bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Importance of Clinical Variables for Propensity Score Matching When Comparing Costs: The Case of ESA Treatments for Chemotherapy Induced Anemia
Authors: Polsky Daniel , Eremina Daria , Hess Gregory P. , Hill Jerrold , Hulnick Scott , Roum Adam , Whyte Joanna , Kallich Joel 
Published: April 2020

Abstract
Background: The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) are treatments for chemotherapy-induced anemia. Therapy choice depends on many factors, including cost. Previous analyses have demonstrated differences in the characteristics of patients receiving EA vs. DA. We estimated cost differences between DA and EA in patients with cancer receiving chemotherapy using a propensity score matched analysis of baseline patient characteristics with and without hemoglobin (Hb) values.
Methods: Data were extracted from electronic medical records in two US databases between January 2004 and December 2006. The study sample included 6743 patients receiving chemotherapy, with ≥ 1 visit during the study period, who received an ESA during a chemotherapy episode. Episodes of chemotherapy care were constructed using a 90 day gap in administration to identify the start and end. Patients receiving both, or neither, DA and EA during their initial chemotherapy episode, or with missing descriptive data were excluded. Drug costs were calculated from cumulative dose multiplied by 106% of the average sales price (ASP) for DA or EA. Two propensity score matches were conducted: first using variables available in administrative billing claims systems, then adding the baseline Hb test result. Regression-adjusted cost differences were estimated with and without baseline Hb, using generalized linear models.
Results: Using baseline Hb as a variable resulted in a better match of the baseline characteristics for the EA and DA treatment groups compared to the original sample or the matched sample without baseline Hb. Mean ESA costs for the original sample were $4171 for EA and $3811 for DA (mean difference: $360; P &lt;0.001, SE $99). With propensity score matching without baseline Hb, mean estimated costs were $3836 for EA and $3599 for DA (mean difference: $237; P = 0.053, SE $123). With propensity score match including baseline Hb, mean costs were $3965 for EA and $3536 for DA (mean difference: $429; P = 0.001, SE $125).
Conclusions: Addition of baseline Hb as a variable in propensity score and ESA cost models affects ESA treatment cost estimates in patients with cancer receiving chemotherapy. Cost comparisons based on observational data should use analytical methods that account for differences in clinical variables between treatment groups.
Outpatient Treatment with Intravenous Antimicrobial Therapy in Patients with Febrile Neutropenia and Hematologic Malignancies
Authors: Bellesso Marcelo , Pracchia Luis Fernando , Dias Lucia , Chamone Dalton , Dorlhiac-Llacer Pedro 
Published: April 2020

Abstract
OBJECTIVES: The purpose of this study is to evaluate outcomes like success of the initial therapy; failure of outpatient treatment and death in outpatient treatment with intravenous antimicrobial therapy in patients with febrile neutropenia (FN) and hematologic malignancies. In addition, it was compared clinics, laboratory data and Multinational Association for Supportive Care of Cancer index (MASCC) with failure of outpatient treatment and death.
PATIENTS AND METHODS: In a retrospective study we evaluated FN following chemotherapy events that were treated initially with Cefepime, with or without Teicoplanin.
RESULTS: Of the 178 FN episodes in 128 patients, it was observed success of initial therapy in 63.5% events, failure of outpatient treatment in 20.8% and death in 6.2%. In multivariate analysis, significant risks of failure of outpatient treatment were smoking (OR: 3.14, IC: 1.14 – 8.66, p=0.027) and serum creatinine &gt; 1.2mg/dL (OR: 7.97, IC: 2.19 – 28.95, p = 0.002). About death, the risk was pulse oximetry &lt; 95% (OR: 5.8, IC: 1.50 – 22.56, p = 0.011). Analyzing MASCC index, 165 events were classified as low risk and 13 as high-risk. Failure of outpatient treatment were reported in connection with 7 (53.8%) high-risk episodes and 30 (18.2%) low-risk, p=0.006. In addition, death in 7 (4.2%) lowrisk and 4 (30.8%) high-risk events, p=0.004.
CONCLUSIONS: The outpatient treatment with intravenous antibiotic was satisfactory. The risks: smoking, serum creatinine elevated and pulse oximetry should be considered in FN evaluation. It was validated MASCC index in Brazilian population.
Persistence of Human Parvovirus B19 in Multipotent Mesenchymal Stromal Cells Expressing the Erythrocyte P antigen: Implications for Transplantation
Authors: Sundin Mikael , Lindblom Anna , Örvell Claes , Barrett A. John , Sundberg Berit , Watz Emma , Wikman Agneta , Broliden Kristina , Le Blanc Katarina 
Published: April 2020

Abstract
Multipotent mesenchymal stromal cells (MSC) are used to improve the outcome of hematopoietic stem cell transplantation (HSCT) and in regenerative medicine. However, human MSC may harbor persistent viruses that may compromise their clinical benefit. Parvovirus B19, known to cause the childhood disease erythema infectiosum (“fifth disease”), can be hazardous to HSCT recipients due to development of a virus mediated severe pancytopenia. Retro spectively screened, 1 of 20 MSC from healthy donors contained B19 DNA. The donors exhibited a seroprevalence of anti-B19 IgG comparable to the reported normal level. Using flow cytometry, we found that human MSC (n=6) expressed the erythrocyte P antigen (also called globoside), reported as the B19 receptor, and Ku 80, a reported B19 co-receptor. After in vitro exposure to plasma derived from B19 viremic patients, MSC (n=3) were found positive for intracellular B19 proteins as determined by immunofluorescence. This demonstrates that MSC can be infected by B19. Further studies revealed that MSC could transmit B19 to bone marrow cells in vitro, suggesting that the virus can persist in the marrow stroma of healthy individuals. Two HSCT patients received the B19 positive MSC as treatment for graft-versus-host disease. Neither developed viremia nor symptomatic B19 infection, even though they where severely immunocompromised by means of subnormal Ig levels, low leukocyte counts and poor responses in mixed lymphocyte cultures. These results demonstrate for the first time that persistent B19 in MSC can infect hematopoietic cells and underscore the importance of monitoring B19 transmission by MSC products.
Role of Homing Regulation in Coculturing Human Cord blood–derived Mesenchymal Stem cells with CD34-Positive Cells from Umbilical Cord Blood
Authors: Lee Mark , Hong Heesun , Kim Sung Yong , Cho Yo Han , Yoon So Young 
Published: April 2020

Abstract
Background and Objectives Mesenchymal stem cells plays an important role in the hematopoietic stem cell engraftment condition with SDF-1 (CXCL12)-CXCR4 signaling and in their homing in various tissues. In this study, we evaluated that the regulation of homing efficiency for mesenchymal stem cells to support ex vivo expansion of hematopoietic stem cells from umbilical cord blood.
Methods We investigated the expression of CXCR4 and Stromal-Derived Factor-1 (SDF-1) in cocultured mesenchymal stem cell with umbilical cord blood-derived CD34-positive cell, which stimulated with granulocyte macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) cytokine.
Results In this study, we evaluated that coculturing of SDF-1+ mesenchymal stem cells with stimulated CD34+ cells significantly increased the expression of CD34, CD45, and CD19 for myeloid surface marker and intracellular CXCR4 within a few hours as compared with culturing of CD34-positive cells alone or with SDF-1− mesenchymal stem cells or untreated mesenchymal stem cells by Flow cytometre. In the result of stimulation for 48 hours with various cytokines in CD34-positive cells, CXCR4 gene and ERK-1,2 protein up-regulated, and increased in vitro migration capacity of cocultured SDF-1+ mesenchymal stem cell with CD34+ cells as examined by quantitative RT-PCR of human GAPDH. To enhance homing effect by mesenchymal stem cell, we maintained expanded mesenchymal stem cells for up to 5–10 passages with monitoring of the expression of various tissue surface antigens, such as skeletal muscle, neural, liver, and endothelial cells. SDF-1+ mesenchymal stem cells induced the homing of cellular products of stimulated cord blood-derived CD34-positive cells for 10 days. Moreover, the tranfected SDF-1+ cells with a green fluorescent protein gene using lentivirus maintained their capacities of protein release and homing in culture system. SDF-1− mesenchymal stem cells reduced CXCR4 expression in cocultured CD34-positive cells.
Conclusions: These results demonstrate that the role of the SDF-1/CXCR4 axis is an important rold in the regulation of homing and engraftment of mesenchymal and hematopoietic stem cells. SDF-1+ mesenchymal stem cells have clinical potential to regulate homing and short-term engraftment for hematopoietic stem cell transplantation.
Hypoxia Increases IL-8 Secretion of Mesenchymal Stroma Cells Affecting Migratory Capacity in An Autocrine Manner
Authors: Wobus Manja , Mueller Katrin , Ehninger Gerhard , Bornhaeuser Martin 
Published: April 2020

Abstract
Hypoxia increases IL-8 secretion of mesenchymal stroma cells affecting migratory capacity in an autocrine manner Manja Wobus, Katrin Müller, Gerhard Ehninger, Martin Bornhäuser Department of Hematology/Oncology, University Hospital Dresden, Fetscherstr. 74, 01307 Dresden, Germany Adult bone marrow-derived stem cells represent an important source of cells for regeneration and repair of a number of damaged tissues. Mesenchymal stromal cells (MSCs) give rise to the cellular components of the bone marrow microenvironment and support expansion and differentiation of hematopoeitic stem cells in the respective niche. Low oxygen tension is thought to be an integral component of the endosteal niche microenvironment. When used for therapeutic purposes, MSCs cultured in standard conditions must adapt from 21% oxygen to less than 1% oxygen in the ischemic tissue. Understanding the mechanisms by which the production of cytokines and growth factors by MSCs is regulated may represent an important way to optimize their beneficial paracrine and autocrine effects. Human primary MSCs were incubated under normoxic (20% O2) and hypoxic (0.5% O2) conditions over five days and the pattern of released cytokines in the cell culture supernatants was compared using a human cytokine array (R & D Systems). Amongst others, we found upregulated IL-8 levels under hypoxic conditions leading us to further investigation of IL-8 expression in MSCs and its role for in-vitro migration. As expected, IL-8 mRNA levels were significantly higher in hypoxic MSCs. The result of the cytokine array was confirmed by examination of secreted IL-8 in the cell culture supernatant by ELISA (PeproTech). The migration capacity was investigated in a 24-well transwell chamber assay with 8 μm pore size. Using recombinant IL-8 as a chemoattractant in the lower chamber, we detected an almost twofold enhanced MSC migration rate after 24 hours under hypoxic conditions. As a different approach to investigate the migratory capacity, we used an in-vitro scratch assay. A wound was applied to a MSC monolayer in absence or presence of IL-8 which clearly enhanced the migration of MSCs into the wound area after 24 hours. In summary, IL-8 secretion by human primary MSCs is clearly increased under hypoxic conditions. IL-8 in turn seems to be a chemotactic factor for MSCs and enhances their migratory capacity in an autocrine manner.
A Novel Mechanism Underlying the Expression Regulation of An IFN-Inducible Gene RIG-G
Authors: Lou Ye Jiang , Pan Xiao Rong , Jia Pei Min , Li Dong , Xiao Shu , Chen Sai-Juan , Chen Zhu , Tong Jian Hua 
Published: April 2020

Abstract
The RIG-G gene, originally identified due to its markedly up-regulated transcriptional expression in acute promyelocytic leukemia cell line NB4 after treament with all-trans retinoic acid (ATRA) for 72 hours, is actually a member of Interferon (IFN)-inducible genes family. It acts as an important molecular mediator of the antiproliferative activity of IFN-related pathways through upregulation of cell cycle inhibitors p21 and p27. The fact of a synergistic induction of RIG-G mRNA in NB4 cells by the treatment with ATRA and IFNs implies a possible role of RIG-G in cross-talk between these two signaling pathways. However, the mechanism underlying the expression regulation of RIG-G gene remains unknown. In this work, we show that IRF-9 and STAT2 are two basic components required for RIG-G expression, although the tyrosine phosphorylation of STAT2 could further enhance the transactivation activity of the complex of IRF-9 and STAT2 by facilitating their interaction. In addition, we demonstrate the ability of ATRA to induce IFNa synthesis and secretion along with subsequent phosphorylation of STAT2 in NB4 cells, which may not only account for the dramatic expression of RIG-G after ATRA treatment but also provide a new view of signaling cross-talk between IFNa and ATRA. Moreover, we also observe that IRF-1, a primary response gene of both IFNa and ATRA, can modulate the transcription of RIG-G in both STAT2/IRF-9 dependent and independent ways. Taken together, we report for the first time that the complex of IRF-9 and STAT2 is sufficient for RIG-G expression even without the phosphorylation, and suggest a novel mechanism, different from the classical IFN-induced JAK-STAT pathways, through which IFN modulates its target genes. Our studies regarding the transcription regulation of RIG-G gene enrich our knowledge on IFN signaling pathways and will be beneficial to further better understanding of the complexity of biological responses to IFNs.
Molecular Mechanisms Underlying the Regulation of Alternate Macrophage and Neutrophil Gene Programs by the Egr Transcription Factors
Authors: Cheng Jason X , Laslo Peter , Spooner Chauncey , Bertolino Eric , Singh Harinder 
Published: April 2020

Abstract
Cell fate determination in the hematopoietic system involves the onset and resolution of mixed lineage patterns of gene expression. Molecular mechanisms underlying the concerted activation and repression of alternate lineage genes remain to be elucidated. We have proposed a gene regulatory network for macrophage development in which the transcription factors PU.1 and the Egr’s function in a feed forward loop to activate macrophage genes. In the network, the Egr’s counteract the neutrophil regulator Gfi-1 and also repress alternate lineage genes. Using mutant alleles of Egr-1 and Egr-2 we validate the model and demonstrate that the Egr’s are required for initiating but not maintaining the repression of neutrophil genes during macrophage differentiation. Employing a PU.1−/− progenitor cell line we show that PU.1 transiently binds to and activates both macrophage and neutrophil gene promoters thereby leading to the onset of mixed lineage gene activity. While inducing macrophage cell fate determination, PU.1 remains persistently bound to macrophage gene promoters aided by the Egr’s. Surprisingly, the Egr’s displace PU.1 from neutrophil gene promoters by interacting with a co-repressor Nab-2 thereby repressing the alternate lineage program. We propose that the Egr’s have evolved to molecularly discriminate distinct sets of target genes and delineate divergent patterns of gene activity.
A Novel B220+ NK Cell Progenitor Found in the Murine Lung with Potent in Vitro NK Potential Gives Rise to Mature NK Cells with Distinct NK Cell-Surface Receptor Expression
Authors: Halim Timotheus You Fu , Takei Fumio 
Published: April 2020

Abstract
Natural Killer (NK) cells are important effector cells in innate immunity, and play a vital role in antiviral defense, tumor surveillance and modulation of the adaptive immune response. NK cells were originally believed to arise from a lin−NK1.1−CD122+ bone marrow (BM) progenitor. However, recent findings have identified NK progenitors (NKP) and distinct NK differentiation pathways in the thymus, lymph node, spleen and liver. The physiological role of these extra-BM developmental pathways remains to be determined. We hypothesized that these alternative pathways on NK development would have an impact on the generation of the phenotypic heterogeneity observed in cell-surface receptor expression and functional NK cell subsets. Here, we demonstrate the identification of a small population of cells in the lung of C57Bl/6 mice (0.02% of lung leukocytes) that have a lin−NK1.1−CD122+B220+ cell surface phenotype. These cells also show potent in vitro NK cell activity when cultured on OP-9 stromal cells with IL-7, mSCF, Flt3L and IL-15, as well as in vivo NK cell potential upon adoptive transplant into RAG-2−/− IL2Rγ−/− and NOD/SCID IL2Rγ−/− hosts. Mature NK cells (CD3−NK1.1+) derived in vitro from conventional BM NKP and lung B220+ NKP were characterized for cell-surface receptor expression after 16–18 days (figure 1, mean with SEM). Clear differences in activating and inhibitory NK cell-surface marker expression were observed between NK cells derived in vitro from conventional BM NKP and lung B220+ NKP (Ly49D p&lt;0.05, Ly49G2 p&lt;0.05, NKG2A/C/E p&lt;0.05). These findings suggest that B220+ NKP may generate phenotypically and functionally distinct NK cell types.
Figure 1: Cell-surface receptor expression on in vitro derived NK cells Figure 1:. Cell-surface receptor expression on in vitro derived NK cells
Up Regulation of transendothelial migration on Hematopoietic Progenitor Cells (HPC) and neutrophils by Leukotreine B4 (LTB4) via elevated Endothelial Permeability
Authors: Mun Yeung-Chul , Oh Soo A. , Choi Moon Young , Ahn Jee-Young , Lee Kyoung-Eun , Yoo Eun-Sun , Seong Chu-Myong 
Published: April 2020

Abstract
Backgrounds : The mechanisms on HPC mobilization by Hematopoietic growth factors seem to be multifactorial processes. Though the roles of protease (ie. NE, MMPs) and cell adhesion molecules (CAMs) seem to be important, the precise mechanisms on HPC mobilization are still unknown. LTB4 is lipid mediator derived from membrane phospholipids during the process of inflammation, and have many roles (ie; inducer of chemotaxis, the production of nitric oxide, transepithelial migration of neutrophil). The major activities of LTB4 include the recruitment and activation of leukocytes, suggesting that it has considerable functional overlap with the chemokine family of chemoattractant peptides, which also direct the recruitment of leukocytes. We previously had reported that LTB4 was able to mobilize HPC of 8.5-fold baseline within only 4 hours without significant side effects in the murine models (Blood 2005, 106;11(2):401b-402b) and LTB4 receptor and reactive oxygen species (ROS) were involved in the pathway of mobilization induced by LTB4 or G-CSF using C57BL/6 mice (Blood 2006, 108;11(2):395b, Blood 2007, 110;11(2):303B). In this study, we investigated the cellular mechanisms of HPC mobilization which was induced by LTB4.
Methods : We studied the expression of LTB4 receptors (BLT1 and BLT2) on the surface of murine HPC using RT-PCR. To elucidate the effects of LTB4 on the cells which compose the bone marrow environment for the HPC mobilization, we studied the influence of LTB4 on proliferation, transmigration, permeability, and expression of CAMs on HPC and neutrophils from C57BL/6 mice and MS5 cells, murine stromal cell line cells, and bEnd3 cells as well.
Results : Proliferations of b.End3 cell and MS-5 cell were not affected by treatment of LTB4. But, permeability of b.End3 cell monolayer were increased 1.3-fold by LTB4 treatment (100 nM) compared with control. After LTB4 treatment, transendothelial migrations of total nucleated cells (TNC) (22.2% vs 9.4%), HPC (2.7% vs 0%) and neutrophils (75.6% vs 13.6%) from the C57BL/6 mice bone marrow were increased compared with control group respectively. These effects were reversed by LTB4 receptor antagonists (ie; LTB4APA and U75302). Transendothelial migration of neutrophil was increased quickly compared with those of HPCs and total nucleated cells from the bone marrow. However, LTB4 didn’t affect on the expression of ICAM-1 and VCAM-1 of b.End3 cell, murine microvascular endothelial cell.
Conclusions : Through our data, it is suggested that transendothelial migration of HPCs and neutrophils were upregulated by LTB4 via elevated endothelial permeability. Further studies are necessary to find the molecular mechanisms on the mobilization by LTB4. Prompt mobilization by LTB4, which takes only 4 hours may be very useful in the clinic if safty profiles are completed in human.
Hematopoietic Differentiation of Human Embryonic Stem Cells in Vitro : Comparison of Three Cell Lines
Authors: Brenot Marion , Bennaceur-Griscelli Annelise , Peschanski Marc , Mitjavila-Garcia Maria Teresa 
Published: April 2020

Abstract
Human embryonic stem cells (hES) isolated from the inner cell mass of a blastocyst have the ability to self renew indefinitely while maintaining their pluripotency to differentiate into multiple cell lineages. Therefore, hES represent an important source of cells for perspective cell therapies and serve as an essential tool for fundamental research, specifically for understanding pathophysiological mechanisms of human diseases for the development of novel pharmacological drugs. The generation of hematopoietic stem cells from hES may serve as an alternative source of cells for hematopoietic reconstitution following bone marrow transplantation and an interesting approach to understand early stages of hematopoietic development which are difficult to study in human embryos. Using two different methods, we have differentiated three hES cell lines (SA01, H1 and H9) into hematopoietic cells by generating embryoid bodies and co-culturing on the murine Op9 cell line. In both experimental approaches, we obtain cells expressing CD34 and when cultured in hematopoietic conditions, SA01 and H1 cell lines differentiate into various hematopoietic lineages as demonstrated by BFU-E, CFU-GM and CFU-GEMM colony formation, whereas H9 have almost exclusively granulo-macrophage differentiation. Cells composing these hematopoietic colonies express CD45, CD11b, CD31, CD41 and CD235 and staining with May Grundwald-Giemsa demonstrate neutrophil and erythrocyte morphology. These results demonstrate the capacity of hES to differentiate into mature hematopoietic cells in vitro. Nevertheless, there exist some quantitative and qualitative differences about hematopoietic differentiation between the hES cell lines used. However, we still have to evaluate their capacity to reconstitute hematopoiesis in vivo in an immune deficient mouse model. We will also be interested in developing in vitro methods to expand these hematopoietic precursor cells derived from hES which may be used as a viable source for future cell therapy.