bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Leukemia in Hispanic Americans: Incidence and Incidence Rate Differences by Nativity.
Authors: Pollyea Daniel A , Kohrt Holbrook E , Yang Juan , Chang Ellen T , Gomez Scarlett Lin , Clarke Christina A 
Published: October 2019

Abstract
Abstract 3160

Introduction:
Acute leukemias (AL) have a distinct incidence pattern in Hispanics versus Caucasians, with higher rates of B-cell acute lymphoblastic leukemia (ALL) and acute promyelocytic leukemia (APL), and lower rates of non-APL acute myeloid leukemia (AML). Despite the fact that incidence differentials between foreign- and native-born populations can inform the relative contributions of environmental and genetic factors in cancer etiology, no such investigation has been undertaken in Hispanics with AL.

Methods:
To better understand heritable genetic versus environmental contributors to occurrence patterns, we assessed AL incidence in a large population of California Hispanics according to birthplace. Cancer incidence data were obtained from the California Cancer Registry, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Patients were included if they were living in California and diagnosed between 2000–2009 with AL. Population estimates were obtained from the 2000 Census Summary Files 3, and estimates by nativity were derived from the 20% Integrated Public-Use Microdata Sample of the censuses.

Results:
Compared to Caucasians, Hispanics had an increased incidence of B-cell ALL and APL, with incidence rate ratios (IRR) of 2.13 (95% confidence interval [CI] 1.93–2.35) and 1.33 (95% CI 1.12–1.57), respectively. There was no difference in B-cell ALL incidence by nativity, with an IRR for foreign- to native-born Hispanics of 1.07 (95% CI 0.85–1.34). However, foreign-born Hispanics had a greater incidence of APL than native-born Hispanics (IRR 1.79, 95% CI 1.11–2.94).

Conclusions:
Our findings suggest the increased B-cell ALL incidence for foreign-born Hispanics is influenced by heritable genetic factors. Furthermore, the increased incidence of APL for foreign-born Hispanics may result from environmental exposures currently not described and which require further epidemiologic investigation.

Disclosures:
No relevant conflicts of interest to declare.
Transcriptome- Based Analysis of EPO Dependent Cfu-e to Erythroblast Development
Authors: Verma Rakesh , Narayanan Aishwarya , Kuhrt David , Li Lei , Su Su , Asch Ruth , Jachimowicz Edward , Wojchowski Don M. 
Published: October 2019

Abstract
Abstract 3188
To provide molecular insight into erythroid developmental programs, including EPO- regulated aspects, we have employed transcriptome-based approaches to analyze the stage-wise development of purified murine bone marrow- derived CFUe, proerythroblasts and maturing erythroblasts. In vivo and ex vivo, these progenitors develop as KitposCD71highTer119neg; KitnegCD71highTer119neg; and KitnegCD71highTer119pos cohorts (designated as E1, E2, E3 stages, respectively). In the context of EPO- modulation, stage E1 cells exhibited ∼250 EPO- regulated target genes. In stage-E2 proerythroblasts, in contrast, 750 transcripts proved to be EPO- regulated while stage-E3 erythroblasts exhibited only select EPO- modulated genes (<50). At E1 and E2 stages, EPO- regulated targets included overlapping yet distinct sets, and this was reflected in functional sets of GO terms. Major EPO- targets at stage E1 included cell cycle and cell biogenesis genes, while in E2 proerythroblasts, negative regulators of protein kinases (and kinase activity) constituted a major EPO/EPOR target set. As E1 CFUe transitioned to E2 proerythroblasts, an unexpected transient narrowing in the complexity of overall expressed genes was exhibited. Stage- modulated global sets of transcripts included myeloid cell differentiation factors, cell number homeostasis factors and heme biosynthetic processes. As E2 proerythroblasts transitioned to E3 erythroblasts, functional GO sets were associated predominantly with dynamics in organelle and cellular compartments. In addition, HomoloGene and Connectivity Mapping approaches were applied to compare transcriptomes of stage E1, E2 and E3 murine bone marrow erythroid progenitors with four recently studied stages of human erythroid progenitor cell development (here, termed H1, H2, H3 and H4). High correlation of stage E1 m-CFUe with not only human H1 CFUe but also H2 proerythroblasts was observed (0.59 and 0.57 correlations). Stage E2 murine proerythroblasts best corresponded to H2 human proerythroblasts (0.36 correlation score), while E3 murine erythroblasts aligned closely with human H4 late stage erythroblasts (0.58 correlation score). These latter analyses provide novel transcriptome- based comparisons, and transcript specific insight, into conserved vs distinct features of murine and human erythroid development at CFUe to maturing erythroblast stages.

Disclosures:
No relevant conflicts of interest to declare.
Dietary Supplementation with Genistein Increases Hepcidin Expression in Wild Type Mice
Authors: Zhen Aileen W. , Volovetz Josephine , Fraenkel Paula G. 
Published: October 2019

Abstract
Abstract 3208
Iron overload is an important cause of morbidity and death in patients with hemoglobinopathies, transfusion-dependent anemias, and hereditary hemochromatosis. As humans have no means of excreting iron, regulation of iron homeostasis depends on limiting intestinal iron absorption and optimizing iron release from macrophages to developing erythrocytes. Hepcidin, a peptide hormone produced in the liver, modulates intestinal iron absorption and macrophage iron release via effects on ferroportin. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. We conducted a small-scale chemical screen and found that the isoflavone genistein, a major dietary component of soybeans, enhanced Hepcidin transcript levels in zebrafish embryos. Furthermore genistein treatment increased Hepcidin transcript levels and Hepcidin promoter activity in human hepatocytes (HepG2 cells) in a Stat3 and Smad4-dependent manner. To evaluate genistein's effect in a mammalian model, we placed groups of 4 four-week old male C57BL/6 mice on an iron-sufficient, low soy diet (AIN93G containing 35 mg of iron/kg) supplemented with 0, 250, or 500 mg of genistein per kg of food for 7 weeks, and then sacrificed the animals for analysis. Plasma genistein levels (mean±SE) at the time of sacrifice were 0.015±0.015, 0.52±0.173, and 2.07±0.65 micromolar, respectively. Compared to mice not treated with genistein, the 250 mg/kg dose produced a significant increase in hepatic Hepcidin (HAMP1) transcript levels (1.49±0.10 vs 0.93±0.10, p=0.01), while the 500 mg/kg dose did not. Although liver iron content, spleen iron content, and weight gain were not significantly different among the groups, the ratio of Hepcidin expression to liver iron content was significantly increased in the animals treated with genistein 250 mg/kg compared to controls (0.013±0.0009 vs 0.0074±0.00068, p=0.0068). In conclusion, genistein is the first orally administered small molecule experimental drug shown to increase Hepcidin transcript levels in vivo. Future experiments will evaluate the effects of genistein on genetic models of iron overload syndromes.

Disclosures:
No relevant conflicts of interest to declare.
Erythropoietin Levels in Patients with Sickle Cell Disease Not in Vaso-Occlusive Crisis
Authors: Pulte Dianne , Nagalla Srikanth , Caro Jaime 
Published: October 2019

Abstract
Abstract 3242

Background:
Previous studies of erythropoietin production in sickle cell disease have shown that patients with sickle cell disease generally have an erythropoietin level in the lower end of the expected range. However, this finding was based on a relatively small number of patients including some who were in crisis when the erythropoietin level was drawn. A crisis might affect erythropoietin level by increasing inflammation beyond background and if the patient is transfused, the erythropoietin may not be well correlated with the apparent hemoglobin or hematocrit. In this study, we examine erythropoietin levels in patients with sickle cell disease seen in the outpatient clinic and not in crisis when the level was drawn.

Methods:
Patients receiving outpatient care at the Thomas Jefferson University Cardeza Sickle Center underwent laboratory evaluation as part of routine standard of care for their disease. Hemoglobin level, creatinine, erythropoietin level, lactate dehydrogenase, and reticulocyte count were extracted anonymously from patient charts for evaluation of erythropoietin in sickle patients in the outpatient setting without crisis and correlation of level with kidney function, hemoglobin level, and ongoing hemolysis.

Results:
Forty-eight measurements of erythropoietin from 39 unique patients were extracted. Two were not included as chart review suggested that the patient was in crisis when the values were obtained. Of the remaining 36 patients, three patients had SC disease, four sickle-thalassemia, the rest sickle cell anemia. Three patients received exogenous erythropoietin for hypoplastic anemia or chronic renal failure complicating sickle cell disease. Of the remaining 30 patients, creatinine ranged from 0.2–1.8.
Erythropoietin was higher than the normal range for most patients, as would be expected in a chronic anemia. Erythropoietin level was roughly correlated with hemoglobin, but some patients had erythropoietin levels much lower than expected for their hemoglobin (figure). Erythropoietin was not well correlated with creatinine or with hemolysis. Hemoglobin was higher for patients with SC disease than for sickle cell anemia or sickle-thalassemia, but erythropoietin levels were not significantly different between disease types.

Conclusions:
Patients with sickle cell disease who are not in crisis have erythropoietin levels that are elevated, but lower than expected for a healthy patient with chronic anemia, with a greater lack in patients with sickle cell anemia as compared to SC disease. Erythropoietin did not correlate well with kidney function as measured by creatinine or calculated glomerular filtration rate, suggesting that current measures of kidney damage may not be entirely adequate to detect early kidney disease in sickle cell disease.

Disclosures:
No relevant conflicts of interest to declare.
The Role of the IAP Livin in Megakaryocytes Differentiation and Thrombopoiesis
Authors: Abd-Elrahman Ihab , Deutsch Varda R , Pick Marjorie , Kay Sigi , Neuman Tzahi , Perlman Riki , Ben-Yehuda Dina 
Published: October 2019

Abstract
Abstract 3297
In this study we observe that Livin plays a role in thrombopoiesis. Livin is a member of the Inhibitor of Apoptosis Proteins (IAP) family of intracellular anti-apoptotic proteins that acts by binding and inhibiting caspases. Previously we found that Livin is unique among the IAP members as upon strong apoptotic stimuli, it is specifically cleaved by caspases to produce a truncated protein (tLivin) that has a paradoxical pro-apoptotic activity. Here we have shown that Livin is expressed in normal mature bone marrow MK and in platelets.

Objective:
The objective of this study was to evaluate the potential role of Livin in thrombopoiesis.

Methods:
We studied Livin expression in normal BM using immunohistochemistry staining. We studied the ability of primary MK generated from CD34+progenitor cells over-expressing Livin to produce platelets. While, the human cell line, LAMA-84, was induced by a phorbol myristic acid (PMA) to differentiate to megakaryocytes (MK) to evaluate the potential role of Livin in thrombopoiesis.

Results and conclusions:
Livin over-expression in CD34+ progenitor cells induced differentiation of these cells into MK and increased the ability of these primary MK to produce platelets. LAMA-84, upon differentiation into MK, produces platelets that are functional and capable of aggregating. This thrombopoiesis was accompanied by increased Livin expression and downregulation of other IAPs: XIAP and Survivin. Our results show that Livin plays a dual role in thrombopoiesis, demonstrating both an anti and pro-apoptotic role in cell activity.

Disclosures:
No relevant conflicts of interest to declare.
Spontaneous Atherosclerotic Lesions in TREM-Like Transcript-1 Deficient Mice
Authors: Gonzalez Marieli , Reyes Fiorella , Marrero Deborah , Washington A. Valance 
Published: October 2019

Abstract
Abstract 3312
It is well known that platelets, aside from regulating hemostasis, play an important role in inflammation-associated conditions like sepsis, viral infections, and atherosclerosis. In the latter, platelets not only form occlusive thrombi at lesions, but also play a role in the initiation of the disease by depositing activating molecules such as cytokines on the developing plaque. Although the mechanism by which platelet aggregation leads to occlusion is well-defined, the role of platelets in lesion initiation and progression is poorly understood and thus remains a gap in our knowledge. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a receptor exclusively found on megakarocytes and platelets that has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface along with p-selectin from the α-granules. Studies using the treml1−/− mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms and therefore should play a role in the development of atherosclerosis. Our original hypothesis was that evaluation of atherosclerosis lesions in the treml1−/− mouse would demonstrate fewer lesions and hence, a similar phenotype as the psel−/− mouse. Evaluation of 50 week old mice fed a chow diet surprisingly revealed spontaneous lesions in C57Bl/6 treml1−/− mice. Subsequent evaluation of cholesterol levels in treml1−/−mice on an atherogenic diet for four weeks demonstrated that they have significantly higher cholesterol levels when compared to WT mice. To evaluate atherosclerosis progression in TLT-1 deficiency, we developed the apoE−/−/treml1−/− double knockout mice and assessed lesion development after a four weeks atherogenic diet. Our results demonstrate that double null mice have exacerbated lesions when compared to the apoE −/− mice. Accordingly, 50 week old double null mice fed a chow diet also have larger atherosclerotic lesions in the aortic sinus than apoE −/− mice. These results clearly support a role for TLT-1 in dampening the progression of atherosclerosis. Current data from our laboratory suggest that TLT-1 may affect leukocyte function, therefore based on our model that TLT-1 deficiency leads to a heighted inflammatory state we hypothesized that treml1−/− mice will demonstrate greater leukocyte recruitment into the injured vessel wall, leading to greater deposition of factors that recruit more platelets and macrophages that later become foam cells. To delineate the mechanism by which TLT-1 affects atherosclerosis progression, we have evaluated neutrophil and monocyte infiltration into the vessel wall of the aortic sinus after four weeks atherogenic diet. The current state of our investigation is reported here.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy of Immunomodulatory Therapy with All-Trans Retinoid Acid for Adults with Chronic Immune Thrombocytopenia
Authors: Dai Lan , Wang Zhaoyue , Zhang Ri , Bai Xia , Zhu Mingqing , Ruan Changgeng 
Published: October 2019

Abstract
Abstract 3335

Objective:
Immune thrombocytopenia (ITP) is an immune-mediated disorder characterized by antibody- and cell-mediated platelet destruction and impaired platelet production. In addition of antibody-mediated platelet clearance, T-cell is also involved in platelet destruction or marrow suppression. During immune responses CD4+ T cells can differentiate into a range of cell types, including T helper type 1 (Th1), Th2, Th17 and regulatory T cells (Treg). The goal of the present study is to investigate the therapeutic effects of all-trans-retinoic acid (ATRA) plus prednisone treatment on adult refractory idiopathic thrombocytopenic purpura (RITP) and to further explore the underlying mechanisms.

Methods:
All 35 patients were treated with ATRA at fixed dose of 10 mg/tid plus prednisone and were started after discontinuation of other previous ITP treatment. Peripheral blood samples were collected from 35 RITP patients and 20 healthy subjects. The concentrations of the peripheral blood CD 4+ T cells (Th1, Th2, TH17, TREG) were analyzed by flow cytometry, the levels of cytokines were confirmed by enzyme-linked immunoassay (ELISA), and the expression of T-bet, GATA-3, RORγt, FOXP3 were detected by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) in 35 RITP patients before and after treatments, with 20 normal individuals as respective controls.

Results:
The overall response rate of ATRA plus prednisone treatment in RITP patients was 54.3%, 28.6%(n=10) of patients with a complete response and 25.7%(n=9) of patients with a partial response. Among the 19 responders, the mean platelet count was 34+13×106/ml before ATRA therapy and 106+29×106/ml after treatment. No severe adverse effects happened. The levels of regulory T cells were significantly increased in patients after ATRA plus prednisone treatment (P < 0.05); the levels of Th1, Th2, Th17 were not significantly improved (P >0.05) in effective patients after treatments in flow cytometry analysis. The concentrations of IL-10, TGF-β was increased (P<0.05), whereas IFN-γ, IL-4, IL-17 factor showed no obvious change in the effective groups after treatment (P > 0.05). The expression levels of Foxp3 enhanced dramatically after treatment in real-time RT-PCR analysis (P < 0.05). However, the concentrations of T-bet, GATA-3 and ROR-γ showed no obvious change after the therapy in real-time RT-PCR analysis(P > 0.05).

Conclusions:
54.3% of RITP patients recovered after ATRA plus prednisone treatments. The therapeutic effects of ATRA plus prednisone may be involved in the increased levels of regulory T cells in peripheral blood through increased expression of TGF-β, IL-10, and Foxp3. In comparison, the therapeutic effects may not be attributed to the expression of TH1, TH2, TH17, IFN-γ, IL-4, IL-17, T-bet, GATA-3, RORγt.

Disclosures:
No relevant conflicts of interest to declare.
Measurement of the Absolute Immature Platelet Number Reflects Marrow Production and Is Not Impacted by Platelet Transfusion
Authors: Bat Taha , Leitman Susan F. , Calvo Katherine R , Chauvet Donna , Dunbar Cynthia E. 
Published: October 2019

Abstract
Abstract 3425

Background
The ability to distinguish increased platelet destruction from platelet hypo-production is important in the care of patients with bone marrow failure syndromes and patients receiving high dose chemotherapy. The measurement of immature circulating platelets based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent platelet transfusion on measurement of immature platelet parameters.

Study Design and Methods
The immature platelet fraction (IPF) and absolute immature platelet number (AIPN) were measured using the Sysmex XE-5000 analyzer prior to and following platelet transfusion in 9 transfusion-dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in 3 plateletpheresis components collected from normal donors.

Results
Platelet transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 ±4.6% at day -1 to 2.3 ±1.4% at day 0 before returning to 4.3 ±2.3% at day +1. In the platelet component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored platelets, no longer detected in vivo once the platelets were transfused.

Conclusion
Platelet transfusion decreases the IPF due to the resultant increase in circulating platelet count. However, platelet transfusion does not change the circulating absolute immature platelet number (AIPN), validating this assay as a reflection of ongoing platelet production by the bone marrow in various clinical settings, regardless of proximity to platelet transfusion.

Disclosures:
No relevant conflicts of interest to declare.
Vitamin K3 Is a Potential Ultraviolet Photosensitizer for Pathogen Reduction of Human Platelets and Plasma
Authors: Xu Fei , Vostal Jaroslav 
Published: October 2019

Abstract
Abstract 3434
Human platelets are stored up to 5 days at room temperature and may support bacterial growth before transfusion. Transfusion of bacterially contaminated platelets remains the highest transfusion transmitted infectious disease risk today. One approach to reducing this risk is the development of safe and effective pathogen reduction methodologies. We evaluated UV light (A and B) with vitamin K3 (VK3) as a photosensitizer for efficacy in reducing bacterial growth in platelet concentrates and plasma.
Six species of bacteria, including Bacillus cereus, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae and Escherichia coli, were spiked respectively into phosphate buffered saline (PBS) buffer and exposed to UVA irradiation before bacterial growth was determined. As shown in Figure 1, the bacterial colony forming units (CFU) were reduced with increasing VK3 concentrations and UVA dosages. The VK3 at 400 uM plus UVA-radiation (2.88 J/cm2) significantly reduced the bacterial CFU in PBS spiked with bacteria.
The same six-bacteria panel were spiked respectively into platelet concentrates (PCs) diluted with platelet additive solution and mixed with 400 uM VK3 before the UVA irradiation. As shown in Fig 2a, the bacteria CFU were reduced with increasing dosage of UVA but efficacy declined with lower dilution of PCs. At VK3 concentration of 400 uM and PC diluted to 20% a UVA-dose of 5.76 J/cm2 significantly reduced bacterial CFUs in PCs spiked with E coli, K pneumoniae, P aeruginosa and S epidermidis respectively. Similar results were obtained with the same six-bacteria panel spiked into plasma as shown in Fig 2b.
UVB and VK3 combination had a biphasic inhibitory effect as shown in Fig 3. The VK3 at 200 uM plus UVB-radiation (0.015 J/cm2) also significantly reduced the CFU from the same six-bacteria panel spiked into PBS. However higher concentrations of 1600 uM VK3 could partially reverse the bacterial growth inhibition under UVB-radiation at 0.0038, 0.0075, and 0.015 J/cm2 for E coli, K pneumoniae and S aureus bacterial organisms.
These findings suggest that VK3 may serve as an effective UVA photosensitizer for pathogen reduction of human platelets. With UVB light, lower concentrations of VK3 are effective at inhibiting bacterial proliferation but higher concentrations of VK3 may serve as a weak UVB blocker. Additional studies will need to be conducted to determine the impact of UV light and VK3 on platelet in vitro and in vivo performance.
“This abstract reflects the views of the author and should not be construed to represent FDA's views or policies.”

Disclosures:
No relevant conflicts of interest to declare.