bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety Profile of Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM) from Post-Authorization Safety Surveillance (PASS) Program.
Authors: Luu Huong , Spotts Gerald , Gajek Hartwig , Kriukov Alex , Berg Roger , Stephens Darby , Barker Kerry , Ewenstein Bruce 
Published: October 2019

Abstract
ADVATE rAHF-PFM was licensed by the FDA in 2003 and the EMEA in 2004 based on studies of previously treated patients (PTPs) with FVIII levels ≤2%. Subsequent to licensure, a PASS program was launched to document rAHF-PFM experience during the first year of routine therapy in subjects with FVIII baseline levels ≤5%, irrespective of prior FVIII exposure or inhibitor history. As of May 25, 2007, a total of 537 subjects (519 male, 2 female, 16 unreported) were enrolled. Of these 537 subjects, 67 were previously untreated or minimally treated patients (PUPs/MTPs) (≤50 exposure days [EDs]), 444 PTPs (>50 EDs), and 26 subjects had an unknown prior exposure status at study entry. Furthermore, 451 had FVIII ≤2%, 62 FVIII >2% to ≤5%, 5 FVIII >5%, 19 unreported. At enrollment, 421 reported switching from recombinant FVIII therapies (343 first generation FL-rFVIII, 38 second generation FL-rFVIII, and 12 BDD-rFVIII), and 76 from plasma-derived-FVIII (34 VWF-containing pdFVIII). Sixty-four subjects had a history of an inhibitor; 33 underwent immune tolerance induction (ITI). Age cohorts were as follows: 0–2 years (n=29), 2–16 years (n=184), and ≥16 years (n=297); 27 were unreported. A total of 417 subjects completed the one-year observation period; 42 withdrew. Twenty AEs were judged at least possibly related to rAHF-PFM; 11 (mostly inhibitors) were rated as serious. Among 387 PTPs with baseline FVIII ≤2%, 2 recurrent, low-titer (1.4 BU and 1.5 BU) and 1 de novo, low-titer (1.4 BU) inhibitors were reported, providing an interim inhibitor risk estimate of 0.78% (95% CI: 0.16–2.25%). In the remaining PTPs, 1 de novo, high-titer (23 BU) inhibitor was reported in a 60-year-old man (FVIII >5%) following surgery, and 1 de novo, low-titer (4 BU) inhibitor, which disappeared 12 months later, developed in a 4-year-old boy (baseline FVIII=5%). Two high-titer inhibitors were reported in PUPs; 1 successfully eradicated with 5 weeks of ITI using rAHF-PFM (100 IU/kg QD). Other related serious AEs included 2 allergic reactions, 1 ineffective drug response in a subject with an inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Overall, 2771 new bleeds were recorded. Annual bleed rates were 4.3 and 8.3 among subjects on prophylactic and on-demand therapy, respectively. Of 259 subjects with physician-rated prophylaxis efficacy, 91% had only excellent/good ratings. Of 369 subjects with physician-rated bleed treatment efficacy, 94% had only excellent/good ratings. Ratings were comparable among subjects with an inhibitor history. Interim PASS results indicate rAHF-PFM is safe and effective in the management of hemophilia A patients, including those typically excluded from controlled clinical trials.
Relationship between Procalcitonin Levels and Severity of DIC Induced by Bacterial Infection.
Authors: Kawasugi Kazuo , Shirasaki Ryousuke , Noguti Mizuho , Tashiro Haruko , Shirafuji Naoki 
Published: October 2019

Abstract
<Background and Methods> In the past few years, structural and functional studies have demonstrated an increasingly tight interplay between the coagulation and inflammatory systems. These studies support an important role of systemic inflammatory response syndrome (SIRS) in the development of disseminated intravascular coagulation (DIC) in these critically ill patients. Although PCT is important clinical marker, it role in the DIC process is unkown. We measured serum levels of PCT in septic patients with DIC (n=15) and acute promyelocytic leukemia (APL)-induced DIC (n=5). Serum levels of PCT were determined by the EIA (BIOMERIEMX, France).
<Results> The thrombin antithrombin complexes (TAT) levels were higher in both DIC patients as reported by others. ?Levels of PCT elevated in all patients with bacterial infection. In the septic patients with DIC, we found significant elevations of serum PCT levels (97.3±72.3 ng/ml) as compared with septic patients with non overt DIC (30.5±42.4 ng/ml). All the patients that levels of PCT increased than 100 ng/ml died. However, we did not find any difference serum levels of PCT in the APL and EB virus infected patients with DIC.
<Conclusion> These results suggest that assess of thrombin generation capacity may be helpful in the making the diagnosis in septic patients with DIC. It appears that serum levels of PCT may contribute to the severity of DIC induced bacterial infection.
Direct Interaction of G-CSF-Stimulated-Neutrophils and HUVECs Are Necessary for Production of IL-8 in Endothelial Cells.
Authors: Okamoto Yasuhiro , Watanabe Tsutomu , Onishi Toshihiro , Watanabe Hiroyoshi , Yamaki Yuni , Kodama Yuichi , Nishikawa Takuro , Tanabe Takayuki , Shinkoda Yuichi , Kawano Yoshifumi 
Published: October 2019

Abstract
Background: We previously reported that interleukin (IL)-8 increased up to 207 pg/ml in vivo after administration of granulocyte colony-stimulating factor (G-CSF) at a dose 5μg/kg for five days to mobilize peripheral blood stem cells (PBSC) in hematopoietic stem cell transplantation in cancer patients or healthy donors. Since pre-apheresis serum IL-8 levels correlated with the yield of CD34-positive cells, IL-8 production may be critical to G-CSF induced stem cell mobilization. IL-8 is known to be surged from granules of endothelial cells (EC) by stimulation of GM-CSF, however, precise mechanisms of increased production of IL-8 by G-CSF in vivo is unclear. First, in this study we examined the relationship between G-CSF and IL-8 in vitro.
Method: Peripheral blood was drawn from healthy donor with consent. Neutrophils were separated by density centrifugation method. Human umbilical vein endothelial cells (HUVECs) and G-CSF were purchased. HUVECs were cultured under serum-containing medium and stimulated by G-CSF or HUVECs were co-cultured with neutrophils. IL-8 in culture media was measured by ELISA.
Results: G-CSF alone does not increase IL-8 production in the culture medium either of neutrophils or HUVECs alone, in either short time (6 hours) or long time (up to 4 days) stimulation. However, when HUVECs were co-cultured with neutrophils, IL-8 started to increase 10 hours after starting co-culture and gradually increased up to 3000pg/ml after 4 days culture. IL-8 in co-culture media increased five fold compared to that in the single culture of HUVECs. This increased production of IL-8 was dependent on the number of neutrophils. Further, when neutrophils were pre-incubated by G-CSF at a dose 50ng/ml, IL-8 production in co-culture media increased 70 percent compared to pre-incubation without G-CSF. This increased production of IL-8 was dependent on G-CSF dose. IL-8 production remarkably decreased to 15% when HUVECs and neutrophils were cultured separately by mesh to avoid direct contact.
Conclusion: These data indicates that direct contact between HUVECs and neutrophils is necessary for production of IL-8. Some molecule(s) induced by G-CSF might play an important role in IL-8 production. The effect of stimulation by G-CSF seems less important than that of direct interaction between neutrophils and HUVECs. This correlates well to the fact that high WBC count after G-CSF administration in vivo correlates with the yield of CD34-positive cells in peripheral blood stem cells mobilization. Molecular mechanisms of interaction between HUVECs and neutrophils need to be clarified further.
β2-Glycoprotein I Is a Cofactor for t-PA-Mediated Plasminogen Activation.
Authors: Bu Chunya , Gao Lei , Xie Weidong , Zhang Jianwei , He Yuhong , Cai Guoping , McCrae Keith 
Published: October 2019

Abstract
Regulation of the conversion of plasminogen to plasmin by tissue-type plasminogen activator (t-PA) is critical in the control of fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate fibrinolysis have not been characterized. Here, we report that the abundant plasma glycoprotein, β2-glycoprotein I (β2GPI), stimulates t-PA - dependent plasminogen activation both in the fluid phase and within a fibrin gel. Moreover, depletion of β2GPI from plasma reduced the lysis of fibrin thrombi, and exogenous β2GPI enhanced the activity of t-PA in a rat arteriovenous shunt thrombosis model. β2GPI bound t-PA with high affinity (Kd ∼ 20 nM), and caused a 20-fold increase in the catalytic efficiency (kcat/Km) of t-PA - mediated conversion of Glu-plasminogen to plasmin, primarily by stimulating t-PA amidolytic activity. Structure-function analysis revealed that the region within β2GPI responsible for stimulating t-PA activity is at least partially contained within β2GPI domain V. Finally, stimulation of t-PA - mediated plasminogen activity by β2GPI was inhibited by monoclonal anti-β2GPI antibodies, as well as by anti-β2GPI antibodies from patients with antiphospholipid syndrome (APS). These findings suggest that β2GPI may be an endogenous regulator of fibrinolysis. Impairment of β2GPI-stimulated fibrinolysis by anti-β2GPI antibodies may contribute to the development of thrombosis in patients with APS.
Hepatocytes of Donor Origin in Recipients Liver, after Hematopoietic Stem Cell Transplantation in BetaThalassemia Major.
Authors: Ghavamzadeh Ardeshir , Mirzania Mehrzad , Sedighi Nahid , Yaghmaie Marjan , Kamalian Naser , Alimoghaddam Kamran , Ghaffari Seyed Hamidollah , Azimi Parisima 
Published: October 2019

Abstract
Background Bone marrow and circulating stem cells contains stem cells with the potential to differentiate into mature cells of various organs. We determined whether stem cells transformed to hepathcytes.
Methods Biopsy specimens from the liver were obtained from 11 patients who had undergone transplantation of hematopoietic stem cells from peripheral blood (8 patients) or bone marrow (3 patients). Four female patients had received transplants from a male donor and seven male patients had received transplants from a female donor.All patients had beta thalassemia major and fibrosis in biopsy specimens from the liver before hematopoietic stem-cell transplantation. Hematopoietic stem-cell engraftment was verified by short tandem repeat analysis. The biopsies were studied for the presence of donor-derived hepatocytes with the use of fluorescence in situ hybridization of interphase nuclei and immunohistochemical staining for CD45 (leukocyte common antigen), and a hepatocyte-specific antigen.
Results All 11 recipients of sex-mismatched transplants showed evidence of complete hematopoietic donor chimerism. XY-positive hepatocytes accounted for 4 to 6.7 percent of the cells in histologic sections of the biopsy specimens of female patients. These cells were detected in liver tissue as early as 1 year and as late as 8.5 year after the hematopoietic stem cell transplantation.
Conclusions Bone marrow and circulating stem cells can differentiate into mature hepatocytes in beta thalassemia major patients who undergone hematopoietic stem cell transplantation.
In Vitro Aging of Rat Mesenchymal Stem Cells.
Authors: Zhang Xiaoyan , Li Jianyong , Wu Yujie , Xia Jun , Zhang Yaping , Lu Hua 
Published: October 2019

Abstract
Background Mesenchymal stem cells (MSCs) are now used in repair medicine and transplantation because of its multipotency and immunomodulatory effect. They need in vitro expansion to get adequate number for clinical use. Human MSCs had been observed to enter senescence during in vitro culture. We evaluated that the same phenomenon existed during long term culture of rat MSCs.
Methods Bone marrow from ten male Sprague-Dawley (SD) rats (198±2.12g) were cultured and nonadherent cells were removed three days later. MSCs were identified by osteogenic differentiation and adipocytic differentiation. Cells of each passage were detected for morphology by Wright’s staining, ultrastructure by scanning electron microscope, growth curve by CCK-8 kits detection, osteogenic differentiation and von kossa staining, adipocytic differentiation and oil red staining, βgalactosidase staining, quantitative assay of p16INK4a gene.
Results Rat MSCs were Fusiform shaped or polygon. Cells were becoming flatter and bigger during passaging. More swelling endoplasmic reticulum and demyelinate mitochondrion were observed by scanning electron microscope during passaging. The proliferation of the cells slowed from the 6th passage and stopped at the 8th or 9th passage. The positive rate of βgalactosidase staining and p16INK4a gene increased in cells after 5th passage. Osteogenic and adipocytic potential were attenuated in cells after 6th passage. Conclusions MSCs enter senescence during long term culture. Their potential of proliferation and multipotency dropped.
MicroRNAs 155 and 451 as Possible Key Molecules for Human Erythroid Differentiation.
Authors: Umemura Tsukuru , Masaki Shizuka , Ohtsuka Rie , Abe Yasunobu , Muta Koichiro 
Published: October 2019

Abstract
MicroRNAs (miRNAs) are 18–25-nucleotide noncoding RNAs which play important roles for cell death, proliferation, development and differentiation. MiRNA is an important molecule to regulate genes by suppressing the translation or inducing instability of miRNAs, and is consist of the network system to regulate gene functions in combination with transcription factors. Many recent works demonstrated that some of miRNAs are playing key roles for hematopoiesis and leukemogenesis. In this study, we analyzed the expression of miRNAs(miRNA-155, miRNA-221, miRNA-223, miRNA-451) during differentiation of purified normal human eryhroid progenitors in the liquid culture system. Cells increased almost 500-folds in a number, and differentiated to benzidine-positive mature erythroblasts after days 7 to 9 which were partly red blood cells on days 12 to 14. Since mature erythroid cells loose cellular nucleic acids at the final maturation stages, we measured changes in U6 RNA contents as the internal control for assays of miRNA. Each expression levels of miRNAs were normalized using U6 RNA contents. Analyses of miRNA expressions using quantitative real-time reversetranscriptase polymerase chain reaction have shown that the expression level of miRNA-155 decreased about 200-folds from day 3 to day 12 with almost 87.5% reduction between days 3 and 5. On the other hand, the expression levels of miRNA-451 increased about 270-folds by day 12 in parallel to an increase in benzidine-positive cell numbers. To extend our observation on the up-regulation of miRNA-451 in mature blood cells, we analyzed the miRNA-451 levels in each mature blood cells (red blood cells, granulocytes, lymphocytes and monocytes, platelets) purified from normal human peripheral blood by using a density centrifugation method. miRNA-451 was expressed in red blood cells about 104 folds more than in granulocytes, about 102 folds more than in platelets. Moderate down-regulations of miRNAs 221 and 223 were observed. In conclusion, our observations suggest that the down-regulation of miRNA-155 and the up-regulation of miRNA-451 are key events for normal erythroid differentiation, and that quantitative assays of the two miRNAs may be useful tools for specifying the differentiation stage of each erythroid cells.
GATA-1 Is Functionally Involved in the Human CD11b+ Interstitial/Dermal Dendritic Cell Pathway.
Authors: Gobel Florian , Taschner Sabine , Vaculik Christine , Kumerz Mario , Waltenberger Darina , Elbe-Burger Adelheid , Strobl Herbert 
Published: October 2019

Abstract
CD34+ cord blood progenitors can develop into interstitial/dermal (int) dendritic cells (DC) and Langerhans cells (LC). IL-4 induces common progenitors to differentiate into intDC and suppresses TGF-β1-dependent LC. The transcriptional mechanisms underlying DC versus LC development remain unclear. We found that the erythroid master transcription factor GATA-1 is differentially expressed in DC subtypes: LC were negative for GATA-1. However, GATA-1 was detected in CD34+-derived intDC and the related monocyte derived DC (moDC) with late kinetics and at low expression levels compared to erythroid cells. Induced expression of GATA-1 in DC/LC precursors promoted the formation of intDC and inhibited concomitant monocyte differentiation. Interestingly, GATA-1 and PU.1 are simultaneously expressed during moDC differentiation and both synergise in CD11b expression. Additionally, GATA-1 suppressed vitamin D3 receptor expression, which is a side-effect of moDC development. Taken together, these data indicate the crucial role of GATA-1 in DC development.
Regulation of Chemerin Bioactivity by Plasma Carboxypeptidase N, Carboxypeptidase B (TAFIa) and Platelets.
Authors: Du Xiao-Yan , Zabel Brian A. , Allen Samantha J. , Handel Tracy M. , Lee Peter P. , Butcher Eugene C. , Leung Lawrence L. 
Published: October 2019

Abstract
Chemerin is a potent chemoattractant for cells that express the serpentine receptor CMKLR1 (chemokine-like receptor 1), such as plasmacytoid dendritic cells and tissue macrophages. Chemerin circulates in the blood in a relatively inactive form (prochemerin). Its chemotactic activity is unleashed following proteolytic cleavage of carboxyl-terminal amino acids by serine proteases including plasmin, factor XIIa and VIIa. Recruitment of plasmacytoid dendritic cells and macrophages by chemerin may play a role in local tissue immune and inflammatory responses. The shortest bioactive chemerin peptide NH2-YFPGQFAFS-COOH (9mer) is present in the carboxyl-terminal domain. In this work, we show that plasma carboxypeptidase N (CPN) and B (CPB or activated thrombin-activatable fibrinolysis inhibitor (TAFIa)) (30 nM) remove the C-terminal lysine (K) from YFPGQFAFSK (10mer) (200nM) and enhance the migration of CMKLR1-transfected cells by ∼16-fold. To investigate if sequential proteolysis by plasmin and carboxypeptidases can modulate the activity of chemerin peptides, we generated the carboxyl-terminal 15mer of prochemerin, NH2-YFPGQFAFSKALPRS-COOH. Plasmin cleavage (1 μM) generated a 10mer, which was further processed to 9mer by CPN or CPB (30 nM) cleavage. These sequential cleavages were paralleled by corresponding increases in chemotactic activity. At concentrations as high as 1 μM the 15 mer did not induce chemotaxis; after plasmin cleavage and conversion to 10mer, however, significant chemotactic activity was demonstrated. Treatment with CPN or CPB further enhanced this chemotactic activity. We observed a similar enhancement in bioactivity following sequential plasmin/CPN-or-CPB cleavage of full-length prochemerin. Endogenous plasma CPN supports the activation (∼2.5 fold increase in bioactivity) of plasmin-cleaved prochemerin (0.2 nM). This activation was blocked by incubating plasma with MGTA (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid), a specific CPN inhibitor. In addition, we show that platelets are a rich source of chemerin (20–30 ng of chemerin/5x108 platelets). Chemerin released from activated platelets triggers CMKLR1-transfectant chemotaxis, which was blocked by anti-chemerin antibodies. Thus, the circulating humoral factors reported here (platelets, serine proteases, and carboxypeptidases) may contribute to the regulation of chemerin bioactivity in vivo and therefore play a critical role in CMKLR1-mediated immune responses.
Hematopoiesis in Bone Marrow Regenerated from Adipose-Derived Stromal Cells.
Authors: Migita Makoto , Fujita Atsushi , Ogawa Rei , Ueda Takahiro , Fukunaga Yoshitaka , Shimada Takashi 
Published: October 2019

Abstract
Background: Adipose-derived stromal cells (ASCs) are highly promising cells for tissue engineering because of their pluripotency and low donor morbidity. We have previously shown that ASCs differentiate into a variety of mesenchymal tissues including bone and bone marrow (BM) like architecture. Osteoblastic cells lining the endosteal surface are a key component of the hematopoietic niche to promote and regulate hematopoietic stem cells (HSCs). In the present study, we investigated whether ASCs derived BM can functionally support hematopoiesis.
Methods: ASCs were isolated from the inguinal fat pads from C57/BL6 mice (Ly5.2) after collagenase treatment and were cultured for three passages in the culture plates. The attached cells were trypsinized and replated onto a hydoxyapatite (HA) scaffold with numerous small pores for 3 days. The scaffold with attached cells was implanted subcutaneously onto the back of C57/BL6 recipient mice. 4.0×105 Lineage negative (Lin-) Ly5.1 BM cells transduced with a lentiviral vector containing the luciferase (Luc) gene were intravenously administered into the recipient mice after lethal irradiation. After 8 weeks, the scaffolds including Luc+ cells were removed and re-transplanted to the lethally irradiated second recipient mice.
Results: Excised HA scaffolds were totally covered with adipose tissues. Hematoxylin-eosin staining showed that microspores were filled with typical bone marrow architecture composed of adipocytes, vasculatures, stroma, and a variety of hematopoietic cells. In vivo bioluminescence imaging showed that Luc+ hematopoitic cells were detected in the scaffolds in the secondary transplanted mice for at least 6 months after transplantation. Bioluminescence signals were also detectable on the whole body including the head, extremities, chest, and abdomen after G-CSF injection.
Conclusions: We demonstrated that BM could be regenerated by ASCs. The ASCs derived BM were capable of maintenance of hematopoietic progenitor cells in vivo. BM regeneration from non-BM cells raises new possibilities to treat various hematopoietic diseases.