bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pilot Trial of Two Dose Levels of Rabbit Antithymocyte Globulin, (rATG), Thymoglobulin, as Part of a Myeloablative-Conditioning for a HLA Identical Matched Related Donor Stem Cell Transplant (SCT) with Cyclosporine (CsA) as Graft Versus Host Disease (GvHD) Prophylaxis.
Authors: Miller Kenneth B. , Chao Nelson J. , Messner Hans A. , Goldstein Steven C. , Reddy Vijay , Vaughan William , Devine Steven , Rowley Scott D. , Waller Ned , Devetten Marcel , Schiller Gary J. 
Published: April 2020

To determine the role of rATG to modify the development of acute GvHD we conducted a randomized, prospective, open-label, multi-center pilot study in patients with ALL or AML in first or second remission. CsA was the only agent used for GvHD prophylaxis. Patients (N=22) were randomized (1:1) to receive either 4.5 mg/kg or 8.5 mg/kg of ATG during the preparative regimen. The rATG infusions were completed on Day -1, within 18 hours prior to SCT on Day 0. The low (N=11) and high dose groups (N=11) were comparable for age, diagnosis and remission status. The mean age was 41.4 and 39.6 years in the low and high dose groups respectively. In both groups 6/11 patients had AML and 5/11 had ALL. All patients received a fully ablative preparative regimen from a HLA matched related donor.
Results: Mean time to neutrophil engraftment was 6.5 and 7.3 days for the low and high dose arms, respectively. The incidence of Grade &gt; II acute GvHD was 0/11 for the low dose arm and 3/11 for the high dose arm. Infections were seen in 9/11 patients in both groups. The cumulative number of hospitalization days was 30.4 and 47.6 days (p=n.s.) in the low and high dose groups respectively. The overall survival at 180 days was 63.6 % in the low dose group and 54.5 % in the high dose group (p=n.s.). The disease free survival (DFS) at day 180 was 54.5% in both groups. The treatment related mortality (TRM) was 18.2 % in the low dose and 45.5 % in the high dose (p=n.s.) The relapse rate was 18.2 % in the low dose group and 0% in the high dose group (p=n.s).
Conclusion: This pilot study suggests that rATG may modify the development of serious acute GvHD in patients who received a fully ablative SCT. The low, combined, 3/22, incidence of acute GvHD (13.6%) in patients who received rATG(Thymoglobulin) and post transplant CsA suggests that this combination is an acceptable regiment for GvHD prophylaxis. The lower dose of rATG, 4.5 mg/kg, was as effective and was associated with a lower TRM as compared to the higher, 8.5mg/kg dose. The use of rATG administered during the preparative regimen was well tolerated and may provide an effective alternative to methotrexate when used as part of an ablative conditioning regimen in HLA identical related donor SCT.
Matched Unrelated Donor Stem Cell Transplantation for Patients with Diffuse Large Cell B Cell Lymphoma: A Retrospective Analysis of 118 Patients Registered through the European Group for Blood and Marrow Transplantation (EBMT).
Authors: Avivi Irit , Canals Carme , Taghipour Goli , Niederwieser Dietger , Kanz Lothar , Ehninger Gerhard , Finke Jurgen , Greinix Hildegard T. , Nagler Arnon , Vernant Jean Paul , Maury Sebastien , Bregni Marco , Linkesch Werner , Schwerdtfeger Rainer , Sureda Anna 
Published: April 2020

Abstract
Matched unrelated donor stem cell transplantation (MUD-SCT) may provide a treatment option for patients with diffuse large B cell lymphoma (DLBC) who have failed other conventional therapies and do not have a compatible sibling donor available. We present data of 118 DLBC patients, 69 males and 49 females, aged 18 to 66 years (median 43 years), treated with a MUD-SCT between January 1997 and July 2005 and reported to the EBMT registry. Median time from diagnosis to MUD-SCT was 25 months (range, 3 – 205), and 64% of the cases had failed a previous autologous transplant (ASCT). At allogeneic transplantation, 25% of the patients had chemorefractory disease. Peripheral blood was the source of hematopoietic stem cells in 70% of the cases and reduced intensity conditioning regimens (RIC) were used in 52% of the cases. After a median follow up of 26 months, the estimated 2-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS) and overall survival (OS) for the whole series were 29%, 35%, 36% and 43%, respectively. Grade II–IV acute graft-versus-host-disease developed in 32% of patients. Patients selected for RIC protocols were older (median age of 44 years vs 38 years, p = 0.02) and more heavily pre-treated; 75% had failed a previous autograft compared with 53% in the conventionally treated group (CC) (p = 0.01). Despite these unfavorable factors, the 2-yr NRM for RIC patients was significantly lower than in CC patients: 19% vs 39% (p = 0.03). Unfortunately, this advantage was offset by an increased RR in this group of patients (2-yr RR: 46% vs 24%, p = 0.2), resulting in a very similar PFS and OS for both types of conditioning regimens. The prognostic factor with highest impact on PFS was refractory disease at transplantation (RR = 1.8; 95%CI 1.1 −3.1, p = 0.02). The 2-year PFS for patients transplanted with sensitive disease was 40% irrespective of the conditioning regimen used. In sensitive patients undergoing a RIC transplant, the NRM was significantly lower with respect to CC regimen (14% vs 38%, p = 0.02), resulting in an improved PFS and OS (41% vs 37% and 50% vs 46% respectively). PFS in patients transplanted with refractory disease was generally poor (25% at 2 years). However, CC seemed to provide a better outcome than RIC (2-yr PFS of 35% vs 16%). In conclusion, MUD-SCT constitutes a treatment option for patients with DLBCL failing other conventional treatments, particularly for those patients being allografted in sensitive disease. The high RR observed with reduced intensity protocols does not allow to demonstrate a clear long-term benefit of this approach in this setting.
Development of a Myeloproliferative Disease or a T Cell Lymphoblastic Leukemia in a Murine Bone Marrow Transplant Model of NUP214-ABL1.
Authors: Rocnik Jennifer L. , Cornejo Melanie , Lee Benjamin H. , Okabe Rachel , McDowell Elizabeth , Gozo Maricel , De Keersmaecker Kim , Cools Jan , Gilliland D. Gary 
Published: April 2020

Abstract
Leukemias are often associated with aberrant tyrosine kinase activity that occurs as a result of chromosomal translocations. These mutations are able to confer a proliferative and survival advantage to leukemic cells, as well as cooperate with other mutations that impair cell differentiation, thus leading to the development of leukemia. NUP214-ABL1 is one such recently identified fusion gene that is generated by episomal amplification. The presence of the fusion was recently identified in approximately 6% of patients with T-cell acute lymphoblastic leukemia (T-ALL). By the use of a murine retroviral bone marrow transplantation model we have demonstrated that mice transplanted with NUP214-ABL1 transduced bone marrow cells developed either a myeloproliferative disorder (MPD) with a disease latency of 70 to 118 days or a T cell lymphoblastic leukemia with a disease latency of 115 to 124 days. The myeloproliferative phenotype was characterized by splenomagaly and leukocytosis, and analysis of the histopathology revealed extramedullary hematopoiesis in the liver, lung, kidney and Peyer’s patches, and an increase of peripheral blood neutrophils. Flow cytometry of single cell suspensions from spleen and bone marrow samples of mice with a myeloproliferative phenotype demonstrated an increase of Gr-1+/Mac-1+ cells (approximately 70%). Two of the mice that were transplanted with NUP214-ABL1 transduced bone marrow cells developed T cell lymphomas that were characterized by large thymomas, a phenotype that is consistent with other models of activated tyrosine kinases over long disease latencies. Histopathological analysis of the thymi revealed effacement of normal thymic architecture as well as T cell infiltrate into the surrounding skeletal muscle. In addition, flow cytometric analysis revealed a significant increase in the CD4+/CD8+ T cell population in the thymi of these animals. No disease was observed in secondary transplant recipients following 60 days of observation. In conclusion, these results indicate that NUP214-ABL1 is able to cause either a myeloproliferative disease or a T cell lymphoma over longer latencies in mice, the latter being similar to the phenotype observed in humans with expression of the NUP214-ABL1 fusion. These findings provide a useful model for future experiments to determine if there is a contribution of other mutations together with the NUP214-ABL1 fusion towards the development of a T-ALL phenotype in mice.
Risk of Thromboembolism after Short-Term Interruption of Warfarin.
Authors: Garcia David , Hylek Elaine 
Published: April 2020

Abstract
Background: Significant uncertainty exists for patients who must discontinue warfarin prior to an invasive procedure. In part, the controversy results from the lack of published information about the risk of thromboembolism associated with short-term warfarin interruption. The aim of this observational study was to assess the frequency of thromboembolism and bleeding among a large cohort of patients whose warfarin was temporarily withheld before and after an outpatient invasive procedure.
Methods: A prospective cohort of patients taking warfarin was assembled from 101 sites with personnel designated as warfarin managers across the United States during the period August 2000 to December 2001; 98 sites were community-based physician office practices. All episodes of warfarin interruption among the 6,761 patients in the cohort were identified by investigator review of provider-generated progress notes. Surgical procedures (including cardiovascular interventions) that required hospitalization and cases in which follow-up INR values were not available for at least 30 days post-procedure were excluded. The primary outcomes (30 day follow-up) were
thromboembolism and clinically significant hemorrhage.
For each patient, the following data were also recorded: type of procedure, number of days warfarin was withheld, presence or absence of bridging therapy (e.g. low molecular weight heparin [LMWH]).
Results: 1,024 unique patients (1,293 episodes of warfarin interruption) were included in our analysis. The mean age was 71.9 years; 43% were female. The most common procedures were colonoscopy (n=324), oral surgery (n=323), and ophthalmic surgery (116). Other common reasons for withholding warfarin were: epidural injection, prostate biopsy, breast biopsy, and dermatologic procedures. Perioperative heparin or LMWH was used in only 8.3% of cases. The duration of warfarin interruption was variable; however, more than 80% of patients had warfarin withheld for 5 days or fewer. Seven patients (0.7%) suffered post-procedure thromboembolism within 30 days (4 arterial, 3 venous). None of the 7 patients who experienced thromboembolism received peri-procedural bridging therapy; 3 of these thromboembolic events were associated with warfarin interruption ≥ 7 days. Twenty-three patients (2.3%) suffered clinically significant hemorrhage - of these, 14 had received peri-procedural heparin or LMWH.
Conclusion: For many chronically anticoagulated patients who need to undergo a minor, outpatient intervention, a brief (5 or fewer days) peri-procedural interruption of warfarin is associated with a low risk of thromboembolism. The risk for clinically significant bleeding, even among outpatients undergoing minor procedures, should be considered prior to the administration of bridging therapy.
Pure Heterozygous and Mixed JAK2 V617F Genotypes Result in Distinct Mechanisms of Erythrocytosis in Polycythemia Vera.
Authors: Dupont Sabrina , Masse Aline , James Chloe , Casadevall Nicole , Vainchenker William , Delhommeau Francois 
Published: April 2020

Abstract
The JAK2 V617F mutation is present in most patients with polycythemia vera (PV) and half with essential thrombocythemia (ET). Using real-time quantitative PCR, we analyzed the levels of JAK2 V617F in granulocytes and/or bone marrow mononuclear cells from 159 PV and 149 ET patients. High JAK2 V617F levels were correlated with higher leukocyte, granulocyte, hemoglobin values and higher endogenous erythroid colony formation. Thus, the phenotype of PV and ET may be closely linked to the JAK2 V617F level, which may reflect the clonal genotypic pattern of hematopoietic progenitor cells. It is thought that the occurrence of the mitotic recombination, which generates homozygous JAK2 V671F clones, is a key molecular event for the onset of PV. In this work, we aimed to study the consequences of the clonal JAK2 V617F genotype on the amplification properties and erythropoietin (EPO) hypersensitivity of PV (n=14) and ET (n=6) progenitors.
Analysis of clonal genotypic patterns shows that ET patients harbor a mix of heterozygous and normal progenitors. Interestingly, we distinguish pure heterozygous PV profiles (3/14 patients) with no homozygous progenitors from homozygous PV profiles (11/14 patients) with normal, heterozygous and homozygous progenitors. Similar low frequencies of mutated immature progenitors, comprising long-term culture-initiating cells and lympho-myeloid progenitors, are found in ET and PV. In contrast, PV patients with pure heterozygous PV profiles have striking higher proportions (&gt;90%) of mutated committed progenitors than other PV and ET patients. This result suggests a selective amplification of heterozygous cells in the early phases of hematopoiesis. Furthermore, by using increasing concentrations of EPO, homozygous mutated erythroid progenitors are demonstrated to be more sensitive to EPO than heterozygous ones, a majority of the former (69,5%) being EPO independent. Moreover, we demonstrate a two to three fold increase in in vitro amplification of ET and PV progenitor cells when compared to normal ones in serum free liquid culture containing IL3, Stem Cell Factor, Dexamethasone and 1 IU/mL EPO. In addition, the quantification of the mutated allele in immature CD34+CD38- cells, in CD34+CD38+ committed progenitor cells, in mature erythroblasts (GPA+) and in granulocytes shows a marked in vivo selective advantage of mutated cells in late stages of hematopoiesis.
These results suggest that in PV, erythrocytosis results from two distinct mechanisms: a terminal erythroid amplification advantage triggered by homozygosity or a two-step process including the upstream amplification of heterozygous cells that may involve additional molecular event(s).
Prostaglandin E2 Is a Potent Regulator of Vertebrate Hematopoietic Stem Cell Homeostasis.
Authors: North Trista E. , Goessling Wolfram , Kopani Kamden R. , Lengerke Claudia , Walkley Carl R. , Lord Allegra M. , Jang Il-ho , Grosser Tilo , FitzGerald Garret A. , Daley George Q. , Orkin Stuart H. , Zon Leonard I. 
Published: April 2020

Abstract
Hematopoietic stem cells (HSCs) give rise to each of the blood lineages found in the adult vertebrate. Definitive HSCs are derived during embryogenesis in the aorta-gonad-mesonephros (AGM) region and subsequently colonize the niche in fetal and adult hematopoietic organs. To identify regulators of this process, a library of biologically active compounds was screened for effects on zebrafish HSC development. Embryos were exposed to individual chemicals (2498) from the 5-somite stage until 36 hpf, then processed by whole-mount in situ hybridization for the expression of HSC markers cmyb and runx1. Exposure to 47 of the compounds reduced the number of runx1+cmyb+ HSCs, while 35 increased this cell population. Several chemicals isolated in the screen were known to affect the prostaglandin (PG) synthesis pathway. Prostaglandin (PG) precursors, mead acid and linoleic acid, expanded HSCs, while fenbufen and celecoxib, inhibitors of cyclooxygenase (cox) activity, reduced HSC number. An examination of blood and vessel specific molecular markers demonstrated that angiogenesis was not altered significantly in treated embryos, illustrating the specific effect on HSCs. Exposure to exogenous PGE2 modestly increased HSCs, while use of a long-acting version of PGE2, 16,16-dimethylPGE2 (dmPGE2), markedly enhanced HSC number. Incubation of zebrafish embryos with known cox inhibitors confirmed the observation that inhibition of PG synthesis reduces HSCs. Injection of morpholino oligonucleotides designed against cox1, cox2 and PGE synthase inhibited the formation of HSCs in a dose dependent fashion, verifying that signaling through PGE2 is regulating AGM HSC number. Using CD41:GFP;LMO2:DsRed bigenic zebrafish, the modulation of HSCs following exposure to dmPGE2 or indomethacin was documented in vivo by confocal microscopy. Exposure to dmPGE2 following irradiation of adult fish induced HSC gene expression and enhanced hematopoietic recovery, indicating that PGE2 also functions in regulating adult marrow HSC homeostasis. Incubation of murine embryonic stem cells with PGE2 during embryoid body differentiation resulted in a dose-dependent increase of hematopoietic colonies in methylcellulose, while indomethacin exposure inhibited colony formation, demonstrating that the function of PGE2 in HSC regulation is conserved in mammals. Furthermore, ex vivo treatment of murine bone marrow with dmPGE2 resulted in a 2-fold increase in CFU-S number and enhanced the frequency of multi-lineage engrafting HSCs more than 3-fold in a limiting dilution competitive repopulation assay. The identification of the prostaglandin synthesis pathway as a potent regulator of vertebrate hematopoietic stem cell homeostasis has major implications for new treatments of diseases such as anemia and leukemia.
A 48-Week Open-Label Study of Senicapoc (ICA-17043), a Gardos Channel Blocker, in Patients with Sickle Cell Disease.
Authors: Swerdlow Paul , Ataga Kenneth , Smith Wally , Saunthararajah Yogen , Stocker Jonathan W. 
Published: April 2020

Abstract
The Gardos channel, a calcium-activated potassium channel that spans the membrane of red blood cells (RBCs), is a key pathway in RBC dehydration affecting the intracellular concentration of hemoglobin S (Hb S). Inhibition of the Gardos channel in patients with sickle cell disease (SCD) may prevent the formation of dehydrated sickle RBCs, decrease Hb S polymerization, and reduce symptoms. In a Phase II 12-week, randomized, double-blind, placebo-controlled, dose-finding study in 90 patients with SCD, senicapoc (ICA-17043), a novel Gardos channel blocker, demonstrated statistically significant and beneficial hematologic effects including increased hemoglobin levels and decreased indicators of hemolysis. Patients from this study were eligible to enroll in a 48-week, open-label extension study in which all patients received an oral daily dose (10 mg) of senicapoc. Safety assessments included clinical laboratory data, physical exams, vital signs, ECGs, and ophthalmologic exams. Of 56 eligible patients, 44 enrolled in the open-label study. Because all patients received active drug, no formal efficacy comparisons to placebo were available. Within-subject comparison versus baseline levels from the double-blind phase indicated that the beneficial effects of senicapoc were maintained during the open-label study. Patients demonstrated increases in hemoglobin (+6%), hematocrit (+6%), and RBC count (+6%), and decreases in dense cells (−24%), reticulocytes (−19%), indirect bilirubin (−30%), and lactate dehydrogenase (−18%). Senicapoc was generally well tolerated during the open-label extension study. No deaths occurred, and there were no serious adverse events attributable to senicapoc. Twelve of 44 patients discontinued from the 48-week treatment period. Two patients discontinued due to adverse events considered possibly or probably related to study medication (elevation in gamma glutamyl transferase [GGT] level and interstitial nephritis, respectively). Two additional patients discontinued due to adverse events (sickle cell crisis and pain) not considered related to study medication. Of the 8 remaining patients, 1 was lost to follow-up, and 7 discontinued for administrative reasons. The most common adverse events (≥10% of patients) during treatment included sickle cell pain crisis, arthralgia, back pain, headache, upper respiratory tract infection, limb pain, increased GGT, pyrexia, and rash. The only adverse events that occurred in 2 or more patients and considered possibly related to study medication were GGT elevation, rash, and headache. In conclusion, senicapoc 10 mg once daily for 48 weeks appears to be safe and well tolerated in patients with SCD. Hematologic and clinical laboratory data collected in this safety extension study are consistent with the beneficial hematological effects observed during the Phase II double-blind study.
Blocking Adhesion of Sickle Erythrocytes to Endothelial αVβ3 Using RNA Aptamer.
Authors: Nishimura Jun-ichi , Burnette Angela D. , Batchvarova Milena , Nimjee Shahid M. , Zennadi Rahima , Sullenger Bruce A. , Telen Marilyn J. 
Published: April 2020

Abstract
Vaso-occlusive crises are a major clinical feature of sickle cell disease (SCD), and the adhesion of sickle erythrocytes (SS-RBC) to vascular endothelium is crucial to the generation of vaso-occlusion. The αvβ3 integrin is a major endothelial ligand for SS-RBC. Soluble thrombospondin has been thought to serve as a bridging molecule between erythrocyte CD36 and endothelial αvβ3, and high-molecular-weight multimers of von Willebrand factor also promote SS-RBC adhesion to endothelial αvβ3. Our group recently identified SS-RBC adhesion to endothelium via ICAM-4 (LW, CD242)-αvβ3 interactions (Blood, 104, 3774, 2004), suggesting that αvβ3 is a critical target against which to develop reagents to prevent or treat vaso-occlusive crises in SCD. Aptamers are oligonucleotides that bind to molecular targets in a manner conceptually similar to antibodies and have been identified against a wide range of therapeutic targets. RNA aptamers that bind to human integrin αIIbβ3/αvβ3 and inhibit integrin binding to the ligands vitronectin and fibrinogen have previously been identified (Biochem Biophys Res Commun, 338, 956, 2005). We have now tested one of these high-affinity αvβ3 aptamers (clone 17.16: UUCAACGCUGUGAAGGGCUUAUACGAGCGGAUUACCC) for its ability to prevent adhesion of SS-RBC to endothelial cells. Aptamer clone 17.16 bound αIIbβ3 with a Kd of 7–10nM, and the binding was blocked by both Abciximab, a monoclonal antibody against human integrin αIIbβ3/αvβ3 via a common binding motif RGD (arginine-glycine-aspardic acid), and Eptifibatide, a small molecule that binds to the RGD moiety, suggesting the sharing of the binding site at the RGD moiety. To measure its anti-adhesion activity, an in vitro flow chamber assay was adopted. We first induced enhanced expression of αvβ3 on the immortalized HUVEC cell line EC-RF24, using each of the following: TNF-α (10ng/mL for 18.5 hrs at 37°C), thrombin (1nM for 5 min at 37°C), or histamine (25mM for 12 min at RT), and αvβ3 expression by treated and nontreated cells was measured by flow cytometry. The anti-adhesion activity of aptamer clone 17.16 was then confirmed using HUVECs treated with thrombin (1nM for 5mins at 37°C) using a flow chamber assay. Aptamer clone 17.16 (30nM) had anti-adhesion activity similar to LM609, an inhibitory antibody to αvβ3, whereas human complement 8 aptamer (Blood, 106, 57a, 2005, negative control, 30nM) did not have anti-adhesion activity. The anti-adhesion activity of aptamer clone 17.16 (30nM) was enhanced by a dose escalation to 60nM and 120nM. At 2 dynes/cm2, maximal inhibition of adhesion was 57%. In conclusion, we observed significant anti-adhesion activity of αvβ3 aptamer clone 17.16, and it has currently reached a stage suitable for modification to enhance stability and bioavailability. In addition, in vivo experiments in mice will employ intravital microscopy to measure anti-adhesion activity in vivo.
Figure Figure