bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibrinokinetic Deficit in Chronic Kidney Disease and End Stage Renal Disease Patients Contributes to the Hemostatic Abnormalities
Authors: Adiguzel Cafer , Bansal Vinod , Cunanan Josephine , Litinas Evangelos , Hoppensteadt Debra , Fareed Jawed 
Published: April 2020

Abstract
An increase in bleeding is observed in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) despite the normal coagulation profile and fibrinogen level. The hemostatic deficit in these patients may due to the defects in fibrin formation. The fibrinokinetic profile of CKD (n=50) and ESRD patients on hemodialysis prior to and after dialysis was measured. Citrated plasma from each patient was supplemented with 25 μl of 5 U thrombin and 25 μl of 0.05 M CaCl. The rate of fibrin formation was measured by monitoring the optical density (OD) at 405 nM. After reaching steady state, 50 μl of urokinase (30,000 U/ml) was added to measure the fibrinolytic profile. Forty normal male and female individuals were also analyzed. In addition PT, aPTT and fibrinogen levels were also measured. The normal male and female fibrinokinetic profile showed a strong clot formation with the clot reaching an average OD of 1.2±0.3 (range 0.7–1.4). In the CKD patients a much weaker clot was formed with an average OD of 0.21±0.13 (range 0.05–0.41). In the ESRD patients on maintenance hemodialysis, the pre-dialysis sample showed a weaker fibrinokinetic profile reaching near normal levels with a clot density of 1.3±0.4 (range 0.8–1.6). In the urokinase induced fibrinolysis assay, the CKD patients plasma exhibited a much stronger fibrinolytic index in comparison to the normal population (80% clot lysis vs. 20%). In the ESRD patients the clot lysis profile was relatively weaker in comparison to the CKD patients, suggesting that hemodialysis may contribute to impaired clot formation. These results are contrary to the reported observations that dense clot resistant to fibrinolysis are formed in CKD and ESRD patients. Furthermore the clot sobserved in these patients were highly susceptible to lysis. The maintenance hemodialysis results in improving the fibrinokinetic and fibrinolytic profile in the ESRD patients. Therefore maintenance hemodialysis contributes to improved hemostasis in ESRD patients.
Apolipoprotein E Receptor 2′ Mediates Pathogenic Effects of Dimeric β2glycoprotein I and of Anti- β2glycoprotein I Antibodies in Vivo
Authors: Romay-Penabad Zurina , Urbanus Rolf T , Pappalardo Elizabeth , Hwang Yong , Derksen Ronald H.W.M. , Shilagard Tuya , Vargas Gracie , Pennings Maarten TT , De Groot Philip G , Pierangeli Silvia S 
Published: April 2020

Abstract
Antiphospholipid antibodies (aPL) recognize β2Glycoprotein (β2GPI)-bound to receptor (s) in target cells and trigger a pro-coagulant/pro-inflammatory phenotype [i e.:expression of tissue factor (TF), vascular cell adhesion molecule-1 (VCAM-1)] that lead to thrombosis. The interaction of β2GPI with target cells may involve more than one protein. Investigators have shown that dimeric β2GPI binds to apolipoprotein E receptor 2′ (apoER2′) in platelets, in the absence of anti-β2GPI antibodies, increases their activation and induces enhanced thrombosis and TF activity in mice. However, the role of apoER2′ in vivo in Antiphospholipid Syndrome (APS) is not completely understood. Here, we examined the in vivo effects of dimeric β2GPI and of anti-β2GPI antibodies (IgG-APS) in apoER2′ deficient (−/−) mice and in normal mice pre-treated with recombinant soluble domain 1 of apoER2′ (BD1). In vivo, dynamics of thrombus formation (thrombus sizes), TF activities in carotid artery homogenates and in peritoneal macrophages and ex vivo expression of VCAM-1 in aortas and of TF activity in peritoneal macrophages were examined in the various types of mice after two i.p. injections with 40 μg of recombinant dimeric β2GPI – or with the corresponding monomer control – or with 500 μg IgG-APS (isolated from a patient with APS by protein G Sepharose) or with control IgG (IgG-NHS). Mice injected with IgG-APS had significant titers of anticardiolipin (aCL) and anti-β2GPI antibodies in their sera. In vivo, IgG-APS increased significantly the size of the induced thrombi as well as the TF activities in carotid arteries and in peritoneal macrophages in C57BL/6J (wild type) mice when compared to same type of mice treated with IgG-NHS. Similarly, ex vivo expression of VCAM-1 in mouse aortas and of TF in peritoneal macrophages, detected by two photon excitation laser scanning microscopy were increased in normal mice treated with IgG-APS when compared to control mice. The pre-treatment with 40 μg of BD1 i.p., significantly reduced those effects. Importantly, dimeric β2GPI (in the absence of anti-β2GPI antibodies) or IgGAPS did not increase significantly thrombus size, TF activities in homogenates of carotid arteries or in peritoneal macrophages, or ex vivo expression of VCAM-1 and TF in mice lacking apoER2′.
Conclusions: Altogether these data show that dimers of β2GPI mimic pathogenic effects of anti-β2GPI antibodies in mice. Most importantly, apoER2′ is a mediator of those effects in vivo. These findings may provide insights not only for a better understanding of the pathophysiology of APS but may be important in the development of new targeted therapies, by means of interfering with the binding of β2GPI-aPL complexes with their receptor(s) in target cells in vivo.
Recombinant Factor VIIa Combined with Fibrinogen Corrects the Coagulopathy Associated with Cardiopulmonary Bypass Surgery Ex Vivo
Authors: Onundarson Pall T. , Asvaldsdottir Hanna S. , Gudmundsdottir Brynja R. , Sorensen Benny 
Published: April 2020

Abstract
Major cardiac surgery and use of cardiopulmonary bypass (CPB) is often associated with the development of a severe coagulopathy, hyperfibrinolysis and increased risk of bleeding. The present ex vivo study challenged the hypotheses that whole blood thrombelastometry, activated with minute amounts of tissue factor, can reveal the development of a coagulopathy following cardiac surgery, and that supplementation with fibrinogen and rFVIIa, alone or in combination, can improve the ex vivo clotting pattern. In total, 22 patients with a median age of 68, undergoing coronary artery bypass grafting or valve surgery with use of CPB were included in the study. Dynamic thrombelastometric clotting profiles were recorded using citrated whole blood activated with dilute tissue factor (Innovin®, final dilution 1:17000). Blood samples were collected before surgery (control) and immediately following in vivo neutralization of heparin with protamine sulphate. All blood samples for thrombelastometry were treated with heparinase to ensure neutralization of residual heparin. Standard coagulation laboratory parameters and platelet function confirmed the development of a significant coagulopathy following CPB. The post-operative blood samples were spiked with buffer, rFVIIa (2 μg/mL), fibrinogen (1mg/mL), or the combination of rFVIIa+fibrinogen. The post-operative coagulopathy was evident by thromboelastometry as a statistically significant derangements (Wilcoxon signed rank test). There was prolongation of the onset of clotting (CT, from a median value of 183 seconds pre-op to 385 sec post-op), reduced maximum velocity of clot formation (MaxVel, from 17.5 mm*100/sec pre-op to 15.1 post-op) and reduced maximum clot firmness (MCF, from 6234 mm pre-op to 5527 post-op). Ex vivo spiking with rFVIIa shortened the post-operative clot initiation phase (CT) to a median of 232 sec. Fibrinogen also shortened the post-operative clotting time to a median of 246 sec, and additionally increased the MCF to 5839 mm. Finally, the combination of rFVIIa and fibrinogen together corrected the abnormal thromboelastometric findings associated with CPB-coagulopathy into the pre-operative range, i.e. median CT decreased to 155 sec, MaxVel increased to 16.8 mm*100/sec and MCF increased to 5808 mm.
In conclusion, the experiments suggest a potential role of fibrinogen supplementation during control of bleeding following CPB, either alone or in combination with rFVIIa, since the combination corrected the CPB-associated coagulopathy remaining following neutralization of heparin.
Involvement of Pkcε And Stat3 in Apoptosis of Hematopoietic Cells from Patients with Aplastic Anemia
Authors: Liu Hong , Lin Zenghua , Ruan Changgeng 
Published: April 2020

Abstract
Aplastic anemia (AA) is characterized by peripheral cytopenias in the setting of marrow hypoplasia. Recent reports have indicated that apoptosis plays an important role in injure to the stem and progenitor compartments in these patients. We previously revealed that impaired stem cells could be caused by excess IFN-γ in the serum or hypersensitivity to IFN-γ in the patients. To investigate the molecular mechanism of the apoptotic function of the serum from the patients against hematopoietic stem and/or progenitors, the apoptosis of CD34+ cells was assayed with flow cytometry 24 hr after incubation with the serum of normal controls, patients with non severe AA and severe AA. The CD34+ progenitors from the cord blood sample of healthy donors contained a significantly greater proportion of apoptotic cells after incubation with serum from SAA patients than incubated with serum from normal controls and NSAA. Moreover, the percent apoptosis of CD34+ cells after 24hr incubation with serum from NSAA was slight higher than that of normal controls. To further explore the mechanism of increased apoptosis induced by the serum of AA patients, the expression of phosphorylated protein kinase Cε(pPKCε) and phosphorylated signal transducer and activator of transcription 3 (pstat3) were measured after incubation with serum from the normal controls and AA patients using western blot. After incubation with serum from the AA patients, both pPKCε and pstat3 were overexpressed, correlating with the increased apoptosis induced by the same serum from AA patients. In addition, RT-PCR results shown that the stats gene expression had no difference after incubation with serum from AA patient. Together, these results implicate pPKCε and pstat3 may be involved in the apoptosis of CD34+ cells induced by sera from patients with aplastic anemia. Our findings may contribute to understanding the decreased number of stem cells characteristic of AA.
Successful Treatment of Refractory Idiopathic Aplastic Anemia with Rituximab
Authors: Katragadda Sreedhar , Nelson John C 
Published: April 2020

Abstract
We report the first case of refractory idiopathic aplastic anemia who responded to Rituximab (anti-CD 20 monoclonal antibody). The patient is a 22 year old Hispanic male construction worker who presented with a two week history of weakness, dyspnea on exertion and gum bleeding was found to have a platelet count of 11 × 109/L, hemoglobin of 7.4 g/dL, and white blood cell count of 1.6 × 109/L with 30% neutrophils. A bone marrow biopsy showed hypocellular marrow with relative lymphocytosis of mixed B and T cells and a normal chromosome analysis. A paroxysmal nocturnal hemoglobinuria (PNH) panel was negative. Serological studies did not show any evidence of HBV, HCV, CMV or EBV infection, but did show previous infection with parvo B19. He was initially treated with horse antithymocyte globulin (ATG) at a dose of 40 mg/kg for four days and cyclosporine. After ten weeks of treatment he was still requiring weekly packed red blood cell and platelet transfusions and G-CSF support. At that time he was treated with rabbit antithymocyte globulin and cyclosporine was continued. He had a partial recovery with absolute neutrophil count remaining mostly above 1 × 109/L, but he was still requiring red blood cell and platelet transfusions with baseline hemoglobin of 6 gm/dL and platelet count of less than 20 × 109/L. A bone marrow biopsy done ten weeks after the rabbit ATG treatment showed hypocellular marrow (20% cellularity) with trilineage hematopoiesis, with no evidence of dysplasia. Due to his transfusion dependence after eight months from his rabbit ATG treatment, he received Rituximab at a dose of 375 mg/m2 weekly for four weeks. He had a dramatic improvement of hemoglobin to 11.5 gm/dL and white blood cell count to 3.5 × 109/L, with an absolute neutrophil count of 2 × 109/L, although his platelet count remained at 20 × 109/L. He remains transfusion independent for a follow-up period of 8 months after the Rituximab treatment. Review of literature showed partial to good responses with Rituximab in
aplastic anemia patient who refused treatment with ATG and cyclosporine (Hansen PB et al), aplastic anemia associated with CLL (Bharwani L et al), severe aplastic anemia induced by fludarabine and cyclophosphamide in a patient with B-CLL (Castiglioni MG et al) and, refractory Diamond-Blackfan anemia (Morimoto A et al).
Results of Immunosupresive Therapy in Children with Aquired Severe Aplastic Anaemia (SAA). Report Polish Pediatric Hematology Group
Authors: Pawelec Katarzyna , Niewiadomska Edyta , Matysiak Michal , Kowalczyk Jerzy , Stefaniak Jolanta , Balwierz Walentyna , Zaleska-Czepko Ewa , Chybicka Alicja , Szmyd Krzysztof , Sonta-Jakimczyk Danuta , Bubala Halina , Wysocki Mariusz , Kurylak Andrzej , Wachowiak Jacek , Grund Grzegorz , Mlynarski Wojciech , Bulas Monika , Krawczuk-Rybak Maryna , Leszczynska Elzbieta , Urasinski Tomasz , Peregud-Pogorzelski Jaroslaw 
Published: April 2020

Abstract
Introduction: Bone marrow transplantation (BMT) from HLA identical family donors is the treatment chosen, according indication of Polish Pediatric Hematology Group and Working Party SAA of the EBMT, for children with severe aplastic anemia (SAA). When no donor is available, combined immunosuppressive therapy (IST) is given. Material and method: SAA was recognized in 116 children (45 girls, 71 boys) aged 2–18 years in ten pediatric hematological center in Poland between 1993–2007 years. All patients received IST according Polish Pediatric Hematology and Working Party SAA of the EBMT protocol: antithymocyte globulin horse or rabbit, cyclosporine A (CSA), prenisolon and in 90 patients G-CSF or GM-CSF was additionally administered. Hematological response was evaluated on day 112 and 180 of therapy. Results and conclusion: On day 112 remission was obtained in 61children from 116, complete remission (CR) in 47 (40,5%), partial remission (PR) in 24(20,8%). There was no response (NR) to treatment in 45 (38,7). On day 180 remission was obtained in 88 from 116 patients (75,8%), CR in 57 patients (49,1%), PR in 31 (26,7%), NR in 29 patients (24,2%). Period of observation was from 8 months to 14 years. During this time relapse occurred in 32 patients (27.5%). Patients with NR and relapse were treated second course of IST or BMT from matched bone marrow donors. Unrelated BMT was performed in 18 patients with NR or relapsed after IST. We observed 27 deaths (8 early during the first 3 months of IST) in all group. During the 14 year of observation we notice one case with late clonally complication (PNH), one case of transformation to AML and one to MDS. Probably of 14year survival was 76,7% in our group. Our results are effective and compared to other hematological centers.
Israeli Fanconi Anemia Registry
Authors: Tamary Hannah , Alter Blanche P. , Nishri Daniella , Rosenberg Philip S 
Published: April 2020

Abstract
Using epidemiological data from retrospective cohorts of patients with Fanconi Anemia (FA) in North America and Germany a quantitative model to estimate bone marrow failure (BMF) and cancer risk was previously generated. To evaluate generalizability to another population, and to determine the risks for adverse outcomes in Israel, we created an Israeli FA registry and used the model to evaluate complications. We reviewed patient charts of 66 patients with FA diagnosed in Israel between 1964–2005. The data base included demographic information, as well as data describing the congenital abnormalities, FA complementation groups, BMT course and malignancies. Thirty six (36) patients were of Jewish origin [Ashkenzi 7, Sephardic 23, mixed 6] and 30 of Arabic origin. The first adverse event was bone marrow failure (BMF) in 35 patients (53%), hematological malignancy in 7 (11%) and 2 solid tumors in each of 3 patients (5%). The cause-specific hazard of BMF peaked at 10.5%/year at age 10 years (95% CI: 6.7–14.1%/year). The hazard of AML/ALL and MDS were stable at 0.9%/year (95% CI: 0.42–1.85%/year) and 1.4%/year (95% CI: 0.76–2.49%/year) respectively. The cumulative incidence of each outcome to age 32 was 70% for BMF, 13% for AML/ALL, and 17% for solid tumor. A five item congenital abnormality score was significantly associated with the risk of BMF (P = 0.009). The ratio of observed to expected cancer was 71 for all cancers [50 for solid tumors, 175 for leukemia] and &gt;11,000 for myelodysplastic syndrome. Significantly elevated ratios of observed to expected cancers were observed for head and neck squamous cell carcinoma in 2 patients (986-fold), tumor of larynx (13,238-fold), vulva (3,701-fold), cervix (244-fold) and breast (88-fold). The complementation group was known in 41 patients [A 25 (63%), C 9 (22%), G 6 (15%), and D1 1 (2%)]. However, associations between complementation groups and specific outcomes were not significant. Despite the different ethnic background and the smaller number of FA patients in the Israeli cohort the risk estimates compared with the US and German cohorts were similar. As previously suggested the congenital abnormality score was significantly associated with the risk of BMF; an extraordinary risk of developing AML/MDS and later specific solid tumors was also found.
A Novel BACH2-BCL2L1 Fusion Gene in the Burkitt’s Lymphoma Derived Cell Line BLUE-1
Authors: Türkmen Seval , Riehn Mathias , Mundlos Stefan , Thiel Eckhard , Burmeister Thomas 
Published: April 2020

Abstract
Abnormalities of the long arm of chromosome 6 are a common feature in various B-cell malignancies. However, in most cases the involved genes have not yet clearly been identified. We have molecularly characterized the recently established cell line BLUE-1 that has been derived from a relapsed sporadic Burkitt lymphoma. This cell lines carries a t(6;20)(q15;q11.2) rearrangement in addition to the typical t(8;14) with MYC-IgH fusion. The involved gene loci on chromosomes 6 and 20 were up to now unknown.
To identify the involved gene loci on both chromosomes we applied a sequential BAC clone mapping strategy. BAC RP11-243J16 clone (20q11.21, bp 29,756,679–29,925,538) was found to hybridize with der(6) as well as der(20). BAC RP1-104D1 (6q15, bp 91,001,943–91,064,406) also covered the breakpoint region. Two of the involved genes in this region are the transcription factor BACH2 (basic leucine zipper transcription factor 2) on 6q15 and BCL2L1 (BCL-X) on 20q11, a member of the BCL2 anti-apoptosis gene family. We hypothesized that these two genes could be involved and by testing different primer combinations were able to amplify a BACH2-BCL2 fusion mRNA transcript using RT-PCR. In this fusion transcript the first (non-coding) exon of BACH2 was fused to the second (partially coding) exon of BCL2L1 thus effectively placing the BCL2L1 gene under the control of the BACH2 promotor. Western blot analysis showed a strong expression of BCL2L1.
This is the first report of a fusion gene involving the genes BACH2 and BCL2L1. The prototype of the BCL2 family, BCL-2 on 18q21.3 is known to play a crucial role in various lymphomas but a clear role for the closely related BCL2L1 gene in lymphomas has not yet been established. BACH2 is known to be expressed in B-cells at various maturation stages and is believed to be involved in the machinery of class switch recombination (CSR). Bach2 −/− mice show increased IgM but decreased IgG and IgA levels and a deficient T cell-independent and T cell-dependent IgG response associated with defective CSR.
In summary, this molecularly characterized translocation provides a new tool for studying recurrent 6q aberrations in lymphomas and for the action of the BCL2L1 antiapoptosis gene.
Serum BAFF (B-CELL Activating Factor Of The TNF Family) predicts time to First Treatment in Early B-CELL Chronic Lymphocytic Leukemia
Authors: Molica Stefano , Vitelli Gaetano , Cutrona Giovanna , Digiesi Giovanna , Mirabelli Rosanna , Giannarelli Diana , Sperduti Isabella , Ferrarini Manlio 
Published: April 2020

Abstract
We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70− and CD38− expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 125 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently females (P=0.01), patients with Rai stage 0 (P=0.03), mutated IgVH disease (P=0.008) and low ZAP-70 expression (P=0.04). In contrast, age (P=0.35), peripheral blood lymphocytosis (PBL)(P=0.09), hemoglobin (Hb) level (P=0.64), platelet (PLT) count (P=0.12), serum β2-m (P=0.49), LDH (P=0.85) and percentage of CD38-positive B-CLL cells (P=0.63) did not reflect circulating levels of BAFF. We used an optimal cut-point search to determine how to best split soluble BAFF data. Maximally selected log-rank statistics plots identified a BAFF serum concentration of 311 ng/mL as the best cut-off (P&lt;0.0001). Accordingly, patients who had BAFF levels higher than 311 ng/mL experienced a longer TFT (median 108 months) in comparison to patients whose BAFF levels were lower than 311 ng/mL (median 30 months; P&lt;0.0001). Along with serum concentration of BAFF, the univariate Cox proportional hazard model identified Rai substage I–II (P=0.003), lower PLT count (P=0.04), higher PBL count (P=0.01), increased LDH (P=0.01), ZAP-70 expression &gt; 20% (P=0.02) and absence of mutation of IgVH (P&lt;0.0001) as predictor of shorter TFT. In multivariate analysis only soluble BAFF (Hazard ratio [HR], 6.13; CI 95%, 2.31–16.25) and mutational status of IgVH, (HR= 2.99; CI 95% 1.33–6.76, P=0.008) maintained their discriminating power. The effects of BAFF on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. However, serum levels of BAFF and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two groups with different TFT according to BAFF levels (HR= 8.9; P&lt;0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, BAFF along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.