bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0-Related Protein Accelerates the Migration of Human Mesenchymal Stem Cells and Their Progeny by Modulating VLA-5 Interactions with Fibronectin.
Authors: Watt Suzanne M. , Roubelakis Maria , Forde Sinead , Lu Fengjuan , Tsaknakis Grigorios , Martin-Rendon Enca 
Published: April 2020

Abstract
Human mesenchymal stem cells (hMSCs) are capable of expansion, self renewal and generation of several tissues such as bone, fat and cartilage. They also generate microenviromental niche cells that regulate angiogenesis and hematopoiesis. During development and in the adult, hMSCs and their progeny migrate to specific niches where they provide support for hematopoietic cells or they play an important role in tissue regeneration, inflammatory responses and cancer surveillance. There is particular interest in understanding the molecular basis of hMSCs migration which involves numerous transmembrane receptors, cell adhesion and signaling molecules. Here, we demonstrate, for the first time, that human P0 - related protein, hPZR, has the ability to accelerate VLA-5-mediated migration of cultured hMSCs on the extracellular matrix (ECM) protein, fibronectin. This is mediated via the immunotyrosine-inhibitory motif (ITIM) sequences within the hPZR cytoplasmic domain, and the ECM ligand, since it cannot be recapitulated with the hPZR ITIM-less isoform, hPZRb, nor with other ECM components such as laminin or Type IV collagen. It is mediated by interactions with the docking phosphatase, SHP-2. The specificity of these results was confirmed by knocking-down hPZR and hPZRb using siRNA technology. We further demonstrated that hPZR clusters with VLA-5 at the leading edge of the cell, using high-resolution confocal microscopy together with immunoprecipitation and immunoblotting technologies. We propose that hPZR plays a key role in negatively regulating VLA-5 adhesion to fibronectin, a process critical for cell detachment from fibronectin and for the migration of hMSCs and their progeny.
G-CSF Induced Expansion and Mobilization of Hematopoietic Stem Cells Is Altered by the Matrix Protein Osteopontin.
Authors: Forkert Randolf , Ko Yon , Neuhaus Thomas , Gruenewald Elisabeth , Schoeneborn Silke , Vetter Hans , Stier Sebastian 
Published: April 2020

Abstract
Stem cells reside in a physical microenvironment or niche where a balance of signals controls their proliferation, differentiation and death. Components of the specialized microenvironment have generally been defined in terms of cells and signaling pathways affecting stem cell maintenance or expansion. We have defined a role for a matrix glycoprotein that provides a constraining function on hematopoietic stem cells within the bone marrow microenvironment. Osteopontin (OPN) is an abundant glycoprotein in bone that modifies primitive hematopoietic cell number and function in a stem cell non-autonomous manner. Here we analyzed the role of OPN for regulating stem cell mobilization and pool size in times of G-CSF induced marrow stress, a context close to the clinical setting of stem cell mobilization not well understood so far. Bone marrow stromal cells show an enhanced expression of OPN under stimulation with G-CSF, which prompted us to analyze the role of OPN in G-CSF mediated activation of the stem cell niche. First we treated OPN deficient mice and their wild-type littermates with G-CSF for 5 days. We could observe a significant increased stem cell fraction in the peripheral blood and in the bone marrow in the absence of OPN in comparison to the wild-type controls. To evaluate, if this effect is stroma dependent, we first transplanted wild-type bone marrow into wild-type or OPN-deficient recipients. 6 weeks after transplantation we treated these mice with G-CSF for 5 days and analyzed the peripheral blood and the bone marrow for the contents of primitive hematopoietic cells. Here we could detect a significantly increased stem cell fraction in peripheral blood and bone marrow of the OPN−/− recipients in comparison to wild type controls detected by FACS and functional in vitro stem cell assays. We then transplanted the stressed bone marrow in a competitive repopulation assay into wild-type recipients and observed a significant increase of CD45.2 cells from OPN−/− recipient mice up to 12 weeks after transplantation in comparison to wild-type controls, demonstrating an enhanced G-CSF induced expansion of hematopioetic stem cells in the OPN-deficient stem cell niche. Furthermore, we could observe an enhanced expression of Angiopoietin and N-Cadherin in OPN-deficient bone marrow stromal cells after stimulation with G-CSF in comparison to wild-type controls, supporting the stroma dependent expansion of stem cells in the absence of OPN in the G-CSF stimulated stem cell niche. Therefore, OPN is a restricting element of the stem cell niche limiting the size of the stem cell pool and may provide a dynamic mechanism by which excess stem cell expansion is prevented during times of niche stimulation. These findings may provide new insight into expansion and mobilization of hematopoietic stem cells by G-CSF mediated by components of the stem cell niche.
Large Scale Copy Number Variation Upregulates the Expression of MYB in Human T-ALL.
Authors: O’Neil Jennifer , Tchinda Joelle , Gutierrez Alejandro , Moreau Lisa , McKenna Keith , Maser Richard , Wong Kwok-Kin , Wu Wen-shu , DePinho Ronald , Chin Lynda , Lee Charles , Look A. Thomas 
Published: April 2020

Abstract
Using comparative genome hybridization (array CGH), we have discovered a small area of increased copy number on the long arm of chromosome 6 in 8 out of 20 (40%) T-ALL cell lines. The region of increased copy number is very small, containing only one gene, MYB, the cellular homolog of the avian oncogene v-myb. By performing fiber-FISH on these cell lines, we have shown that the increased copy number results from a discrete tandem duplication of the MYB gene on one allele. Although myb is a frequent target of retroviral insertional activation in screens for oncogenes whose overexpression accelerates the onset of murine T-ALL, its overexpression and increased copy number has not previously been implicated in human T-ALL. Using gene expression profiling and Western blotting, we have demonstrated that the duplication in human T-ALL results in increased levels of MYB expression. Furthermore, using quantitative PCR we have confirmed that this tandem duplication occurs in primary human T-ALL samples. In our studies to date, MYB tandem duplication and overexpression appears to occur as part of the major multistep molecular pathway in T-ALL that affects a majority of cases, in which the leukemic cells also have TAL1/SCL and LMO1/2 overexpression, and NOTCH1 gene activating mutations, together with homozygous deletion of the INK4A/ARF locus. We are currently determining the mechanism through which MYB overexpression contributes to the pathogenesis of T-ALL by siRNA knockdown in T-ALL cell lines. Our finding of MYB tandem gene duplication differs from classic forms of oncogene amplification involving double minutes or homogenously staining regions. It is possible that MYB copy number is increased through a novel somatic mechanism of allele-specific, tandem duplication of a small genomic region during the process of malignant transformation. Another possibility is suggested by recent studies documenting that inherited large-scale copy number variation (CNV) accounts for much of the phenotypic diversity within human populations. Further studies will be needed to determine whether MYB tandem duplication is present in the germline DNA of T-ALL patients, which if identified, would provide the first example of an inherited CNV functioning as a mechanism of cancer susceptibility.
Treatment of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-) Adult Acute Lymphoblastic Leukemia (ALL) According to Classical Risk Factors and Minimal Residual Disease (MRD). Interim Results of the PETHEMA ALL-AR-03 Trial.
Authors: Ribera Josep , Oriol Albert , Morgades Mireia , Sarrá Josep , Brunet Salut , Llorente Andreu , Guardia Ramon , Parody Ricardo , Bernal Teresa , Esteve Jordi , Sanz Miguel , Potro Eloy Del , Bergua Juan , Moreno Maria-Jose , Grande Carlos , Bueno Javier , Cladera Antonia , Fernández María-Carmen , García-Boyero Raimundo , Bermúdez Arancha , Feliu Evarist 
Published: April 2020

Abstract
Current therapeutic protocols for adult ALL consider MRD together with the classical risk factors (age, WBC count, immunophenotype, cytogenetics and speed in response to therapy) for treatment decisions. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the feasibility of sequential MRD detection and the response to a differentiated therapy according to MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL pts. HR ALL included one or more of the following: age 30–60 yr, WBC count &gt;25×109/L and 11q23 or MLL rearrangements. Induction therapy included VCR, DNR and PDN for 4 wk. In pts with slow cytologic response (≥ 10% blasts in BM assessed on d14) intensified induction with HD-ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including HD-MTX, HD-ARA-C and HD-ASP. Pts. with slow cytologic response on d14 or MRD level &gt;0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level &lt;0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR.
On May 2006,119 patients were evaluable (mean (SD) age 37(14) yr, 64 males, 75 precursor B-ALL, 44 T-ALL, WBC 67(87) ×109/L). Induction death 7(%), resistance 20 (%), CR 93 (78%) and MRD&lt;0.1% in 64% were observed. Early consolidation was completed in 63 patients. MRD&lt;0.05% was observed in 77% at the end of consolidation. Allo-SCT was performed in 20 pts (TRM 6, relapse 1, CCR 13) and delayed consolidation and maintenance in 38 (toxic death 2, relapse 7, CCR 29). Two-yr DFS for the whole series was 35±13%. No significant differences were observed between pts receiving chemotherapy or SCT. Slow cytologic response was associated with a lower CR. No initial variable was associated with a higher probability of MRD negativity after induction or consolidation. Neither the negativity of MRD nor the pattern of clearance of MRD were associated with a better DFS. These preliminary results suggest that in HR adult ALL pts with adequate response to induction and adequate clearance of MDR the results of late consolidation and maintenance are not hampered by avoiding allo-SCT.
Circulating Levels of Adhesion Molecules and Markers of Endothelial Dysfunction in Acute Inflammation Induced by Prolonged Brisk Exercise: Rapid Endothelial Recovery and Potential Beneficial Effects.
Authors: Papassotiriou Ioannis , Bartzeliotou Anastasia , Margeli Alexandra , Tsironi Maria , Skenderi Katerina , Bacoula Chryssa , Chrousos George 
Published: April 2020

Abstract
The “Spartathlon” ultradistance foot race (246 Km continuous, prolonged, brisk exercise for up to 36 hours) provides a unique model of prolonged duration exercise that reveals dramatic systemic inflammatory changes. In this study we investigated endothelial function of athletes participating in this extreme physical stress paradigm. The circulating levels of adhesion molecules E-, L- and P-selectins, intracellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), along with those of thrombomodulin (TM), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac troponin T, were measured before, at the end of and at 48 h postrace. The E-, L-, P-selectins were quantified in plasma with a biochip array analyzer, the Evidence® (Randox Laboratories, Crumlin, UK). The determination of soluble ICAM-1 and soluble VCAM-1 in plasma was performed on the Luminex-100 system using the multiplex assay kit Linco Human Sepsis/Apoptosis (Linco Research, Inc., Missouri, USA), TM was measured with an immunoassay technique (Euroclone Life Sciences, Pero, Italy), while NT-pro-BNP and cardiac troponin T were quantitatively determined on the Roche Elecsys 2010 immunoassay analyzer (Roche Diagnostics, Mannheim, Germany). The table summarizes the results of the study.
Levels of L- and P-selectins remained the same before and at the end of the “Spartathlon” race, but had a similar decline 48 h postrace. E-selectin, ICAM-1 and TM reached a maximum value at the end of the race and returned to normal 48 h after the race. A similar profile was observed for VCAM-1 and NT-pro-BNP, with a tendency for a decrease 48 h postrace but without reaching complete normalization. Cardiac troponin T remained below the detection limit at all time points examined. The indices of endothelial damage and dysfunction were strongly affected during exercise, with a peak at the end of the “Spartathlon” race and a return to normal 48 h later. In parallel, the indices of endothelial protection were also affected, while no evidence for myocardial damage was observed. These findings suggest that although prolonged brisk exercise activates the endothelium, the latter expresses protective molecules and rapidly recovers, possibly participating in the beneficial effects of exercise on health.
Plasma Biochemical Parameters (mean±SE) Examined in Athletes that Successfully Completed the “Spartathlon” race pre end post ND* non detectable s-VCAM-1 (ng/mL) 328.4±20.7 717.3±102.4 379.5±21.9 s-ICAM-1 (ng/mL) 107.6±12.5 137.7±18.1 107.3±12.6 s-L-selectin (ng/mL) 982.9±35.3 1008.5±51.8 870.9±34.1 s-P-selectin (ng/mL) 175.0±29.5 170.1±11.7 119.8±8.3 s-E-selectin (ng/mL) 10.3±1.0 19.2±1.5 12.1±1.0 s-TM (ng/mL) 4.0±0.3 6.9±0.7 4.5±0.2 NT-pro-BNP (ng/L) 40.1±9.6 964.6±153.9 82.1±12.1 Troponin T (μg/L) ND* ND* ND*
Tissue Factor Firmly Immobilized on Surfaces Promotes Platelet Adhesion and Fibrin Formation in Studies with Circulating Human Blood: Importance of Shear Rate Conditions and FVIIa.
Authors: Tonda Raul , Lopez-Vilchez Irene , Galan Ana M. , Navalon Fulgencio , Pino Marcos , Hernandez Rosa , Ordinas Antonio , Escolar Gines 
Published: April 2020

Abstract
While procoagulant activity of tissue factor (TF) has been widely investigated, its possible proadhesive properties towards platelets have not been studied in detail.
We explored the interaction of platelets with human TF (hTF) firmly attached to a surface using anticoagulated blood with low molecular weight heparin (20 U/ml) at different shear rates. For studies at 250 s−1 and 600 s−1, TF adsorbed on a synthetic surface was exposed to circulating blood in flat perfusion devices. Deposition of platelets and fibrin formation were evaluated by morphometric, immunocytochemical and ultrastructural methods. For experiments at 5000 s−1, we used the PFA-100™ with experimental cartridges with collagen or collagen-hTF. Effect of rFVIIa was assessed in all experimental settings. Prothrombin fragment F1+2 levels were also measured.
At 250 and 600 s−1 platelet interaction was 19.84±1.33% and 26.12±3.42% of the total surface respectively. Our inmunocytochemical results suggest that von Willebrand factor could mediate these interactions. Fibrin formation was significantly higher at 250 s−1 than at 600 s−1 (p&lt;0.05). FVIIa tended to increase platelet deposition without reaching statistical significance, and raised fibrin formation and thrombin generation (p&lt;0.05). Our At 5000 s−1, closure times in the PFA-100 were significantly shortened in the presence of hTF (154.09 ±14.69 s vs 191.45± 16.09 s with collagen alone; p&lt;0.05). Addition of rFVIIa did not result in a further reduction of closure time.
Our studies demonstrate that hTF is reactive for platelets. von Willebrand factor could mediate these interactions. Recombinant FVIIa enhances the procoagulant action of hTF at low and intermediate shear rates, but has no impact on the hemostatic performance at very elevated shear rates.
The Leech Product Saratin Is a Potent Inhibitor of Both VWF and Integrin α2β1 Binding to Collagen.
Authors: White Tara C. , Robinson David K. , Yin Hang , DeGrado William F. , Hanson Stephen R. , McCarty Owen J.T. 
Published: April 2020

Abstract
Background: Subendothelial collagen plays an important role, via both direct and indirect mechanisms, in the initiation of thrombus formation at sites of vascular injury. Collagen binds plasma von Willebrand factor (VWF), which mediates platelet recruitment to collagen under high shear. Subsequently, the direct binding of the platelet receptors GPVI and α2β1 to collagen is critical for platelet activation and stable adhesion. Hematophages, such as leeches, have evolved a number of inhibitors directed toward platelet-colagen interactions so as to prevent haemostasis in the host during haematophagy.
Objective: To elucidate the molecular mechanisms underlying the ability of the leech product saratin to inhibit platelet binding to collagen.
Results: In the presence of inhibitors of adenosine diphosphate (ADP) and thromboxane A2 (TxA2), both saratin and 6D1, a blocking α2β1 mAb, abrogated platelet adhesion to fibrillar and soluble collagen. Additionally, saratin eliminated α2β1-dependent platelet adhesion to soluble collagen in the presence of a Src kinase inhibitor. Moreover, saratin prevented platelet-rich-plasma adhesion to fibrillar collagen, a process dependent upon both α2β1 and VWF binding to collagen. Furthermore, saratin specifically inhibited the binding of the α2I-domain to collagen, and prevented platelet adhesion to collagen under flow to the same extent as observed in the presence of an anti-GPIb and anti-α2β1 mAb.
Conclusions: The present study demonstrates that saratin interferes with integrin α2β1 binding to collagen in addition to inhibiting VWF-collagen binding, presumably by binding to an overlapping epitope on collagen. This has significant implications for the use of saratin as a tool to inhibit platelet-collagen interactions.
Endothelial Microparticles and Their Binding to Leukocytes in Patients with End-Stage Renal Disease.
Authors: Zuckerman David , Hofmeyer Mark , Chirinos Julio A. , Jy Wenche , Jimenez Joaquin J. , Horstman Lawrence L. , Corrales-Medina Vicente F. , Pennel Philip , Ahn Yeon-Soong 
Published: April 2020

Abstract
Background: End-stage renal disease (ESRD) has been associated with endothelial dysfunction, a proinflammatory state and markedly increased cardiovascular risk. Endothelial microparticles (EMP) are released by activated or apoptotic endothelial cells. In vitro studies have shown that EMP can bind and activate neutrophils, suggesting that they may represent not only markers of endothelial status but also mediators of inflammation. The objectives of this study were to:
Assess the levels of free EMP and leukocyte-bound EMP in ESRD; Determine whether EMP binding to neutrophils predicts the degree of neutrophil activation in patients with ESRD.
Methods: We measured the levels of endothelial microparticles (EMP) and EMP-leukocyte conjugates in 80 patients with ESRD and 35 normal controls. We performed flow cytometry in peripheral venous blood before hemodialysis to measure (1) EMP positive for CD31 (EMP31), E-selectin (EMP62E), CD54 (EMP54); (2) EMP54- and EMP62E-leukocyte conjugates; (3) Neutrophil activation, assessed by expression of activation marker CD11b.
Results: Assessment of free EMP revealed that patients with ESRD had slightly elevated levels of free EMP54 but not of free EMP62E or EMP31. However, levels of EMP54-Lymphocyte, EMP54-Monocyte, EMP54-Neutrophil, EMP62E-Lymphocyte and EMP62E-Monocyte conjugates were clearly elevated in patients with ESRD. CD11b expression in leukocytes strongly correlated with levels of EMP54-Neutrophil conjugates (R=0.67; p&lt;0.0001) and EMP62E-Neutrophil conjugates (R=0.66; p&lt;0.0001). Furthermore, both types of conjugates independently predicted CD11b expression (adjusted p&lt;0.05).
Conclusions: ESRD is associated with increased binding of EMP to leukocytes, resulting in normal levels of some species of free EMP. Therefore, measurement of both free EMP and EMP-leukocyte conjugates is necessary for adequately assessing EMP release in ESRD. Levels of EMP bound to neutrophils strongly predict neutrophil activation, suggesting that EMP induce neutrophil activation in vivo, consistent with in vitro studies. EMP may represent important mediators of the proinflammatory state in ESRD.
EMP and EMP-Leukocyte Conjugates in ESRD patients compared to normal controls ESRD (n=80) Controls (n=35) P value IQR=Interquartile range EMP31 (IQR) 842 (484–1546) 807 (566–1240) 0.97 EMP62E (IQR) 69 (39–128) 60 (43–113) 0.96 EMP54 (IQR) 75 (33–144) 34 (18–141) 0.04 EMP54-Lymphocyte Conjugates (±SD) 1.45±0.2 1.21±0.1 &lt;0.0001 EMP54-Monocyte Conjugates (±SD) 1.77±0.6 1.27±0.3 &lt;0.0001 EMP54-Neutrophil Conjugates (±SD) 2.12±0.6 1.85±0.6 0.02 EMP62E-Lymphocyte Conjugates (±SD) 1.30±0.2 1.13±0.1 &lt;0.0001 EMP62E-Monocyte Conjugates (±SD) 1.61±0.5 1.40±0.3 0.01 EMP62E-Neutrophil Conjugates (±SD) 2.04±0.6 2.05±0.5 0.95
Blocking the SDF1/CXCR4 Axis Inhibits Marrow Derived Vasculogenesis in Cancer.
Authors: Russell Kathryn J. , Otero Jacklyn , Fu DongTao , Jorgenesen Marda L. , Scott Edward W. , Cogle Christopher R. 
Published: April 2020

Abstract
Cancer growth and metastasis depend upon a rich supply of oxygen and nutrients from blood vessels. Our previous work found that the hematopoietic stem cell (HSC) is capable of contributing to vasculogenesis in settings of physiologic repair (i.e., retinal ischemia) as well as tumor vasculogenesis. Given that the HSC and its EPC progeny can contribute to tumor vasculogenesis, we hypothesized that factors that affect leukocyte trafficking likely affect the pathologic hemangioblast activity of HSC. The SDF1/CXCR4 axis is pivotal for marrow cell homing and migration, thus was targeted in these set of experiments. To test this hypothesis, we transplanted green fluorescent protein (GFP) marrow into wild-type C57BL/6 mice and then inoculated these mice with lung cancer (LLC). An experimental cohort of mice (n=4) received intra-tumoral anti-SDF1. A control cohort included mice receiving intra-tumoral PBS (n=4). Over the ensuing 14 days, tumors in the anti-SDF1 treated group grew at a much slower rate and to a much smaller size, if at all. After 14 days of injections and tumor growth, microvessel density was markedly decreased in the anti-SDF1 cohort compared to the control cohort. Moreover, marrow-derived tumor vasculogenesis was decreased in the anti-SDF1 treated tumors compared to controls (18% of vessels with marrow-derived endothelial cells vs. 26%). As a complementary approach, we used the same transplant and tumor model, but administered anti-CXCR4 in the experimental group (n=4), compared to controls receiving PBS injections (n=4). The tumors in the anti-CXCR4 group had the same growth kinetics as the control; however, had lower tumor microvessel density and markedly decreased marrow-derived tumor vasculogenesis compared to controls (12% of vessels with marrow-derived endothelial cells vs. 26%). In conclusion, perturbing the SDF1/CXCR4 axis inhibits marrow-derived tumor vasculogenesis and may represent an excellent target for future anti-neoplastic therapy.