues. Currently, we are testing this hypothesis in the murine model of stroke.
Urokinase (uPA) Induces Endothelial Cell Survival Via the X-Linked Inhibitor of Apoptosis Protein (XIAP).
Authors: Prager Gerald W. , Brunner Patrick M. , Mihaly Judit , Koschelnick Yuri , Binder Bernd R. 
Published: April 2020

Abstract
uPA plays an important role in angiogenesis: Originally, the urokinase system has been implicated to assist the angiogenic process by it’s proteolytic properties. It is now becoming increasingly evident that uPA additionally elicits many pro-angiogenic responses like differentiation, proliferation and cell migration in a non-proteolytic fashion via induction of intracellular signal transduction. In this study we demonstrate that in endothelial cells uPA protects against apoptosis by transcriptional upregulation of inhibitor of apoptosis proteins (IAPs), among them most prominently the X-linked inhibitor of apoptosis protein (XIAP). In contrast to canonical growth factors, like vascular endothelial growth factor (VEGF), uPA elicits anti-apoptosis independently of the PI3-kinase pathway. uPA-induced cell survival is dependent on the type of extracellular matrix used indicating the involvement of integrin adhesion receptors. Thereby, uPA induces phosphorylation of the CDC42 downstream effector p21-activated kinase 1 (PAK1), which leads to IkappaB kinase alpha (IKKa) phosphorylation, a prerequisite for NFkappaB activation. Blocking NFkappaB by using the specific NFkappaB inhibitor BAY 11–7082 or by adenoviral-mediated overexpression of its inhibitor, IkB, inhibits uPA-induced XIAP expression as well as uPA-induced cell survival. Downregulating XIAP expression by small interfering RNA techniques significantly reduces cell survival efficiencies of uPA in endothelial cells. From these data we conclude that uPA activation, which is a main player in endothelial cell migration and invasion, provides an additional, PI3-kinase independent cell survival mechanism.
Cleaved Kininogen Inhibits Endothelial Progenitor Cell Differentiation by Interfering with the avb3 Integrin-MMP-2 Pathway.
Authors: Colman Robert W. , Schmuckler Noah G. , Wu Yi 
Published: April 2020

Abstract
Circulating endothelial progenitor cells (EPCs) are involved in repairing damaged vasculature and in tumor angiogenesis, thus promoting wide interest in their therapeutic potential in ischemic diseases and cancer. Cleaved high molecular weight kininogen (HKa) potently inhibits endothelial cell (EC) functions including in vivo angiogenesis. We have shown that HKa inhibits differentiation of ECs. We now test a new hypothesis that HKa can inhibit EPC differentiation by blocking matrix metalloprotease-2 (MMP-2) activation. EPCs were isolated from human blood and cultured on collagen type I-coated surface. As detected by flow cytometry and Western-blot, they expressed MMP-2 and membrane-type 1-MMP (MT1-MMP), avb3 integrin, uPAR and caveolin-1, but did not express monocyte markers such as HLA-DR and CD14. A clone-forming assay using retroviral infection indicated that an early single EPC exhibited colony forming property, but mature ECs such as human umbilical vein endothelial cells (HUVECs) did not. Upon stimulation by VEGF, EPCs, but not HUVECs, formed vacuoles and differentiated into capillary networks. Gene silencing of either MT1-MMP or MMP-2 by siRNA completely blocked the vacuole and tube formation by EPCs, suggesting that MT1-MMP and MMP-2 are both essential for differentiation of EPCs. HKa inhibited tube formation by EPCs, as well as the conversion of pro-MMP-2 to MMP-2 as a functioning concentration in the conditioned medium. CS-1 cells expressing endogenous av subunit were transfected with human b3 cDNA. We found that HKa inhibition of MMP-2 activation in these cells is dependent on avb3 heterodimer. The binding of avb3 integrin to MMP-2 was via RGD-dependent and RGD-independent mechanisms, both of which, however, were completely blocked by HKa. Further, we found that HKa inhibited the association of MMP-2 with immunoprecipitated avb3 integrin, and prevented MMP-2 localization in caveolae in EPCs. Since HKa inhibited VEGF-stimulated proliferation of EPCs but not HUVECs on collagen-coated surface, we postulate that EPCs are more sensitive than mature ECs to HKa inhibition. Thus, HKa targets EPCs and inhibits their differentiation via blocking avb3 integrin and MMP-2 interaction. These observations provide novel insight into understanding the interactions between the kallikrein-kinin system and biologic functions of EPCs.
A Chemical Genetic Screen Identified Small Molecules Modulating Zebrafish Vascular Development and Angiogenesis.
Authors: Xue Rui , Keating Armand , Wang Youdong , Stewart Duncan , Wen Xiao-Yan 
Published: April 2020

Abstract
The zebrafish has emerged as an important model for studying vascular development and angiogenesis. Advantages over other models include rapid embryonic development and optical clarity of the embryos. Abnormal angiogenesis is linked to over 70 health conditions and inhibition of angiogenesis is an excellent target for cancer therapy (including hematopoietic malignancies) as tumor growth requires new blood vessels. In this study, we performed a chemical genetic screen in developing zebrafish embryos to identify compounds that modulate zebrafish vascular development and angiogenesis. A zebrafish transgenic line with the Flk1 promoter controlling the GFP (green fluorescent protein) reporter was used. The entire vascular network of the Flk1:GFP fish was marked by GFP and could be visualized under fluorescence microscopy. Screens were performed in 96 well plates with three embryos/well. The outer membranes of healthy zebrafish embryos expressing green fluorescent vasculature were removed by enzymatic digestion with protease at the 16–18 somite stages. Small molecules/compounds were then added to the water at concentrations of 0.1 μM, 1 μM, and 5 μM for 72 hrs. After 24, 48 and 72 hrs of exposure to the compound, the embryos were visually inspected for viability, gross morphological defects, heartbeating rate and circulation. The known angiogenic inhibitor, PD173074 was used as control. An initial screening of 780 compounds in a small molecule compound library identified four small molecules with potent activities in inhibiting zebrafish vascular development. Notably, 1–5 μM of Hit #1 inhibited the growth of cranial vessels and disrupted vascular patterning, which resulted in uneven spacing between intersegmental vessels. While Hit #2 and #5 also inhibited the growth of cranial vessels, the vascular patterning remained unaffected, however, the drug-treated embryos had weak or missing intersegmental vessels. Fish embryos treated by Hit #3 had an enlarged heart and thinner vessels. Interestingly, this screen also identified one compound (Hit #4) with pro-angiogenic activity. Embryos treated with Hit #4 had increased numbers of intersegmental vessels. Hit #2 is a known inhibitor of c-Jun N-terminal kinase and angiogenesis (SP600125), was recently reported to inhibit the proliferation and migration of human endothelial cells in vitro as well as inhibit solid tumor growth in mice. This observation lends validity to the zebrafish screen and the potential utility of the other hits. Experiments are currently in progress to investigate the detailed time course of the angiogenic inhibition and the potential molecular mechanism. Studies of these angiogenic inhibitors may lead to the development of potent anti-cancer drugs while the pro-angiogenic compound may prove useful in facilitating tissue/organ regeneration. We conclude that the zebrafish model is likely to yield valuable information regarding vasculogenesis and its manipulation.
The Interaction of Platelet GPIB with the VWF-A1 Domain in Solution or Immobilized Is Regulated by the D3 Domain (A.A. 1238–1260) and the A2A3 Domains
Authors: Cruz Miguel A. , Martin Cecilia , Wu Tao , Zu Cheng 
Published: April 2020

Abstract
We have used recombinant von Willebrand factor (VWF) fragments to investigate the influence of the flanking regions of the A1 domain on the interaction with platelet glycoprotein (GP)Ibα. One fragment, the r1261–1874, represented mainly the A1A2A3 domains and the other, r1238–1874, included the C-terminal region of the D3 domain. When immobilized onto a surface, the two fragments tethered platelets similarly at high shear rates. The two fragments bound identically to immobilized fixed platelets in a ristocetin-dependent and saturable manner. In the absence of ristocetin, the r1261–1874 had a 50% of its GPIb-binding activity with the modulator while the r1238–1874 only had &lt; 5% binding activity. The r1261–1874 fragment effectively inhibited both ristocetin-induced platelet agglutination and shear-induced platelet aggregation. In contrast, the r1238–1874 failed to show an inhibitory capacity in the two assays, indicating a limited interaction with platelet GPIbα in solution. We also analyzed the single bond lifetimes in a range of constant forces of GPIbα with either the single A1 domain (a.a. 1238–1471) or the A1A2A3 fragment using atomic force microscopy (AFM). When the protein was directly adsorbed on a Petri dish, the GPIbα bound with longer lifetimes to the A1A2A3 than the isolated A1 domain, suggesting that a conformational change in the A1 is influenced by the A2A3 domains. In conclusion, the C-terminal region of D3 domain (a.a.1238–1260) and the A2A3 domains negatively regulate the binding of the A1 domain to platelet GPIbα in suspension. On the other hand, the A2A3 domains may have a positive influence on the bond formed between the GPIbα and a surface-bound A1 domain.
Delta Like 4 Expressing Bone Marrow-Derived Endothelial Progenitor Cells Regulate Tumour Angiogenesis
Authors: Real Carla , Caiado Francisco , Igreja Catia , Elias Ana P. , Borges Cristina , Duarte Antonio , Dias Sergio 
Published: April 2020

Abstract
Bone marrow-derived endothelial progenitor cells (BM-EPCs) have been implicated in adult neoangiogenesis and consequently used as therapies for human pathologies with endothelial damage. The administration of these cells in human patients temporally improves endothelial function, although the engraftment of these cells in newly formed vessels is inefficient. Conversely, therapeutic stratagies to block EPC contribution during tumor angiogenesis have been proposed. In this work, we analysed the role of the Notch/Delta signalling pathway in EPC function during tumour neoangiogenesis, by regulating the expression of Notch ligand, delta-like 4 (Dll4) in these cells. Sublethally irradiated NOD-SCID mice received WT, Dll4+/− (Dll4 heterozygous mice) or Dll4 SiRNA-treated BM-EPCs and were subcutaneously inoculated with well established Human or murine tumor xenografts. Tumours growing in Dll4-depleted EPCs transplanted mice presented increased microvessel density when compared with WT EPCs transplanted mice or non-transplanted controls, regardless of VEGF expression. Although with increased vessel number, tumours of Dll4+/− EPC transplanted mice presented increased hypoxia and decreased tumour cell proliferation, suggesting an impairment in vessel function. In addition, these tumours present a diminished expression of PDGF, a vessel stabilizing factor, and increased expression of Ang2, known as a vessel destabilizing factor. We next verified whether the vessel destabilization observed in tumors after Dll4-depleted EPCs transplant might be due to a diferential endothelial differentiation or incorporation of EPCs in the tumour vasculature. In order to answer this question we quantified the incorporation of WT and Dll4-depleted EPCs in tumour vessels. Accordingly to our results, the presence of Dll4-depleted EPCs was reduced compared to WT EPCs, suggesting that Dll4-depleted EPCs might have reduced capacity to adhere to the renewing tumor vasculature, or to the underlying basement membrane. To test this, we used an in vitro endothelial differentiation assay, and observed a defect on the adhesion of of Dll4-depleted EPCs to extracellular matrix, which was correlated with a reduced expression of integrin subunits a3 and b1. These results suggest that the reduction of Dll4 on EPCs reduces integrin expression interfering with their ability to adhere, incorporate and stabilize the tumor vasculature during tumor neoangiogenesis. Therefore, EPCs have a major role in vessel stabilization in active neoangiogenic sites by the regulation of Dll4 expression. We propose that targeting the Notch/Dll4 pathway on EPCs, modulating vessel stability, may have therapeutic potential.