bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Hypomorphic Cbfb Allele Reveals Requirements for the Development of T Lymphocytes, Granulocytes, and Monocytes/Macrophages, and for Maintaining Proper Numbers of Hematopoietic Progenitors.
Authors: Talebian Laleh , Li Zhe , Gallagher Torrey L. , Guo Yalin , Speck Caroline L. , Stacy Terryl , Speck Nancy A. 
Published: April 2020

Abstract
CBFβ is the non-DNA binding subunit of the core binding factors, and is required for both the functions of Runx1 in hematopoiesis and Runx2 in osteogenesis. Homozygous disruption of Cbfb results in embryonic lethality at mid-gestation and a severe impairment of fetal liver hematopoiesis, a phenotype similar to Runx1 deficiency. To examine Cbfb requirements at later stages of hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). Mice homozygous for the Cbfbrss allele have a 4- to 5-fold reduction in CBFβ protein levels, while Cbfbrss/− mice have an 8- to 10-fold reduction in CBFβ concentration. Cbfbrss/rss and Cbfbrss/− mice die at P0 for unknown reasons and display minor defects in bone ossification. Granulocyte and macrophage differentiation at E17.5 is impaired in both Cbfbrss/rss and Cbfbrss/−animals, as evidenced by a 2- to 3- fold decrease in GR1+ and Mac1+ cells. The percentages of Ter119+, B220+, and CD19+ cells are normal. Fetal liver hematopoietic progenitor numbers, as determined by cell surface marker and functional analyses, are increased approximately 2-fold. The most severe defects are in the T cell lineage. Cbfbrss/rss fetuses have reduced thymus cellularity and lower numbers of CD8 SP T cells, consistent with a role for Runx1 and Runx3 in epigenetic CD4 silencing. A further 2-fold reduction in CBFβ levels in Cbfbrss/− fetuses results in an absence of CD4/8 SP and DP cells. These hematopoietic defects were also seen upon transplantation of Cbfbrss/rss and Cbfbrss/− fetal liver cells into congenic Ly5.1/5.2 mice. Our data indicate that the threshold level of CBFβ required for normal hematopoiesis, bone development, and postnatal viability is somewhere between 25%-50% of its normal concentration. The data demonstrate that T cell development is particularly sensitive to CBFβ levels, and both granulocyte and macrophage differentiation require CBFβ. Since the conditional knockout of Runx1 in the adult mouse reported by Ichikawa et al. (Nat Med.10, 299, 2004) did not cause either granulocyte or monocyte/macrophage defects, we hypothesize that Runx2 and/or Runx3 are also required in these lineages. Hemizygosity for CBFB-MYH11, the product of the inv(16), is associated with a more severe phenotype than is seen in the Cbfb rss/− fetuses (Castilla et al. Cell87, 687, 1996). We therefore conclude that the hematopoietic consequences for cells expressing the inv(16) are equivalent to a greater than 10-fold reduction in the level of functional CBFβ.
Adoptive Transfer of T Cell Help Breaks Tolerance in Endogenous, Tumor-Specific CD8+ T Cells Responding to a Growing Tumor.
Authors: Wang Jie , Aalamian Maryam , Jalla Sanju , Luznik Leo , Fuchs Ephraim J. 
Published: April 2020

Abstract
Patients who reject allogeneic blood or marrow grafts after non-myeloablative conditioning sometimes develop delayed or sustained clinical disease responses, raising the possibility that a transient graft-versus-host reaction rekindles dormant anti-tumor immunity by recipient T cells. More specifically, we postulate that endogenous tumor-specific CD8+ T cells are not irreversibly tolerant of a growing tumor, and can be activated to effector function by tumor antigen recognition in the presence of adoptively transferred CD4+ T cell help. We have tested this hypothesis by examining the response of influenza hemagglutinin (HA)-specific “endogenous” CD8+ T cells in HA-tumor-bearing mice treated with cyclophosphamide (Cy) and adoptive transfer of allogeneic or tumor-specific CD4+ T cells, with or without concomitant tumor vaccine administration. In these models, this combination therapy induced the clonal expansion of endogenous, tumor-specific CD8+ T cells, their secretion of interferon gamma, and in vivo cytolytic activity against HA-expressing cells. In separate experiments, adoptively transferred, major histocompatibility complex-mismatched CD4+ T cells induced the activation of recipient, CD11c+ dendritic cells, as demonstrated by enhanced expression of the costimulatory molecules CD80 and CD86. The administration of Cy followed by infusion of allogeneic T cells, with or without tumor vaccine administration, also induced regression of B cell leukemia/lymphoma or established prostate cancer. These results highlight the potential cooperation of donor CD4+ T cells and recipient CD8+ T cells in transient or stable mixed hematopoietic chimeras, and open new avenues for the immunotherapy of cancer in the clinic.
Elevation of Plasma Von Willebrand Factor and Tumor Necrosis Factor-α in Obese Subjects and Their Reduction by Low Molecular Weight Heparin.
Authors: Mousa Shaker A. 
Published: April 2020

Abstract
Background: Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease in the general population. We compared associations between vWF level and markers of inflammation as well as the effects of low molecular weight heparin (LMWH) in obese as compared to healthy human subjects.
Methods: Plasma samples were obtained from healthy volunteers (n = 32) and obese subjects (n = 12) before and after administration of a single subcutaneous (SC) dose of tinzaparin, given at a deep vein thrombosis (DVT) prophylaxis dose of 75 IU/kg once a day. These samples were analyzed for vWF and tumor necrosis factor-α (TNF-α) by ELISA. Also examined was the effect of different LMWH on the release of vWF from human umbilical vein endothelial cells (HUVEC) in response to various stimuli, such as oxidized low density lipoprotein (LDL) or endotoxin.
Results: Obese subjects showed higher plasma levels of TNF-α compared with normal-weight subjects. Regression analysis showed plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-α in these obese subjects. Tinzaparin, given at a prophylaxis dose for DVT (75 IU/kg, SC, QD), significantly reduced elevated plasma levels of endothelial dysfunction marker vWF associated with higher inflammatory TNF-α levels (P &lt;0.01). HUVEC, when treated with oxidized LDL or endotoxin, demonstrated a significant elevation of vWF release into the medium in a time-dependent manner. Tinzaparin and enoxaparin significantly reduced this increased vWF release from HUVEC in the media.
Conclusion: Plasma values of vWF and TNF-α are higher in obese than in normal-weight individuals. Treatment with tinzaparin lowers plasma levels of TNF-α in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones because of the higher levels of circulating TNF-α. Tinzaparin reduced vWF levels in these obese subjects.
Table 1. Effect of Tinzaparin (75 IU/kg, SC, QD) on Plasma vWF in Obese and Normal-Weight Subjects
Table 2. Effect of Tinzaparin (75 IU/kg, SC) on Plasma TNF-α in Obese and Normal-Weight Subjects
Subjects Mean Plasma vWF (IU/mL) ± SD Pre-Tinzaparin Mean Plasma vWF (IU/mL) ± SD Post-Tinzaparin (2 h) * P &lt;0.05 obese versus normal-weight subjects before treatment with tinzaparin; †P &lt;0.01 post- versus pre-tinzaparin; vWF = von Willebrand factor. Normal body weight (n = 32) 0.44 ± 0.15 0.36 ± 0.12 Obese (n = 12) 0.68 ± 0.20* 0.29 ± 0.11† Subjects Mean Plasma TNF- α (pg/mL) ± SD Pre-Tinzaparin Mean Plasma TNF- α (pg/mL) ± SD Post-Tinzaparin * P &lt;0.05 obese compared with normal-weight subjects before treatment with tinzaparin; †P &lt;0.01 post- compared with pre-tinzaparin; TNF-α = tumor necrosis factor-α. Normal body weight (n = 32) 1.68 ± 0.55 1.37 ± 0.33 Obese (n = 32) 2.82 ± 0.38* 1.45 ± 0.25†
Correlation of Genetic Polymorphisms Detected by Geneohm EPLEX™ Electrochemical Platform with Functional Study for Venous Thrombosis.
Authors: Xu Bo , Thompson Steven , Koenigberger Carol , Pettay James , Silbergleit Arkadiy , Kawashima Tad , Kottke-Marchant Kandice , Tubbs Raymond R. 
Published: April 2020

Abstract
Venous thrombosis (VT) is a multi-factorial disorder with both congenital and acquired risk factors. Mutations in several genes, such as factor V, prothrombin and methylene tetrahydrofolate reductase (MTHFR), are considered risk factors for thrombophilia. Since multiple mutations compound the risk for (VT), simultaneous discovery of mutations could directly alter patient management. In this study, we employed the GeneOhm ePlex™ platform to simultaneously detect genetic polymorphisms for six markers: factor V Leiden (FVL) and HR2A45374G, prothrombin G20210A, MTHFR C677T and A1298C, and plasminogen activator inhibitor 1 (4G/5G). Fifty-one patient samples were selected. Each sample was genotyped for all six markers on the GeneOhm ePlex™ electrochemical array and data from functional studies were analyzed and compared to the genotyping results. Among the 51 patients, 16 were tested for activated protein C resistance and the average values were 1.22, 1.76 and 2.64 for FVL homozygous, heterozygous and wild type normal patients, respectively. In addition, the average plasma homocysteine levels measured in 17 patients were 15.40, 6.42 and 11.93, 12.63 mmol/L for MTHFR C677T homozygous, heterozygous and MTHFR A1298C heterozygous and C677T/A1298C double heterozygous, respectively. Furthermore, 10 out of 11 patients with history of deep venous thrombosis (DVT) and/or pulmonary embolism (PE) displayed genetic abnormalities in FVL or prothrombin G20210A. The other patient with history of both DVT and PE showed homozygous in MTHFR C677T with high plasma homocysteine level (22.3 mmol/L) and heterozygous mutation in PAI-1. This study demonstrates the principle of multiplexed molecular diagnostics for the polymorphisms associated with thrombophilia and the utility of the GeneOhm ePlex platform. The study is being expanded to test a larger set of samples to establish the relationship between genetic polymorphism and corresponding clinical outcome for all six markers.
Treatment of Deep Vein Thrombosis with Enoxaparin in Pediatric Cancer Patients Receiving Chemotherapy.
Authors: Stine Kimo , Saylors Robert , Saccente Suzanne , Becton David 
Published: April 2020

Abstract
Thrombosis is a known risk in pediatric patients with leukemia. This risk is increased when L-asparaginase is administered. However, children with cancer may have thrombotic complications similar to adults even in the absence of L-asparaginase. The risk may be related to the presence of central lines, surgery, immobilization, or inherited thrombophilia. Cancer in adult patients is also associated with an increased risk of thrombosis that may be related to the disease itself. Low molecular weight heparin such as enoxaparin has become widely used in adult patients with thrombosis. However, there is little data regarding the use of enoxaparin in children undergoing myelosuppressive therapy for malignancies. The purpose of this study was to review the utilization of low molecular weight heparin, enoxaparin (Lovenox), in children with cancer at our institution who had thrombosis while undergoing myelosuppressive chemotherapy. In particular we were interested in the efficacy of enoxaparin in these patients, and if these children were able to continue their chemotherapy without adjustment or interruption secondary to bleeding complications. We conducted a retrospective review from 1999 through April 1, 2004 which yielded seven patients with malignancies and a vascular thrombotic event. The age range was 4–17 years. Diagnosis include: B-precursor ALL (n=3), T-ALL, Hodgkin’s disease, Anaplastic large cell lymphoma, and rhabdomyosarcoma (n=1 each). Six patients developed a deep vein thrombus or clot of the vena cava. One of these 6 patients also had a pulmonary embolus. One patient presented with manifestations of a unilateral cerebral vascular accident without evidence of a DVT. U/S and CT/MRI were performed on patients when appropriate. All patients were screened for Protein C & S deficiency, ATIII deficiency, Factor V Leiden mutation, prothrombin 20210a mutation, and lupus anticoagulant. Treatment was enoxaparin, 1–1.5 mg/kg/dose twice daily to maintain a heparin anti-Xa level of 0.5-1.5 IU/mL. Once the clot had resolved, the enoxaparin was maintained daily for a total of 3–6 months of therapy. All patients had resolution of their thrombosis within 1–2 months of initiation of enoxaparin, and none required delays or dose-reduction of their chemotherapy regimens while on anti-coagulation. There were 10 documented occurences of thrombocytopenia (platelet count &lt; 50,000) in 2 patients without bleeding complications. There was a minimum of 50 days of documented thrombocytopenia while on enoxaparin. We conclude that enoxaparin is effective and safe treatment for thrombotic complications in children undergoing cancer chemotherapy.
Incidence of Ex Vivo Expansion on the Capacity of Cord Blood Graft To Generate Immune Cells: Rational for Co-Infusion of Expanded and Non Expanded Fractions?.
Authors: Rosenzwajg Michelle , Giarratana Marie-Catherine , Gluckman Jean-Claude , Douay Luc , Kobari Ladan 
Published: April 2020

Abstract
The aim of our study was to determine whether ex vivo expansion of umbilical cord blood (UCB) progenitor cells induces changes in their capacity to generate immune cells. CD34+ CB cells were cultured for 14 days with SCF, FLT3-l, TPO and G-CSF, inducing a total cells, CD34+ and LTC-ICs increase of 1500, 120 and 8 fold respectively. Non expanded (d0) and 14-day expanded (d14) CD34+ cells were compared for their capacity to produce T lymphocytes (TLs) using the fetal thymus organ culture system and DCs generated from d0 and d14 CD34+ cells were compared for their differentiation, phenotype and function. Total percentages of CD4+, CD4+CD8− and CD4+CD8+ TLs obtained from d0 and d14 CD34+ cells were comparable. In both fractions, most of the CD4+ T cells co-expressed iCD3 but a lower proportion of d14 derived TLs expressed sCD3. However, there was no significant difference between d0 and d14 derived TLs in term of Vb chain representation, all TCR-Vb chains examined being represented in each case. These data indicate that d0 and d14 CD34+ cells have a similar capacity to generate TLs and that expansion does not induced any skewing of the TCR-Vb repertoire. D0 and d14 CD34+ cells were next cultured with SCF, FL, GM-CSF and TNF-a to compare their capacity to differentiate into DCs. Similar percentages of CD1a+ DCs expressing the same levels of HLA-DR and co stimulatory molecules were obtained. DCs derived from d14 CD34+ cells were less potent to stimulate allogeneic TLs, but the pattern of cytokines produced by stimulated TLs was similar and no shift towards a predominant Th1 or Th2 response was observed. Moreover, in spite of a quantitative increase (15 fold) related to the CD34 pool amplification, we observed a decreased capacity (13-fold) of d14 cells to generate DCs compared to d0 CD34+ cells.
Overall, these results indicate that ex vivo expansion of CD34+ cells doesn’t induce any major modification in T Lymphopoiesis capacity while alters somehow the capacity of the graft to generate DCs. We discuss in the context of UCB transplantation, the putative interest of co-infusion of expanded and non expanded fractions in view of improving myelopoiesis in the graft without subverting the immune reconstitution.
Benefit of Fondaparinux in Medical Patients: A Subgroup Analysis.
Authors: Cohen Alexander T. , Gallus Alexander S. , Davidson Bruce L. , Lassen Michael R. , Prins Martin H. , Tomkowski Witold , Turpie Alexander G.G. , Egberts Jan F.M. , Lensing Anthonie W.A. 
Published: April 2020

Abstract
Aim
In the ARTEMIS study fondaparinux 2.5mg reduced the overall incidence of venous thromboembolism (VTE) by 47% in general medical patients when compared to placebo. Our aim was to identify which medical patient populations with an acute medical illness or risk factor for VTE benefited from fondaparinux prophylaxis.
Method
A total of 849 patients were enrolled in 35 centres in 8 countries. Patients were randomised to receive placebo or fondaparinux 2.5mg subcutaneously once daily for 6 to 14 days. 644 (76%) patients were available for assessment of the primary outcome, occurrence of documented VTE between day 1 and day 15. We performed a subgroup analysis of the incidence of VTE in the placebo and fondaparinux 2.5mg treatment groups. The medical illness subgroups analysed were those predefined in the original study: acute heart failure only, respiratory disease only, infectious/inflammatory disease only and more than one disease.
Results
Conclusion
Fondaparinux 2.5mg is superior to placebo in preventing VTE in patients with acute medical illness. Similar point estimates and overlapping confidence intervals indicate that the results are consistent within all the predefined medical illness.
Population variable Placebo Fondaparinux 2.5mg Relative risk reduction 95% CI * P Value n/N % n/N % *exact CI for RRR based on standardized statistics and inverting a 2-sided test Acute heart failure (NYHA III/IV) 10/82 12.2 7/78 9.0 26.4% [−78.9%;69.7%] 0.61 Acute respiratory disease only 4/73 5.5 1/63 1.6 71.0% [−86.6%;97.7%] 0.37 Acute infectious/inflammatory disease only 10/88 11.4 4/77 5.2 54.3% [−33.1%;85.0%] 0.17 More than one disease 10/80 12.5 6/103 5.8 53.4% [−21.4%;83.4%] 0.12
Targeting the Risks of Specific Antiplatelet Alloimmunization in the Populations of Sub-Saharan Africa, Asia, and Oceania.
Authors: Kaplan-Gouet Cecile , Bigot Andre , Imandy Gisele , M’Bayo Ferdinand , Khanh Hoa B. , Tetaria Claude , Martageix Corinne , Halle Liliane 
Published: April 2020

Abstract
As specific antiplatelet alloimmunization directed against Human Platelet Antigens (HPA) during pregnancy or after platelet transfusion is not a rare event, this study aims at identifying such a risk in the context of the diversity caused by the population migrations we see today in our hospitals and particularly in the Sub-Saharan African (SSA), south East Asia and Polynesian populations. Samples were collected from 155 Beninese, 118 Cameroonian, 96 Congolese (Kinshasa), 107 Vietnamese and 81 Polynesian Ma’ohis, all unrelated, healthy blood donors. DNA was extracted by salting out method and the platelet genotype was determined by PCR-RFLP. We did not observe any significant deviation from the Hardy-Weinberg equilibrium. As opposed to Caucasian populations, the risk of anti HPA-1a alloimmunization is extremely low, due to the absence, or at least the low frequencies of HPA-1 b homozygous individuals in these populations (Cameroon 0.8 % and Benin 1.3 %). An important risk could be associated with HPA-2 immunization in the SSA population, as we observed a relatively high frequency of HPA-2b homozygous individuals. Moreover we noted the frequency of HPA-3b homozygous to be between 11 and 24%. Given that, as neonatal alloimmune thrombocytopenia (NAIT) caused by anti HPA-3a or 3b is similar in severity to disease caused by incompatibility of HPA-1a, this risk should not be ignored particularly in the Vietnamese population with 24.3 % of HPA3b homozygous. We noted the absence of HPA-4b allele. Finally, in contrast to the frequency of HPA-6 heterozygous in the Polynesian population (17%), we do not observe HPA-6b homozygous individuals, suggesting a small risk for that antigen to be implicated in alloimmunization. The repartition of HPA-15 alleles is heterogeneous in these populations. In conclusion: HPA-2 alloimmunization in SSA populations should be identified for platelet transfusion refractoriness or NAIT, similarly for HPA-3 especially in the Vietnamese population and to a lesser degree, HPA-5 in the Cameroon and in the Congo.
Genotype frequencies
HPA-1 HPA-2 HPA-3 HPA-5 HPA-6 HPA-15 bb ...ab ↑bb ...ab ↑bb ...ab ↑bb ↑ ...ab bb ↑ ...ab bb Viet Nam 0.0 ↑ 09.4 0.0 54. ↑24.3 05.6 ↑0.0 02.8 ↑0 ↑ 57.0 24.3 Polynesia 0.0 ↑ 16.3 0.0 ↑ 37.5 18.7 05. ↑0.0 ↑ 17.1 0 ↑ 52.4 28.4 Benin 1.3 ↑ 44.8 7.1 42.8 ↑11.1 34.1 ↑0.8 0.00 ↑0 ↑ 41.6 14.1 Cameroon 0.8 32.7 ↑7.8 ↑ 50.8 13.1 29.8 ↑6.4 ↑ 0.00 0 ↑ 41.2 10.9 Congo 0.0 40.0 ↑2.5 49. ↑18.6 45.2 ↑4.1 ↑ 0.00 0 ↑ 43.8 05.5
Establishing Safety in the Clinic for the First Lentiviral Vector To Be Tested in Humans.
Authors: Dropulic Boro , Humeau Laurent , Slepushkin Vladimir , Lu Xiaobin , Manilla Peter , Rebello Tessio , Afable Cathleen , Lacy Kim , Ybarra Cathy , Levine Bruce , June Carl , MacGregor Rob Roy 
Published: April 2020

Abstract
Lentiviral vectors (LV) offer improved therapeutic benefit of gene therapy applications as a result of their ability to stably transduce a wide range of cycling and non-cycling cells. The first Phase I clinical trial using a lentiviral vector, VRX496, was initiated in January of 2003. The vector evaluated is an HIV-1 based lentiviral vector, fully gutted but retaining the 5′ and 3′ long terminal repeats, the packaging sequence, cPPT/CTS, splice donor and splice acceptor, and rev response element (RRE). VRX496 contains a splice-independent 937-base antisense sequence targeting the envelope gene in the HIV genome, and a small 186-base tag derived from the GFP gene to serve as a molecular marker for vector in HIV infected patient cells. Five (5) HIV-infected patients with CD4 counts between 200 and 500, and viral loads above 5000 copies/ml, no history of opportunistic infections, who have failed two regiments of highly active antiretroviral therapy (HAART), were serially enrolled in the trial. After leukopheresis, patient’s CD4 T lymphocytes were isolated by negative selection of CD8+ cells, and then cultured for three days in the presence of immobilized CD3/28 beads, and VRX496. Thereafter, the vector and beads were removed, cells were expanded to the dose of 1 x 1010, and then given intravenously over 15 minutes. At the time of this abstract, 4 patients have been dosed and have passed the initial 21-day safety assessment; a fifth patient is scheduled for dosing. No serious adverse events have occurred. All patients have steady CD4 counts, and viral loads have decreased below baseline in all patients, notably from 218,000 pre dose to 36,000 1 year post dosing in the first patient, and from 22,000 pre dose to 1,625 at 9 months post dosing in the second patient; patients 3 and 4 are at 3 months and 21 days post-infusion, respectively. Importantly, persistence of vector-modified CD4 cells are detected in the peripheral blood out to 9 months post dosing. This trial establishes for the first time the safety of lentiviral vectors for clinical gene therapy application.