bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clopidogrel Resistance and Aspirin Resistance - a Cause of Coronary Artery Stent Thrombosis?.
Authors: Klamroth Robert , Hoffmann Stefan , Andresen Dietrich , Landgraf Helmut 
Published: October 2019

Abstract
Background: Occlusions of coronary artery stents are a seldom but often fatal complication after coronary artery intervention. With aggressive platelet inhibition therapy (combination of Aspirin (ASS) and clopidogrel) a reduction of stent thrombosis to less than 2% was achieved. The inhibition of platelet function has great interindividual variability and resistance against ASS and/or clopidogrel were previously described. Therefore we studied the relation between coronary artery stent thrombosis and insufficient inhibition of platelet function in patients after coronary artery intervention.
Methods: Between 2000 and 2003 we examined 20 patients (pts) with coronary artery stent thrombosis within 4 weeks after coronary artery intervention. All patients received a clopidogrel loading dose of 300mg followed by 75mg/die and ASS 100mg/die. Platelet inhibition was studied by light transmittance aggregometry in platelet rich plasma (Aggregometer PAP 4, moelab inc.). Aggregation was recorded as the maximum percentage change in light transmittance from baseline using platelet poor plasma as a reference. We defined ASS resistance as platelet aggregation > 30% after induction with 0,5mg/ml arachidonic acid and clopidogrel resistance as platelet aggregation > 30% after induction with 20 μmol ADP. We compared these pts with 20 pts without stent thrombosis within 4 weeks after coronary artery intervention.
Results: In the group with coronary artery stent thrombosis we found 13/20 patients with insufficient platelet inhibition. 2/20 pts in this group were resistent against both ASS and clopidogrel. In 2/20 pts we observed ASS resistance and in 9/20 pts clopidgrel resistance. In the group of patients without stent thrombosis we found only 1/20 pt with ASS resistance and 1/20 pt with clopidogrel resistance.
Conclusions: Insufficient platelet inhibition could be one cause of early stent thrombosis after coronory artery intervention. Platelet function testing is able to detect insufficient platelet inhibition and early testing could be an instrument to prevent coronary artery stent thrombosis.
Down Regulation of Inflammatory Markers after Treatment with Topically Administered Mucopolysaccharide Polysulfate.
Authors: Raake Wolfram , Hoppensteadt Debra , Schultz Christopher , Neville Brian , Fareed Jawed 
Published: October 2019

Abstract
Mucopolysaccharide polysulfate (MPS) represents a mammalian tracheal preparation, which mimics many of the properties of heparins including its anti-inflammatory actions. MPS is used topically for the treatment of inflammatory disorders. This study was designed to test the hypothesis that topical administration of MPS mobilizes many substances to mediate its therapeutic effects. A group of four non-human primates (Macaca Mulatta) were administered 4.5% MPS ointment in a dosage of 45 mg/kg, another four monkeys were administered placebo ointment at a dosage of 1.0 g/kg for 10 days. Citrated blood samples were drawn at baseline, 2, 4, 8 and 24 hours on days 1, 2, 5, 7 and 10. Markers of inflammation including thrombin activatable fibrinolytic inhibitor (TAFI), C-reactive protein (CRP), CD-40 Ligand (CD-40L), plasminogen activator inhibitor (PAI-1) and monocyte chemotactic protein (MCP-1) utilizing ELISA based methods, were used to measure the anti-inflammatory response. In the MPS treated group, a down regulation of all of these markers was observed over the 10 day period. CRP (baseline, 10.2 ±3.6; day 10, 5.1 ± 2.4 μg/ml), CD-40L (baseline, 298 ± 52; day 10, 138 ± 38 pg/ml) and MCP-1 (baseline, 350 ±68; day 10, 178 ± 42 pg/ml) showed a 50% decrease in the levels of these markers at day 10 in comparison to baseline. The PAI-1 (baseline, 65.1 ±21.2; day 10, 48.2 ±12.1 ng/ml) and TAFI (baseline, 138 ±25; day 10, 99 ± 12 % NHP) levels showed a slightly lesser effect. These results suggest that the topical administration of MPS leads to a decrease in the markers of inflammation that may result in promotion of the healing of inflammatory lesions.
The Risk of Deep Venous Thrombosis and Sepsis in Cancer Patients Due to PICC Lines.
Authors: Lin Lee , Walker Stanley 
Published: October 2019

Abstract
Context
Upper extremity deep venous thrombosis (DVT) represents 8–10% of total DVT of the limb. Long term central venous catheters represent a major cause of upper extremity DVT, especially in cancer patients. This study looks specifically at the risk posed by peripherally inserted central catheters (PICC).
Purpose of the Study:
To assess the risk of DVT and sepsis due to PICC lines in cancer patients as compared to non-cancer patients. Furthermore, to assess the risk of PICC line related DVT and sepsis among different cancer types.
Design, Setting, and Patients:
Retrospective chart review of all 190 patients (representing n=244 procedures) who had undergone a PICC line procedure in Union Memorial Hospital (Baltimore, MD) from August 2003 to December 2003. Based on their medical records, it was determined whether or not the patient had experienced PICC line related sepsis or thrombosis. Cancer as a potential risk factor was included in the information collected. 33 of 190 patients were cancer patients. Average patient age 56.7 years.
Results:
Preliminary results show that from August 1, 2003 to December 5, 2003, among the non-cancer patients 6 (3.8%) patients with DVT and 6 (3.8%) patients with sepsis were identified. Among the cancer patients, 3 (9.1%) patients with DVT and 3 (9.1%) patients with sepsis were identified. Though cancer patients made up only 17.4% of the patient population, they represented 33.3% of the cases of DVT and sepsis.
Conclusion:
Cancer patients are at a greater risk of thromboses and sepsis due to PICC lines as compared to non-cancer patients. Cancer patients, therefore, represent a unique population of PICC line patients who may require a different protocol of prophylaxis and complication prevention. While different types of cancers may pose different levels of risk (Sorensen et al), this could not be determined with confidence with the preliminary findings due to the small population evaluated so far.
Non-cancer patients
Cancer patients
DVT 6 3.8% Sepsis 6 3.8% DVT 3 9.1% Sepsis 3 9.1%
MUTZ-3, a Human Cell Line Modell for Osteoclast Differenziation.
Authors: Berardi Anna C. , Parafioriti Antonina , Bottazzo Ginfranco , Ciraci Elisa 
Published: October 2019

Abstract
No human myeloid leukemia-derived cell lines possess the ability to acquire a osteoclstic cell phenotype. In contrast, the CD34+ human acute myeloid leukemia cell line MUTZ-3 responds to macrophage-colony-stimulating-factor (M-CSF), receptor activator NF-kB ligand (RANK-L) and tumor necrosis factor-a (TNF-a), cytokines known to be pivotal both in vivo and in vitro for osteoclasts generation from monocytes and CD34+ stem cells. In all respects, MUTZ-3 cells behave as the immortalized equivalent of CD34+ osteoclasts precursors. Upon stimulation with specific cytokine cocktails, they formed numerous multinucleated osteoclasts expressing tartrate resistent acid phosphatase (TRAP) and calcitonin receptors (CTR) within 12 days of culture. MUTZ-3-osteoclasts formed extensive lacunae mineral resorption when cultured on mineralized surface after 21 day of cultures. These findings demonstrate the unique suitability of MUTZ-3 cells as an unlimited source of human CD34+ osteoclasts progenitors for the study of cytokine-induced osteoclast differentiation.
Ex Vivo Expansion of Mobilized Peripheral Blood Myeloid Progenitor Cells: Pretreated Patients vs Normal Donors.
Authors: De Bruyn Cécile , Delforge Alain , Bron Dominique 
Published: October 2019

Abstract
Background: Additional infusion of ex vivo differentiated myeloid progenitor may reduce or abrogate severe neutropenia following high-dose chemotherapy and peripheral blood (PB) transplantation. Normal HPC as well as HPC from patients in clinical remission can be used as source of cells. The aims of our study were to compare the ex vivo expansion of myeloid progenitor cells starting from pretreated patients (PP) and normal donors (ND) and to evaluate if the cells collected from poor mobilizers -for which the ex vivo expansion is particularly interesting- present similar ex vivo expansion capacities than cells from good mobilizers.
Methods: In this study, 11 normal donors (ND) and 17 patients (PP) were evaluated (5 NHL, 2 HK, 3 MM, 3 lymphoma, 1AML, 1 CLL and 2 solid tumor). The CD34+ cells were plated for 7 days in serum-free medium with SCF, IL-3, G-CSF and FLT3- ligand. The expression of CD34, CD13, CD15 and CD16 Ags and the presence of primary (myeloperoxydase, MPO) and secondary granules (lactoferrin, LF) were used to evaluate maturation into myeloid lineage. Functional capacities of the ex vivo generated cells were also analysed using oxydative burst activity and clonogenic capacities (CFU-GM).
Results: (1) the proliferation capacities of total leucocytes were higher in ND than in PP (28.8±5.6 vs 17.2±4.0 fold, p<0.04) with a comparable CD34+ cell expansion (8.7±3.0 vs 7.8±2.7 fold, NS); (2) in patients, 65.3±5.8% of the expanded cells were CD13+ and 23.2±4.1% remained CD34+ with 7.8±2.5 % of immature CD34+CD13− cells; these results were similar to that observed in ND (72.7±7.5% CD13+, 23.0±5.3% CD34+, 9.0±3.2% CD34+CD13−); (3) the number of myeloid progenitors produced per seeded CD34+ cell consisted of 19.0±3.7 CD13+, 11.8±3.7 CD15+, 10.2±3.2 CD16+ and 15.4±4.4 MPO+/LF+cells in PP and 25.3±5.4 CD13+, 12.5±3.8 CD15+, 7.6±2.1 CD16+ and 21.7±7.2 MPO+/LF+ cells in ND (NS); (4) these cells, essentially promyelocytes and metamyelocytes, were able to proliferate in clonogenic assay and presented oxydative burst activity; (5) we failed to observe a correlation between the cell expansions (total leucocytes, CD34+ cells and myeloid progenitor cells) and the diagnosis; (6) no correlation was observed between the mobilization of CD34+ cells into PB and the capacities of cells to be expanded in vitro.
Conclusions: in our culture system, the generation of cells committed to the myeloid lineage from CD34+ cells is feasible from ND as well as from PP, whatever is the diagnosis. The ex vivo expanded cell population consisted of cells at all stages of differentiation including immature hematopoietic progenitors. The mobilisation rate doesn’t correlate with the proliferative capacities of cells, suggesting that ex vivo expansion can be performed even in subjects with poor mobilization.
Regulated Expression of Activated Notch 1 during Embryonic Stem Cell Differentiation Preserves Multipotential Progenitors and Promotes Erythroid Cell Fate.
Authors: Ganapati Uma , Bui Lynne A. , Lynch Maureen , Dolezal Milana , Tan Hongying Tina , deVos Sven , Gasson Judith C. 
Published: October 2019

Abstract
Hematopoietic stem cells pass sequentially through a series of developmental decision points regulating self-renewal and lineage-specific differentiation. In normal hematopoiesis proliferation is tightly linked to differentiation in ways that are poorly understood. The Notch gene family has been shown to be evolutionarily conserved and to play an important role in determining cell fate, survival, and proliferation in multiple organisms. Numerous in vitro and in vivo studies strongly support a role for Notch signaling in the regulation of stem cell signaling and hematopoiesis. To define the function of Notch in the earliest stages of hematopoiesis, a Tetracycline-inducible system regulating expression of a ligand-independent, constitutively active form of Notch1 was introduced into murine E14Tg2a embryonic stem cells. (Era and Witte, PNAS, 97;1737–1742,2000). During co-culture, OP9 stromal cells induce the embryonic stem cells to differentiate first to hemangioblasts and subsequently to hematopoietic cells. Our studies indicate that activation of Notch signaling in flk+ hemangioblasts dramatically reduces their proliferative capacity without inducing apoptosis. Furthermore, Notch1 activation significantly reduces the levels of hematopoietic stem cell markers CD34, c-Kit and the myeloid marker CD11b. These reversible effects suggest that Notch signaling maintains the hemangioblasts in an immature state and blocks hematopoietic differentiation. When activated Notch is induced in committed hematopoietic progenitors, a shift towards definitive erythroid differentiation and decreased myeloid differentiation is observed. Microarray analysis of day8 hematopoietic progenitors following Notch activation in hemangioblasts indicates upregulation of known downstream targets of Notch signaling. Based on these results, we propose that Notch signaling plays a critical role in the earliest events regulating hematopoiesis.
Implication of HIF-1α but Not HIF-2α in the Hypoxic Response of Human Hematopoietic Progenitors.
Authors: Zhang Yanyan , Foudi Adlen , Berthebaud Magali , Buet Dorothee , Jarrier Peggy , Vainchenker William , Louache Fawzia 
Published: October 2019

Abstract
Maturing hematopoietic cells are exposed to hypoxia as they develop and migrate within the bone marrow microenvironment. Previous studies using non hematopoietic cell lines and monocytes showed that CXCR4 is strongly induced by hypoxia but little is known on the regulation of CXCR4 by hypoxia in the other hematopoietic cells and during hematopoietic development. We analyzed the expression and regulation of hypoxia-inducible transcription factor-1a (HIF1a) and 2a (HIF2a), the master regulators of metabolic adaptation to hypoxia, during hematopoiesis. Real time quantitative RT-PCR showed that HIF-1a mRNA was present on all the non hematopoietic and hematopoietic cells lines including HL-60, HEL, TF1, K562, KG1, U937, Jurkat and Mo7e. In contrast, HIF-2a mRNA expression was variable among the cell lines and was detected only at very low level in some cells such as KG1, Jurkat and HEL. Hypoxia exposure rapidly induced VEGF mRNA expression in the cells that expressed HIF-1a mRNA and exhibited HIF-1a protein accumulation. Interestingly, CXCR4 induction was observed only in the cells that exhibit significant expression of HIF-2a mRNA and HIF-2a protein accumulation. A strong correlation between HIF-2a mRNA levels and the induction of CXCR4 mRNA expression by hypoxia was found. Human CD34+ cells also expressed high levels of HIF-1a mRNA, whereas HIF-2a mRNA was barely detected. Interestingly, as observed for several myeloid cell lines, CD34+ cells exhibited a strong induction of VEGF expression in response to hypoxia and hypoxia mimetic agents cobalt chloride and desferrrioxamine whereas CXCR4 receptor expression was not induced suggesting that CXCR4 mRNA induction is related to the expression of HIF-2a. Altogether these data indicated that the hypoxic responses of human hematopoietic progenitors are independent of HIF-2a. Moreover, they establish that CXCR4 regulation by hypoxia is linked to HIF-2a protein expression.
An SCL +19 Core Enhancer Targets Three Mesoderm-Derived Cell Lineages - Blood, Endothelium and Smooth Muscle.
Authors: Silberstein Lev , Sanchez Maria Jose , Socolovsky Merav , Hoffman Gary J. , Piltz Sandie , Bowen Mark , Green Anthony R. , Gottgens Berthold 
Published: October 2019

Abstract
The stem cell leukaemia (SCL) gene encodes a basic helix-loop-helix transcription factor with a critical role in normal haematopoiesis and angiogenesis. The SCL gene is normally expressed in haematopoietic stem cells, mast cells, megakaryocytes, endothelium and smooth muscle. Aberrant expression of the SCL gene leads to T-cell acute lymphoblastic leukaemia, whereas SCL−/− mice die due to the absence of haematopoiesis. Hence, temporal and spatial regulation of SCL expression is essential. Our laboratory has previously characterised a 5.5 kb enhancer located 3′ of the SCL transcription start site, which is capable of targeting expression of b-galactozidase (LacZ) reporter gene to haematopoietic stem cells in the foetal liver and the bone marrow, as well as embryonic endothelium. Subsequent experiments showed that a 641-base pair core enhancer gave an identical pattern of lacZ expression in the embryo. However, it was unclear if the same element (later referred to as +19 core enhancer) was capable of maintaining reporter gene expression into the adulthood, since no lacZ activity was observed in postnatal mice. Using a transgenic construct containing a eukaryotic reporter gene, human placental alkaline phosphatase, we show that in the haematopoietic system, the +19 core enhancer is sufficient to target foetal liver and bone marrow HSCs, as well as mast cells and megakaryocytes. In the erythroid lineage, the enhancer is active only during the earlier stages of erythropoiesis, despite high level of SCL expression throughout erythroblast maturation, suggesting that an additional element is likely to be required to maintain SCL expression. The enhancer also targets embryonic and adult endothelium, together with vascular and visceral smooth muscle. Taken together, our results demonstrate that the 641-bp +19 core enhancer is sufficient to integrate signals upstream of SCL in blood, endothelium and smooth muscle. Our data also suggest that developmental relationship between these three mesoderm-derived lineages could be defined through a common transcriptional environment, and indicate that SCL may play a wider role in mesodermal development than previously thought.
Interaction of AF4 Wildtype and AF4•MLL Fusion Protein with SIAH Proteins: Indication for T(4;11) Pathobiology?.
Authors: Bursen Adelheid , Sven Moritz , Anne Gaussmann , Theo Dingermann , Rolf Marschalek 
Published: October 2019

Abstract
The human AF4 gene (4q21) is recurrently involved in recipro cal translocations to the MLL gene (11q23), correlated with high-risk acute lymphoblastic leukemia (ALL) in infants and early childhood. The t(4;11) translocation is one of the most frequent MLL translocations known today. In general, MLL translocations are the result of an illegitimate recombination process leading to reciprocal fusions of unrelated translocation partner (TP) genes with the MLL gene. Due to the constant presence of the derivative(11) product, the hypothesis was posed that only MLL•TP fusion genes are responsible for the leukemogenic process. This concept has been successfully tested for some known MLL fusions, while some other MLL fusions failed. Here, we demonstrate growth transforming potential of AF4 wildtype and the AF4•MLL fusion protein. The underlying oncogenic mechanism involves the two E3 ubiquitin ligases SIAH1 and SIAH2, the N-terminal portion of AF4 and the protection of the AF4•MLL fusion protein against proteosomal degradation. Supported by grant Ma 1786/4-1 from the DFG.
Shared and Differential Gene Expression Profiles between Anaplastic Large Cell Lymphoma and Hodgkin Lymphoma Revealed by Supervised Clustering Analyses.
Authors: Maesako Yoshitomo , Nishikori Momoko , Ohno Hitoshi , Uchiyama Takashi 
Published: October 2019

Abstract
Although anaplastic large cell lymphoma (ALCL) and Hodgkin’s lymphoma (HL) are distinctive disease entities, there is a considerable overlap in morphological and immunophenotypical features between the two lymphoma subtypes. We performed a supervised clustering analysis comparing gene expression profiles of ALCL/HL cell lines with those of a variety of B-cell tumor cell lines. The result showed that the genes, expressions of which in the ALCL/HL cluster were lower than those in B-cell tumors, included a set of genes for protein tyrosine kinases. It is suggested that in ALCL/HL, genes encoding for signal transduction molecules downstream of T- and B- cell receptor are down-regulated, even though both diseases are of lymphoid cell origin. On the other hand, we found a total of 21 genes whose expressions were shared with ALCL and HL, including JUN, ems 1 oncogene (EMS1), cyclin-dependent kinase 6 (CDK6), and integrin alpha 4 (ITGA4). We next performed a second supervised clustering to effectively separate ALCL and HL. Of 87 genes differentially expressed between ALCL and HL, 54 genes were expressed to a higher degree in ALCL than HL, whereas expression levels of 33 genes were higher in HL than ALCL. The ALCL-associated genes included cdk inhibitors, p19INK4d and p21WAF1/CIP1, suggesting that genes involved in cell cycle-regulating pathways are differentially expressed between ALCL and HL. Our study provided potentially interesting molecules that can account for the similarity and difference of ALCL and HL.
GATA1 Mutations in Clonal Disorders of Children with and without Down Syndrome.
Authors: Magalhaes Isis Q. , Splendore Alessandra , Emerenciano Mariana , Ferrari Iris , Pombo-de-Oliveira Maria S. 
Published: October 2019

Abstract
Down Syndrome (DS) children are 10–20 times folder likely to develop acute leukemia (AL) within the first four years of life compared to general pediatric population. Recently acquired somatic mutations in GATA1 gene on chromosome X have been described in most cases of DS AML and congenital TMD of DS carry the same type of mutations in exon 2 of GATA1. Here we report the preliminary results of GATA1 mutation in AL with and without DS children. The aim of this study is to provide insights in the relationships of GATA1 mutations and trisomy 21 in leukemogenesis process. GATA1 mutations were assayed in genomic DNA in 34 children with DS and AL, 2 with transient myeloproliferative disorder (TMD), 3 with myelodisplastic syndrome. Sequential sample including 2 pre-diagnosis in neonate period and 1 year before diagnosis were available in two children and 40 randomly selected DS children without known hematological disorder. A rare case of a non-DS neonate with TMD and clonal trisomy 21 were also examined. Genomic DNA was extracted and the exon 2 of GATA1 was PCR amplified as described by Wechsler et al. PCR products were sequenced in both directions and analyzed in a MegaBACE 1000 automated sequencer. Presently, GATA 1 mutations were found in 7 cases of AL, in all TMD cases with DS and none MDS case of DS. Interesting, a neonate girl with no phenotypic features of DS, but TMD features whose karyotype revealed 47, XX, +21/46, XX mosaics. A G-to-T transversion was detected which is predicted to result in a premature stop codon (c.119G>T; p.Glu67X) at the time of onset of TMD. However this same mutation was not detcted at 5 years of age.To our knowledge, this is the first reported case of TMD without DS with a detected GATA1 mutation. The presence of both somatically acquired abnormalities probably confers a proliferative advantage to the cell, resulting in TMD. We postulated in this case that both genetic abnormalities were temporary because of the non self-renewing nature of the progenitor that first had a non-disjunction event and this progenitor and the proliferative clone eventually disappeared. Therefore, even the proliferative advantage that the combination of trisomy 21 and GATA1 mutation confer, maintenance of these genetic changes are necessary for full leukemic transformation and persistence.