bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenalidomide (Revlimid™), Adriamycin and Dexamethasone Chemotherapy (RAD) Is Safe and Effective in Treatment of Relapsed Multiple Myeloma - First Results of a German Multicenter Phase I/II Trial.
Authors: Knop Stefan , Gerecke Christian , Topp Max S. , Liebisch Peter , Hess Georg , Kotkiewitz Sandra , Einsele Hermann , Bargou Ralf 
Published: April 2020

Abstract
A more widespread use of thalidomide (Thal) in patients (pts) with relapsed multiple myeloma has been prevented by its considerable neurotoxicity. The immunomodulatory drugs (IMiDs) form a new class of Thal successors aiming at reduced toxicity with reliable anti-tumour effect. Recently, lenalidomide (CC-5013; Revlimid™) was the first IMiD to be approved by the FDA for treatment of both MDS and multiple myeloma. Several trials in pts with advanced myeloma demonstrated lenalidomide (alone or in combination with dexamethasone) to induce significant and durable response. We sought to establish a protocol with superior efficacy and decided to add lenalidomide (R) to adriamycin (A)/dexamethasone (D; RAD). A dose escalation study was set up to include pts after a maximum of 3 previous treatment lines. They had to have measurable disease and adequate organ and bone marrow function. No dose limiting toxicity occurred until two cases of non-febrile neutropenia were seen with R 15 mg, day 1–21; A 9 mg/m2 for days 1–4 as a continuous infusion; and D 40 mg, days 1–4, and 17–20. The protocol was amended for G-CSF support (Pegfilgrastim [Neulasta™] 6mg, day 6) resulting in an uneventful course in all pts treated subsequently at the two highest dose levels. Surprisingly, maximum tolerated dose of lenalidomide in combination with A and D as described before was 25 mg day 1–21, thus being the daily dose from the monotherapy trials. Up to now, 41 subjects have been enrolled, 37 of whom had received autologous and five additional allogeneic stem cell transplants. 31 pts are currently evaluable for response and toxicity: 26 pts achieved reduction of paraprotein levels of at least 50% for a response rate of 84 % including one confirmed CR and 14 PRs according to the EBMT criteria (Bladé et al). An additional three pts had SD while two progressed. Notably, eight of ten pts who displayed del (13) on cytogenetic analysis responded up to now, including six confirmed PRs. One patient each experienced acute renal failure due to emesis and hypovolemia, pneumocystis pneumonitis, and catheter related infection. All subjects recovered without sequelae. Neither somnolence nor constipation, thromboembolism or neuropathy occurred. We conclude that RAD induces substantial remission with an acceptable toxicity profile and thus significantly contributes to the therapeutic armamentarium even in heavily pretreated myeloma pts.
Trombophylia Prevalence in 444 Patients with Clinical Suspicion of Thrombosis.
Authors: Guerra Joao Carlos C. , Aranda Valdir F. , Mendes Claudio A. , Hamerschlak Nelson , Bacal Nydia S. , Colombini Marjorie P. , Pasternak Jacyr , Sitnik Roberta , Graca Claudia H. , Pinho Joao Renato R. 
Published: April 2020

Abstract
Objetives: to evaluate the prevalence of genetic polymorphism of coagulation factors: Leyden factor V (FVL), prothrombin mutation, deficiency of coagulation inhibitors, protein C, protein S and antithrombin (AT), test for the lupus anticoagulant/anticardiolipin and homocistein levels, during the laboratory investigation of patients with clinical suspicion of thrombosis.
Patients and methods: This was done as a retrospective chart review study on 444 patients admitted at our hospital between November 2003 and December 2004 ( males 188, females 256). Medium age was 46 years. Prothrombin mutation and Factor V Leyden were searched by multiplex PCR, Protein C, S and lupus anticoagulant were studied by coagulometric methods, AT by chromogenic method, anticardiolipin by immunoenzymatic assay and homocistein by immunometric assay. Statistical analysis was performed using exact Fischer test or × Pearson test.
Results and conclusions: Prevalence of FVL was 32 cases, 7.2 %, 2 homozygotes and 30 heterozygotes. Prothrombyn mutation was found in 25 cases, 5.6 %, 1 homozygote and 24 heterozygotes. On 57 cases with genetic alteration 46 (80%) had thrombosis, 39 venous and 7 arterial. On 183 cases that done anticardiolipin test 27 cases were positive, 14.7 % (18 IgG, 6 IgM and 3 IgA). On those cases 22, 81.4 % had thrombosis, 15 venous and 7 arterial. All 3 cases with lupus anticoagulant had thrombosis. Hyperhomocistein was found in 7 cases, 3.2 %, with 4 cases associated with venous thrombosis and 1 with arterial thrombosis. Deficiencies of Protein C, Protein S and AT were found in 117 cases, l2.8 %, associated with 63 cases of thrombosis, 52 venous and 11 arterial, 56.3 %. Pathogenesis of thrombosis is complex and clearly associated with genetic and environmental factors - risk factors. On populations at risk for thrombosis laboratory investigation is essential.
IL6 -174 G/C and Fibrinogen-β-455 G/A Polymorphisms in Ischemic Cerebrovascular Disease (ICD).
Authors: Moreno B Vanessa , Garcia-Raso Arantxa , Garcia-Bueno Maria Jose , Sanchez Carmen , Subira Dolores , Mata Raquel , Llamas Pilar , Martinez Jose 
Published: April 2020

Abstract
Ischemic cerebrovascular disease (ICD) is a multi-factorial entity whose anatomopathologic substrate is atherosclerosis. The inflammatory cells migrate to vascular endothelium and release chemokines such as interleukin 6 (IL6), resulting in the atheroma plaque development. The IL6 production induces acute phase proteins synthesis such as fibrinogen.
Objective. The purpose of this case-control study is to analyze the ICD risk associated to the polymorphisms IL6-174 G/C and beta chain of fibrinogen-455 G/A (fibri-β-455). The association of these polymorphisms, classic vascular risks factors and ICD subtypes according to TOAST classification has also been explored.
Methods and patients. A total of 159 ICD diagnosed patients (82 female and 77 male; mean age 67.7±15) were analysed. They were matched for age (±5 years) and sex with a control group (65.6±14) without thrombotic history. AHT, DM, dyslipidaemia and smoking habit data were collected for each group. Polymorphisms were analysed by PCR-RFLP. Serum IL6 was measured by ELISA and fibrinogen by Clauss method. Statistic analysis was made with the SAS v9 software.
Results. Genotype analysis showed a significant higher prevalence of the genotypes G/G and G/C IL6 -174 in the patients (OR: 1.49, IC 95%: 0.95–2.34, p: 0.049). By contrast, the fibri-β-455 genotypes were not different in patients and controls (p= 0.230). When the stroke subtypes were analysed, we found that IL6-174 G/C genotype was more frequent in cardioembolic (60.0%) and atherothrombotic ICD subtypes (58.3%). In relation to fibri-β-455 G/A, the A allele showed a increased prevalence in atherothrombotic stroke (43.2%) (p= 0.049).
We observed an association between the dyslipidaemia and IL6-174 G/C polymorphism (p= 0.034) and smoking habit with fibri-β-455G/A (p= 0.072). No synergic relation were found between IL6-174 G/C and fibri-β-455 G/A. The G allele IL6-174 G/C carriers group presented higher serum IL6 levels than C allele carriers, 5.85 pg/ml (2.9–34.5) vs. 4.94pg/ml (2.5–11.4). Also, allele A fibri-β-455 G/A was associated with a higher fibrinogen levels than G allele, 329 mg/dl (210–686) versus 280 mg/dl (107–783).
Conclusion. There is an association between-174 IL6 G/C polymorphism and ischemic stroke. By contrast, we did not find any association between fibri-β-455 G/A, and ICD. Besides, the analysis performed by ICD subtypes showed an association of this polymorphism and atherothrombotic subtype. These results suggest a relation between smoking habit and fibri-β-455 G/A, and dislypidaemia and-174 IL6 G/C polymorphism.
Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Elderly Patients.
Authors: Bartholomew John R. , Pietrangeli Carolynn E. , Hursting Marcie J. 
Published: April 2020

Abstract
Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). Although its clearance is reduced in elderly, vs younger, healthy volunteers (4.3 vs 5.0 mL/min/kg), argatroban therapy in elderly patients with HIT has not been specifically described. In this retrospective analysis of a 118-patient, multicenter registry database, we evaluated argatroban dosing, anticoagulant responses, and clinical outcomes in adults aged ≥65 years with clinically diagnosed HIT or history of HIT administered argatroban therapy. From the registry, we identified 62 argatroban-treated patients with HIT (n=54) or history of HIT (n=8). Baseline characteristics, argatroban doses and responses, and outcomes were summarized for patients overall and stratified by age (65–74 years, n=31; 75–84 years, n=26; ≥85 years, n=5). Indications for anticoagulation were similar among groups, typically cardiac-related. Argatroban was infused and adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5–3 times baseline. In each group, the initial median argatroban dose as determined by the treating physician was 1.0 mg/kg/min (a similar initial dose was used for all registry patients, irrespective of age) and maintained at or near that dose during therapy (median, 5–7 days). Overall, therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds. By regression analysis, mean argatroban dose decreased ~0.1 mg/kg/min with each 0.2-mg/dL increase in serum creatinine but was unaffected by patient age, total serum bilirubin, calculated creatinine clearance, or blood urea nitrogen. Platelet counts in HIT patients increased a median 41% from baseline during therapy. Within 37 days of argatroban initiation, 13 (21%) patients died (1 while on argatroban), 5 (8%) had new thrombosis (2 while on argatroban), and none experienced amputation or major bleeding. The oldest group had no event. By univariate regression analysis, the risk of developing new thrombosis decreased with increasing mean argatroban dose (hazard ratio=0.020; 95% CI, 0.001–0.757; p=0.035), yet was not significantly affected by age, gender, baseline platelet count, or mean aPTT. We conclude that argatroban at a median initial dose of 1.0 mg/kg/min, adjusted to achieve aPTTs 1.5–3 times baseline, provides safe and effective anticoagulation in elderly patients with HIT or history of HIT. For patients ≥65 years old, age is not a significant factor determining therapeutic argatroban doses or thrombotic risk.
Thrombotic Complications in Young Adults at High Altitude Areas: An Indian Experience.
Authors: Nair Velu , Sharma Ajay , Das Satya R. , Mishra D.K. , Kotwal J. , Agarwal Mohan B. 
Published: April 2020

Abstract
High altitudes(HA) have been a source of great adventures to sea land natives during short visits. But they also result in life threatening situations. There is no definite protocol to predict these likely complications. Certain thrombotic tendencies have been identified as possible risks for these complications but there have been some times such complications can occur in the individuals otherwise not known to have any known abnormalities of thrombosis. Also the duration of exposure to high altitude required to trigger this complication is uncertain. We present 24 cases of high altitude associated thrombotic complications. All patients were incidentally males in an age group of 22–38 years (median age 28 years). They were all otherwise healthy individuals having undergone a basic medical examination before moving to HA (defined as an altitude above 9000 ft.). They all moved to HA by air and underwent standard acclimatization program before they were allowed to move out there. The duration of stay ranged between 2 weeks to 4 months. The complications encountered included deep vein thrombosis (DVT) of lower limbs (n- 18) pulmonary embolism(PE; n- 9), cortical venous thrombosis (CVT) in 5 cases and splenic infarctions in 5 cases. 25 of these also developed features of pulmonary hypertension as confirmed by echocardiography in these patients and pulmonary angiography in 3 cases who had developed pulmonary embolism. They all were treated with heparin followed by oral anticoagulation. These all patients were told to move out of HA at earliest possible opportunity. They were all investigated for possible thrombotic abnormalities. These tests included assays for Protein C,S,AT, APC resistance and mutation analysis for MTHFR and Factor V leiden. Two of the Five patients, who had developed splenic infarction were detected to have sickle cell trait. These patients underwent splenectomy besides anticoagulation. The anticoagulation was stopped 6 months later. They all later moved out of HA and were advised to avoid re-exposure to HA. These individuals arte on regular follow up and are free of any subsequent recurrence of thrombotic complications. We conclude that HA itself may be a risk for various thrombotic complications especially in individuals exposed to HA for a longer duration.
Evaluation of the Hemochron Junior Signature Analyser for Oral Anticoagulant Point of Care Testing.
Authors: Bogo Peter H. , Maddox Jamie , McGregor Ewan , McKay Jayne , Bancroft Anne , Pippard Martin J. , Kerr Ron 
Published: April 2020

Abstract
The community anticoagulant service in Tayside, Scotland provides point of care testing for around 5000 patients at 25 sites using 43 analysers. Since December 2004 this service has used the Hemochron Junior Signature (HJS) analyser (International Technidyne Corporation) for INR measurement.
Following satisfactory initial laboratory evaluation, we have compared results of capillary samples analysed using the HJS to venous samples collected simultaneously and analysed in Ninewells Hospital using a Sysmex CA1500 analyser. Reagents used were Citrate PT test cuvettes (International Technidyne Corporation) which uses rabbit brain thromboplastin for the HJS and Dade Innovin (Dade Behring) for the CA1500. Samples for comparison were collected randomly from approximately every tenth patient tested in the anticoagulant clinics for a 12 month period. Results of the comparison are given for 3 separate periods within the 12 months of study as ongoing analysis of data during the study period led to the introduction of a correction factor for results obtained using the HJS analyser. The first correction factor was introduced after the first 4 weeks of study and there was a subsequent revision of this correction factor after a further 5 months.
Results for these 3 periods are as follows (all results given are INR units).
Period 1:
Mean INR 2.8 CA 1500 vs. 3.8 HJS, mean difference −1.0, 95% upper limit of agreement 0.5, 95% lower limit of agreement −2.5 (n=145).
Period 2:
Mean INR 2.6 CA 1500 vs. 2.7 HJS, mean difference −0.1, 95% upper limit of agreement 1.1, 95% lower limit of agreement −1.2 (n=345).
Period 3:
Mean INR 2.7 CA 1500 vs. 2.8 HJS, mean difference 0.0, 95% upper limit of agreement 1.3, 95% lower limit of agreement −1.3 (n=662).
Additionally, local external quality assurance was performed on 13 occasions (683 total tests) during the period of study. Cumulative results demonstrate that 86% of results were within 15% of the median.
We have demonstrated an approach to quality assurance for oral anticoagulant point of care testing and conclude that the HJS is a suitable analyser for this purpose.
In Vitro Evaluation of Apixaban, a Novel, Potent, Selective and Orally Bioavailable Factor Xa Inhibitor.
Authors: Luettgen Joseph M. , Bozarth Tracy A. , Bozarth Jeffrey M. , Barbera Frank A. , Lam Patrick Y. , Quan Mimi L. , Pinto Donald J. , Wexler Ruth R. , Rendina Alan R. , Knabb Robert M. 
Published: April 2020

Abstract
Apixaban, previously known as BMS-562247, is a high affinity, highly selective, orally-active, reversible inhibitor of coagulation factor Xa (fXa), in clinical studies as a therapeutic agent for prevention and treatment of thromboembolic diseases. The in vitro characteristics of apixaban were evaluated in purified systems and in human blood from healthy volunteers. Detailed kinetic analysis of apixaban inhibition of human fXa showed that it is a readily reversible, potent and competitive inhibitor versus a synthetic tripeptide substrate with a Ki of 0.08 nM, an association rate of 2 × 107 M−1s−1and a dissociation half life of 3.4 min. Weak affinity (Ki ~3 μM) is observed for thrombin, plasma kallikrein, and chymotrypsin. Affinity for trypsin and all other serine proteases tested is negligible with Ki &gt; 15 μM. Apixaban is an effective inhibitor of free fXa and of prothrombinase, in buffer, platelet poor plasma, and whole blood. The anticoagulant activity of apixaban was determined in platelet-poor human plasma. Apixaban causes concentration dependent prolongation of the fXa mediated clotting assays. The human plasma concentration required to produce a doubling of the clotting time is 3.6 μM for prothrombin time, 7.4 μM for activated partial thromboplastin time and 0.4 μM for HepTest. To support preclinical efficacy and safety studies purified fXa from rabbit, dog and rat plasma was also found to be inhibited by apixaban (0.17, 2.6, and 1.3 nM, respectively). In summary the in vitro properties of apixaban show that it is a highly selective and potentially potent antithrombotic agent for venous and arterial thrombotic diseases.
Expression of Tumor-Associated Antigens (TAAs) in Acute Myeloid Leukemia (AML) Correlated with Specific T Cell Responses and Survival.
Authors: Greiner Jochen , Schmitt Michael , Li Li , Giannopoulos Krzysztof , Bosch Katrin , Dohner Konstanze , Schmitt Anita , Schlenk Richard F. , Pollack Jonathan R. , Dohner Hartmut , Bullinger Lars 
Published: April 2020

Abstract
Several Tumor-associated antigens (TAAs) are expressed in acute myeloid leukemia (AML) and elicit specific immune responses of CD8 positive T cells. These specific T cell responses against leukemic blasts expressing TAAs might play a critical role in the control of minimal residual disease (MRD) in AML. Therefore, we investigated whether TAAs inducing specific immune responses in AML patients were associated with the clinical outcome. A DNA-microarray analysis of 116 AML samples was performed to correlate expression of TAAs to the clinical outcome. In these AML patients specific T cell responses to TAAs were assessed by ELISPOT analysis, tetramer staining and chromium release assays. Quantitative RT-PCR based validation of our results demonstrated the power of DNA microarray technology. We found a significant correlation of high mRNA expression of the TAA G250/CA9 with a longer overall survival (P=0.022), a trend for better outcome in patients with high expression levels of PRAME (P=0.103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1 we found no correlation with clinical outcome of AML patients. Moreover, co-expression of RHAMM/HMMR, PRAME and G250/CA9 provided a favorable prognostic effect (P=0.005). We found specific T cell responses at high frequency for these three antigens in AML patients. Positive immune reactions were detected in 8/17 (47%) AML patients for RHAMM/HMMR-R3-derived, in 7/10 (70%) for PRAME-P3-derived, and in 6/10 (60%) for newly characterized G250/CA9-G2-derived peptides. We detected a significant increased immune response of AML patients in complete remission compared to AML patients with refractory disease (P&lt;0.001). Furthermore, we could demonstrate specific lysis of T2 cells and AML blasts presenting these epitope peptides RHAMM/HMMR-R3, PRAME-P3 and G250/CA9-G2. In conclusion, the expression of the TAAs RHAMM/HMMR, PRAME and G250/CA9 can induce strong anti-leukemic immune responses of CD8 positive T cells possibly enabling the control of MRD in AML patients. Thus, the antigens RHAMM/HMMR, PRAME and G250/CA9 represent interesting target structures for polyvalent immunotherapeutic approaches in AML.
Hematopoietic Stem and Progenitor Cell Biology in the Zebrafish.
Authors: Traver David , Bertrand Julien , Kim Albert , Cisson Jennifer , Violette Emily 
Published: April 2020

Abstract
Over the past decade, the development of forward genetic approaches in the zebrafish system has provided unprecedented power in understanding the molecular basis of vertebrate blood development. Establishment of cellular and hematological approaches to better understand the biology of resulting blood mutants, however, has lagged behind these efforts. We have recently developed the means to identify zebrafish hematopoietic stem cells (HSCs), transgenic lines to mark hematopoietic precursors and their progeny, and the assays to test these populations functionally. Like other vertebrates, zebrafish demonstrate differential waves of hematopoiesis during embryogenesis. These waves can be visualized directly by fluorescent transgenesis in living embryos. The earliest blood-forming cells in the zebrafish embryo express the scl and lmo2 genes. By directing expression of GFP to early blood precursors using the lmo2 promoter, we have isolated early hematopoietic cells by flow cytometry and tested them functionally by transplantation. Transplantation of lmo2::GFP+ cells isolated from embryos at 14 hours post-fertilization (hpf) resulted in only transient reconstitution of erythrocytes, suggesting that the earliest identifiable blood-forming cells are committed to the erythroid lineage. Later in embryogenesis, lmo2:GFP+ GATA-1:dsRED+ cells are found in the posterior blood island (PBI) from approximately 30–60 hpf. Molecular and functional characterization of these cells suggests that they possess limited myeloid and erythroid, but not lymphoid differentiation potentials. This suggests that committed progenitors with definitive hematopoietic potential arise in the embryo before HSCs can be identified. Additional studies have suggested that the first multipotent HSCs are born later in the zebrafish aorta/gonad/mesonephros (AGM) region. We have visualized putative HSCs in the AGM by their expression of the lmo2 and cd41 transgenes. Using confocal timelapse imaging in living embryos, lmo2::GFP+ cells have been observed to emigrate from the AGM region into circulation. Transplantation studies are underway to test putative HSC populations for repopulation activity. Taken together, our findings suggest that at least three independent waves of blood cell precursors are formed during zebrafish embryogenesis.