bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Anticoncipient Induced Angiosarcomatosis and Disseminated Intravascular Coagulation.
Authors: Pfliegler George P. , Kovacs Erzsebet , Nemeth Hajnalka , Szollosi Zoltan , Sapy Peter , Peter Mozes , Koncsek Marta 
Published: October 2019

Abstract
A 50-year old woman presented herself with fever, hemoptoe and cough. On the basis of the clinical signs, elevated d-dimer and suggestive lung-scan, pulmonary embolism was diagnosed and low molecular weight heparin was started. Sonography, however, revealed one giant and two smaller hemangiomas in the liver and CT-scan small angiomas in the lung. Anemia, low platelet count, d-dimer positivity lead to a revision and the diagnosis of dissemniated intravascular coagulation (DIC) was set up. A sudden and severe abdominal pain, preshock, blood in the abdominal cavity indicated the rupture of the hemangioma. The ruptured hemangioma was successfully embolized. While preparing for surgical resection a subsequent bleeding developed but after the addition of rFVIIa it seized, and she became suitable for the removal of the large cavernous hemangioma. In two-month she recovered when bloody sputum reappeared, histological diagnosis from the lung was the same as that of the liver. She recovered, however, the hemangiomas both in lung and the liver were rapidly increasing, therefore a revision of histology was asked. Unfortunately before revision was completed she died from an additional major intrathoracal bleeding. Revised histology proved hemangiosarcoma. This rare and very aggressive disease is usually induced by toxic materials, e.g. vinyl-chloride, thorium dioxide or arsene. In our case her long-term estrogene therapy (from 20 to 44 yrs; subsequently restarted 4 month prior the present complaints due to gynecological bleeding) is probably responsible for the development and transformation of her hemangiomas. In patients with liver angiomas regular control (including sonography) seems to be justified, especially once they are on the pill. Therapeutic options e.g. angiogenesis inhibition by cyclooxygenase II inhibitors or peroxisome proliferator-activated receptor-gamma agonists are discussed.
Compositional Differences in the Oligosaccharide Components of Generic Versions of Enoxaparin and Dalteparin.
Authors: Jeske Walter P. , Brubaker Aleah , Hoppensteadt Debra , Walenga Jeanine M. , Ma Qing , Fareed Jawed 
Published: October 2019

Abstract
Generic versions of the low molecular weight heparins (LMWHs) enoxaparin (Sanofi-Aventis, Paris, France) and dalteparin (Pfizer Inc, NY, USA) have been developed and marketed in India and South America. Regulatory bodies in North America and Europe are evaluating generic versions of enoxaparin and dalteparin. No regulatory approval guidelines exist for these hybrid drugs which are of natural origin and exhibit structural differences due to differences in manufacturing processes. To investigate the oligosaccharide composition of enoxaparin and dalteparin, molecular profiles were compared prior to and after digestion with heparinase-1 (0.1–1.0 U/ml). Functional properties of the pre- and post-heparinase digested agents were profiled in anticoagulant, antiprotease and protease generation assays using whole blood, plasma and serpins such as antithrombin and heparin cofactor II. Additionally, protein binding profiles for both the branded and generic LMWHs were carried out using human serum albumin. At concentrations of heparinase <0.5 U/ml, significant differences in oligosaccharide composition were noted. At higher concentrations, branded and generic LMWHs showed a comparable digestion profile with the exception of differences in salt content and disaccharide formation. The branded and generic products exhibited product-dependent differences in their affinity to heparin cofactor II and antithrombin. The amount of AT affinity components ranged from 20–46% in the nondepolymerized products and was markedly reduced after depolymerization (5–15%). Protamine sulfate and platelet factor 4 titration curves were distinct for the generic versions of enoxaparin. Dalteparin and its generic version showed a stronger inhibition of thrombin generation as measured by amidolytic assay. Protein binding profile also showed measurable differences among these agents. These studies suggest that the manufacturing processes for generic versions of enoxaparin and dalteparin result in products that can be differentiated despite identical anti-Xa unit potencies and molecular profiles. Additional microstructural features such as the presence of anhydromanno groups and other anomeric transformations may also contribute to the chemical and biologic heterogeneity among the generic versions of the branded products. Therefore, besides the molecular profile, additional biologic actions and protein binding profiles can also be used to demonstrate biosimilarities of differentiation among these agents.
The Direct Factor Xa Inhibitor Apixaban Produces Broad Antithrombotic Activity with Limited Effects on Bleeding Time in Rats.
Authors: Schumacher William A. , Bostwick Jeffrey S. , Stewart Anne B. , Steinbacher Thomas E. , Pinto Donald J. , Wong Pancras C. 
Published: October 2019

Abstract
Apixaban is an oral, direct and highly selective factor Xa inhibitor which is in late stage clinical development for the prevention and treatment of thromboembolic diseases. Apixaban is potent against human and rat factor Xa (Ki = 0.08 and 1.3 nM, respectively). The efficacy/safety profile of apixaban was determined in experimental models of thrombosis and hemostasis performed in anesthetized rats. Thrombosis was induced either by topical application of FeCl2 to the vena cava (VT) or carotid artery (AT), tissue factor infusion into the vena cava (TF-VT), or within an extracorporeal arterial-venous shunt (ST). Bleeding time was measured in response to template incision of the renal cortex. Apixaban was administered as a continuous i.v. infusion of 0.1, 0.3, 1 or 3 mg/kg/h starting 60 min before each experimental procedure (n=5 or 6 per dose). These respective doses increased the ex vivo prothrombin time by 1.3, 1.9, 3.0 and 3.9 times control baseline, and achieved plasma concentrations of 0.3, 1.4, 5.0 and 12.2 μM. In comparison to vehicle treatment, the 3 mg/kg/h dose of apixaban decreased thrombus weight by 90 ± 2% in VT, 62 ± 7% in TF-VT, 62 ± 4% in AT, and 79 ± 3% in ST (all p<0.05). A 50% thrombus weight reduction sufficient to prevent vascular occlusion in each model would require projected doses (mg/kg/h) of 0.4 (VT), 1.9 (TF-VT), 0.8 (AT) and 1.1 (ST). The lowest dose level which preserved carotid blood flow at the pre-injury level during thrombus formation was 0.3 mg/kg/h. Apixaban prolonged bleeding time in a dose-dependent manner with no effect detected at 0.1 and 0.3 mg/kg/h, while significant (p<0.05) increases of 1.34 ± 0.12 and 2.13 ± 0.17 times control were observed at 1 and 3 mg/kg/h, respectively. In comparison, aspirin increased bleeding time by 1.42 ± 0.1 times control (n=7, p<0.05) when tested at a 10 mg/kg dose, a dose which produced maximum cyclooxygenase inhibition. These studies predict a wide therapeutic index for apixaban based on the prevention of occlusive thrombosis in a variety of experimental models without excessive bleeding time prolongation. These results are consistent with the safety and efficacy observed with apixaban in phase II clinical trials.
Possible Involvement of Heparin-Binding Protein in Antibody-Mediated Non-Hemolytic Transfusion Reaction.
Authors: Furuta Rika A. , Yasui Kazuta , Matsuyama Nobuki , Fukumori Yasuo , Kimura Takafumi , Hirayama Fumiya , Tani Yoshihiko , Shibata Hirotoshi 
Published: October 2019

Abstract
In antibody-mediated non-hemolytic transfusion reactions, Transfusion-Related Acute Lung Injury (TRALI) tends to occur immediately after a blood transfusion. Leukocyte antibodies or immune complexes have been frequently shown to be associated with the syndrome, although the mechanisms by which they induce TRALI are poorly understood. To explore the mechanism of TRALI, an in vitro whole blood cell culture assay was established in which cells were stimulated by human antibodies and the activation of neutrophils was monitored by a cell surface marker (Mac-1) with FCM. To identify soluble mediators that were released instantly following immune stimulation, we examined the release of soluble factors, including, Perforin, IL-6, TNF-a, and Heparin binding protein (HBP) using ELISAs. In addition, the involvement of two neutrophil FcγRs (FcγRIIIb and FcγRIIa, also known as CD16 and CD32, respectively) in release of HBP was examined during antibody-induced cell activation using anti-FcγR blocking antibodies. Substantial amounts of HBP were released within 30 min upon stimulation by human antibodies, although other soluble mediators were not released within such an eary period. Furthermore, the release of HBP was mediated via signals though both FcγRIIIb and FcγRIIa. HBP that have been known as a multifunctional molecule in early inflammation appears to be a one of the primary effector molecules of antibody-mediated non-hemolytic transfusion reactions including TRALI.
Low ADAMTS13 Activity in Clinical Remission Predicts the Risk of TTP Relapses.
Authors: Wu Haifeng M. , Casper T. Charles , Cataland Spero R. , Lin Shili , Kennedy Melanie , Jin Ming 
Published: October 2019

Abstract
Idiopathic thrombotic thrombocytopenic purpura (TTP) is a devastating disorder characterized by frequent recurrences. A predictive biomarker that allows for the early identification and intervention prior to the overt relapse of disease is needed. In the present study, the assay for ADAMTS13 activity was modified to adequately detect ADAMTS13 activity as low as 0.5%. Serial samples (n=157) collected from 24 TTP patients during periods of sustained clinical remission were then studied. These patients were followed up quarterly for an average of 23 months, during which time 9 episodes of TTP relapses from 6 patients occurred. We measured ADAMTS13 activity in these samples and then employed logistic regression modeling to evaluate the relationship between ADAMTS13 activity levels and the risk of TTP relapses. Our data demonstrated that lower ADAMTS13 activity and younger age are significantly associated with a higher probability of relapse in the 3 months following the date the specimens were taken. In contrast, ADAMTS13 antibody IgG levels are not predictive of TTP relapses. Identification of low ADAMTS13 activity during remission as a key risk factor for TTP relapses provides a new screening strategy to identify patients who may benefit from prophylactic therapy prior to disease relapses.
CD34+ Hematopoietic Progenitor Cells Express CD 184 Antigen and to a Minor Extend MMP9.
Authors: Abendroth Jens , Schmoll Hans J. , Wolf Hans-Heinrich 
Published: October 2019

Abstract
For clinical purposes the CD34 surface antigen characterises hematopoietic progenitor or stem cells (HSC) and will be measured routinely for peripheral hematopoietic stem cell transplantation (PBSCT). Concerning homing mechanisms of HSC not only the number of CD34+ cells could be important. However, there are several other characteristic surface antigens indicating proliferation. For example, the cell surface receptor CD184 has been found on CD34+ HSC and seems to be necessary for stem cell development and migration. CD184 knock-out mice are known to present insufficient hemato- and lymphopoiesis. MMP9, a gelatinase cleaving collagen typ IV, expressed on HSC, is necessary for migration and probably also for HSC engraftment. In leukapheresis products used for PBSCT we were interested in CD184 and MMP9 protease expression on CD34+ cells and their impact on homing.
Methods: 84 leukapheresis products for autologous stem cell transplantation were analysed in 65 patients. The patients suffered from oncologic (n= 45) and haematological (n=20) malignancies. There was no bone marrow infiltration found before starting leukapheresis. Expression of CD184 and MMP9 on CD34+ cells were analysed by flow cytometry. Additionally, the number of CD45+ cells was measured (BD Biosciences). Statistical analysis was run by SPSS using students t-test and Mann-Whitney-U test.
Results: 44,7% (+/− 3,1%) of CD34+ cells presented the CD184+ antigen, but MMP9+ expression was found only in 5% (+/− 1,4%) of CD34+ HSC, respectively. Regarding the patients age, sex or underlying diseases no significant differences were seen.
Discussion: High expression rate of CD184 antigen and MMP9 on CD34+ HSC could be favorable for engraftment and success of hematopoietic stem cell transplantation. Surprisingly, in our study on leukapheresis products less than half of CD34+cells were found to express CD184+ antigen, and only 5% presented MMP9 expression. As time to engraftment after PBSCT of the patients did not differ from mean values either antigen expression could develop on a further step of hematopoietic reconstitution or the patients presented an "alternative pathway" establishing hematopoiesis and immune defense mechanisms. Further studies on proliferation and differentiation mechanisms of HSC are requested.
Fetal Immune Responses Post In Utero Transplantation of Embryonic Stem Cells, Bone Marrow and Fetal Liver Hematopoietic Stem Cells.
Authors: Nedelcu Elena , Moustafa Mohamed , Srivastava Anand , Donahue Jody , Carrier Ewa 
Published: October 2019

Abstract
Introduction: We have previously shown that in utero transplanted ES cells survive and integrate into the fetus development and have established a murine model for the study of the in vivo differentiation of ES cells. The goal of this study was to monitor the fetal immune responses post in utero transplantation of ES cells, bone marrow (BM) and fetal liver (FL) hematopoietic stem cells.
Materials and Methods: Murine (MHC)-mismatched ES cells genetically engineered to express yellow fluorescent protein (YFP-ES cells) were cultured on mitomycin-treated feeder layers for four days prior to in utero transplantation (IUT) in medium containing leukemia inhibitory factor. A cell dose of 5x104 YFP-ES cells ((H-2kb) was injected intraperitoneally in the fetuses of Balb/c (H-2Kd) pregnant mice at E12- E14. BM and FL hematopoietic stem cells (H-2kb) were transplanted in utero at a dosage of 1×109 cells/kg fetal body weight into E12-E14 BALB/c fetuses (H- 2Kd). Fetal immune responses were monitored by in vitro mixed lymphocyte reaction and cytotoxicity assays performed with self (Balb/c), allogeneic ES cells, BM or FL hematopoietic cells, and 3rd party (C3H cells). Cytokine levels (IL-2, IFN-gamma, IL-4 and IL-10) were determined in the cell culture supernatants from cytotoxicity assays. Liver tissue sections were prepared from in utero transplanted fetuses and examined for the presence of lymphocytic infiltration.
Results: In utero transplantation of YFP-ES-cells did not induce tolerance in the fetuses and was associated with increased cytokine production compared with BM and FL groups. Microscopic examination of liver sections of ES cell transplanted group revealed the presence of marked inflammatory infiltrate.
Conclusions: Embryonic stem cells transplanted in utero induce fetal immune responses and increased cytokine production associated with (MHC) upregulation.
Differentiation of Mesenchymal Stem Cells from Rat Bone Marrow into Dopaminergic Neuron-Like Cells In Vitro.
Authors: Chen Li , He Dongmei , Zhang Yuan 
Published: October 2019

Abstract
Mesenchymal stem cells (MSC) from bone marrow cavity are multipotent cells. Their primary function is to support the growth and differentiation of hematologic progenitors. MSCs have been shown to differentiate into a variety of cell types including: bone, adipocytes, cartilage, neuron-like, and muscle-like cells. This project aimed to induce MSCs from rat bone marrow into mature dopamine secreting cells. MSCs were isolated from rat bone marrow, cultured and passaged. After propagating for three generations in vitro culture, MSCs were induced by epidermal growth factor, basic fibroblast growth factor and retinoic acid. After induction, morphologic change was examined by light microscope. NSE,MAP-2a, b and tyrosine hydroxylase (TH) was examined by immunocytochemistry. The related genes of the differentiated neurons, such as Nurr-1, nestin, mash-1,DR2-L,AADC and TH were detected by RT-PCR. After MSCs were inducted for 7 days,14 days and 21 days, dopamine production and release in the extract and medium of dopaminergic-induced cultured cells was assayed by dopamine ELISA. After 14 days of induction, MSC showed neuron-like morphologic changes and expressed NSE, MAP-2a, b and TH. RT-PCR. showed that these induced cells expressed nerves stem cells gene Nestin,Nurr-1 and dopamine nerves gene mash-1,DR2-L,AADC,TH. Most importantly, dopamine ELISA analysis showed the evidence of dopamine release in the extract and medium of dopaminergic-induced clonal MSCs. The results suggest that bone marrow MSCs from rat can be induced to differentiate into dopaminergic neuron-like cells in vitro. Bone marrow MSCs will provide a promising source of neural progenitor cells and may be a favorable candidate for cellular therapy of Parkinson’s disease.
α-Enolase Is the c-myc Promoter-Binding Protein.
Authors: Miller Donald M. , Campbell Hunter , Thomas Shelia D. , Sedoris Kara C. 
Published: October 2019

Abstract
Quadruplex-forming sequences occur disproportionately in the promoters of growth regulatory genes, including c-myc. These sequences appear to play important roles in the regulation of gene expression. The c-myc quadruplex-forming sequence occurs in the c-myc P1 promoter region which is responsible for more than 80% of c-myc expression. We have used proteomic techniques used to identify quadruplex-binding proteins. Two dimensional electrophoretic gels of nuclear extracts were blotted and screened with G-rich (quadruplex forming) and C-rich (control) oligonucleotides. We were surprised to observe that α-enolase binds the G-rich, but not C-rich oligonucleotide. Using electrophoretic mobility shift assays (EMSA), we confirmed that both α-enolase and its alternative translation product, MBP-1, bind quadruplex-forming oligonucleotides. We then tested the hypothesis that both α-enolase and MBP-1 may play important physiologic roles by binding the c-myc quadruplex-forming sequence. Electrophoretic mobility shift assays were used to characterize the binding of α-enolase and MBP-1 to the c-myc quadruplex-forming sequence. Binding of AS1411, a quadruplex forming oligonucleotide, was used as a control. Both α-enolase and MBP-1 demonstrated strong binding to the c-myc P2 promoter sequence (containing the quadruplex-forming sequence). A “supershift” was seen when an anti-α-enolase antibody was included in the incubation although control antibodies did not alter the EMSA pattern. The quadruplex oligonucleotide aptamer, AS1411, competed for α-enolase and MBP-1 binding to the c-myc promoter sequence. However, a nonquadruplex-forming oligonucleotide did not compete. A mutation in the c-myc quadruplex sequence abrogated binding of both α-enolase and MBP-1. In order to test the biological effect of the α-enolase/MBP-1 interaction with the c-myc promoter, we characterized the effect of constitutive overexpression of each α-enolase product, individually. Although, overexpression of MBP-1 by transfected cells resulted in down regulation of c-myc expression and induction of apoptosis, constitutive overexpression of α-enolase did not alter c-myc expression or the rate of cellular proliferation. Cells grown in low glucose medium demonstrate increased MBP-1 levels which results in decreased c-myc expression and inhibition of cellular proliferation. A similar response was seen in hypoxic cells, indicating that enolase/MBP-1 plays an important role in cellular responses to external stress. These results suggest that MBP-1 down regulates c-myc expression by simultaneous binding to the P1 and P2 promoter sequences, while α-enolase binds only the P2 sequence. This suggests a very important regulatory role for α-enolase/MBP-1 in the relationship between cellular metabolism and growth regulation. Enolase/MBP-1 quadruplex-binding likely plays an important role in regulation of c-myc expression.
Lenograstim Treatment Following Cytotoxic Therapy in Tumor Patients.
Authors: Wolf Hans-Heinrich , Krohn Ilka , Sippel Christoph , Jordan Karin , Voigt Wieland , Krueger William 
Published: October 2019

Abstract
Incidence of febrile neutropenia following cytotoxic treatment of tumor patients can be reduced by prophylactic G-CSF treatment. We report results of a prospective open non-interventional multicenter observational trial in 2233 patients on lenograstim, a recombinant glycoprotein (rHuG-CSF) expressed and glycosylated in Chinese hamster ovary cells. In total 10 846 courses of chemotherapy followed by G-CSF treatment have been documented for either hematologic or oncologic malignancies (breast and ovarian cancer 4207 courses, Hodgkin’s disease and Non Hodgkin’s lymphoma 4381 courses, lung cancer 780 courses, other malignancies 1478 courses, respectively). Lenogratim was administered either interventionally or to less amount for prophylaxis of granulocytopenia; the mean daily dosage was 263 micrograms subcutaneously. A significant number of patients were treated for stage III or IV disease. Almost 1/3 of the patients (34,2%) were elderly aged at least 65 years old. The patients had not been hospitalized for cytotoxic therapy. Lenograstim treatment was started on day 6 (median 6,8 + 4,0) of chemotherapy regimens for almost 5 days (median duration of treatment 5,2 + 3,1 days). Median leukocyte count was 1,9 × 109/L when lenograstim treatment was started, and 5,9 × 109/L at the end of lenograstim treatment, respectively. Especially supporting the CHOP regimen in lymphoma patients lenograstim was administered prophylactically: in 39,5% of lymphoma patients, but only in 24,1% of patients with gynecologic tumors lenograstim treatment was performed for at least 5 days. The rate of infection or fever reported was 9,8% (7,8% in breast cancer patients, 9,0% in lymphoma patients, respectively). 87,1% of chemotherapy courses (87,5% in lymphoma patients and 86,6% in breast cancer patients) could be performed according to the protocol initially scheduled without reduction of dosage or delay of treatment intervals. We conclude that lenograstim was feasible and efficacious for prophylaxis of neutropenic fever in chemotherapy patients. In 2/3 of the patients daily lenograstim dosage of 263 micrograms was suitable to stimulate granulocytopoiesis after conventional cytotoxic therapy within 5 days. No serious adverse events possibly related to lenograstim were reported.