bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Role for Apolipoprotein E Receptor 2 as a Platelet Receptor for Factor XI
Authors: White Tara C , Berny Michelle A , Tucker Erik I , Pang Jiaqing , Gailani David , Urbanus Rolf T , de Groot Philip G , Gruber András , McCarty Owen JT 
Published: October 2019

Abstract
Factor XI (FXI) promotes hemostasis and thrombosis through the enhancement of thrombin generation, and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. Although the binding of FXI to platelets has been demonstrated, the role that FXI binding might play in platelet activation has not been studied. It is also unknown if FXI-platelet binding is solely mediated by GPIbα or if other platelet receptor(s) exist that can support interactions with FXI. This study has identified apolipoprotein E receptor 2 (ApoER2, LRP8), a member of the low-density lipoprotein (LDL) receptor family, as a platelet receptor for FXI. Surface-bound FXI supported platelet spreading and elevation of intracellular Ca2+, while platelet spreading on FXI was eliminated in the presence of either Src-kinase or PI3-kinase inhibitors. Platelet adhesion to immobilized FXI was abrogated in the presence of the universal LDL receptor antagonist, receptor-associated protein (RAP), soluble recombinant ApoER2′ or the LDL-binding domain 1 or 2 of ApoER2. FXI supported wild-type murine platelet binding; in contrast, ApoER2-deficient murine platelets did not adhere to FXI. Soluble FXI binding to immobilized platelets or purified recombinant ApoER2′ was abrogated in the presence of binding domain 1 of ApoER2 or RAP, respectively. These results identify FXI as a novel ligand for the platelet receptor ApoER2. While many of the details regarding the role of FXI in vivo are still undetermined, the ability of FXI to bind and activate platelets via ApoER2 suggests that FXI may contribute to hemostasis and thrombosis in a manner unrelated to contact activation or thrombin generation. Furthermore, these findings suggest that FXI may play a role in promoting cell signaling in other cells that express ApoER2, such as neurons, immune system cells and smooth muscle cells.
Investigation of Parent-Related Etiologic Factors in Children with Acute Lymphoblastic Leukemia
Authors: Yilmaz Oznur , Timur Cetin , Yoruk Asim , Erguven Muferet , Senturk Gunes , Kavakli Kaan 
Published: October 2019

Abstract
In this study, we investigated parental history and habits in children with acute lymphoblastic leukemia and we wanted to point at possible factors that can affect the risk of leukemia. The parents of 105 children diagnosed and treated as ALL between the years 1997–2007 in our Clinic of Pediatric Hematology-Oncology were questioned and results were compared with control group that consisted of 102 healthy children with similar age and gender. There was no significant difference between the groups in terms of maternal and paternal age (p>0.05). Even though the rates of family history of leukemia and other cancer types were higher in the leukemia group, there was no statistically significant difference (p>0.05). Rate of having genetic disease in family history was significantly higher in leukemia group and was associated with an increased leukemia risk (OR: 8.33; %95 CI= 1.02–67.85, p:0.035). Although the rate of miscarriages of mother was higher in leukemia group, there was no statistically significant difference (p>0.05). There was no significant difference between the groups in terms of maternal food consumption. The rate of vitamin and iron supplement use was significantly lower in leukemia group (p:0.017; p:0.002). The rate of folic acid and fish oil use was higher in control group; however there was no significant difference (p>0.05). There was no difference between the groups in terms of oral contraceptive use, X-ray exposure of mothers before conception, infection during pregnancy, hypertension and other diseases in pregnancy. The rate of medication use among mothers was significantly higher in leukemia group (p:0.001). Cigarette smoking was not common among mothers in both groups. When fathers were compared, the rates of cigarette smoking ≥1 package/day (OR: 2.00; %95 CI= 1.02–3.91, p:0.041) an ≥20 package-years (OR: 1.95; %95 CI= 1.00–3.66, p:0.048) were significantly higher in leukemia group. Besides, the rate of routine alcohol consumption was significantly higher among fathers in leukemia group (OR: 6.45; %95 CI= 1.42–29.59, p: 0.029). No significant difference was found between the groups in terms of prenatal x-ray exposure and drug intake when fathers were compared (p>0.05). In conclusion, leukemia is a disease with multi-factorial etiology like most of the other cancer types that arise as a result of interactions between genes and environment. The risk of leukemia may increase as a result of cigarette and alcohol consumption that can lead to chromosomal abnormalities especially in genetically susceptible children.
Genome-Wide Association Study for Determinants of Acute Graft Vs Host Disease (aGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation: Development of 7 SNP Model Predicting aGVHD
Authors: Park Eunkyung , Yang Song Joo , Kim Inho , Jeon Eun Hyung , Park Seonyang 
Published: October 2019

Abstract
Abstract 1010

Background:
Numerous studies have been reported non-HLA genetic associations with acute graft vs host disease (aGVHD) developing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, however, relatively few genes have been examined in each cohort. Meanwhile, aGVHD represents one of the most attractive targets to study the effect of normally silent genetic polymorphisms. We intended to elucidate genetic determinants predicting aGVHD in patients undergoing allo-HSCT by genome-wide screening of genetic polymorphisms, and develop a SNP model to predict development of aGVHD.

Methods:
Genetic polymorphisms predicting development of aGVHD were determined through successive 5 stages in a total of 429 patients who underwent allo-HSCT. Firstly, we screened genomic determinants predicting aGVHD using 109K SNP chip (Sentrix Human-1 GT Bead Chip, Illumina) in 15 patients (7 patients with aGVHD and 8 without aGVHD). At stage 2 and 3, low-density Immumina chips comprising 768 candidate SNPs and 96 SNPs, respectively, were manufactured and tested in independent cohorts of 91 patients (34 patients with aGVHD and 57 without aGVHD) and 84 patients (35 patients with aGVHD and 49 without aGVHD), respectively. At stage 4, 76 SNP chips comprising 33 SNPs discovered from the previous studies and also 43 SNPs reported to be associated with aGVHD in the literature were manufactured and evaluated in 36 patients (13 patients with aGVHD and 23 without aGVHD) undergoing allo-HSCT. Finally, 7 SNPs were chosen and validated in an independent cohort of 203 patients (50 patients with aGVHD and 153 without aGVHD) using TaqMan assay.

Results:
At stage 1, 955 SNPs were identified to be significantly associated with development of aGVHD by whole genome assay. At stage 2, candidate genetic determinants were narrowed down to 74 SNPs. Through stage 3 and 4, 7 SNPs including the two selected from the literature review (transforming growth factor beta receptor II (TGFBR2) and interleukin-18) were finally determined as predictive markers for aGVHD. The 7 SNP model was found to be effective in predicting the development of aGVHD after allo-HSCT. When decision tree model was applied, the sensitivity, specificity, accuracy, and area under ROC (AUR) of the 7 SNP model to predict aGVHD were 80.5%, 80.4%, 80.4% and 91.6%, respectively.

Conclusion:
A genome-wide association study approach was successful in elucidation of genetic determinants associated with development of aGVHD in patients undergoing allo-HSCT. The 7 SNP model was effective in predicting the development of aGVHD after allo-HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Heart T2* for Prediction of Cardiac Complications in Well-Treated TM Patients
Authors: Pepe Alessia , Meloni Antonella , Rossi Giuseppe , Cianciulli Paolo , Spasiano Anna , D'Ascola Domenico , Maggio Aurelio , Maddaloni Domenico , Carollo Antonella , Rizzo Michele , Perrotta Ketty , Secchi Giuseppina , Lai Maria Eliana , Positano Vincenzo , Lombardi Massimo 
Published: October 2019

Abstract
Abstract 1089

Introduction:
T2* Magnetic Resonance Imaging (MRI) technique allows noninvasive quantification of organ-specific iron burden, playing a key role in the management of thalassemia major (TM) patients. There are few data on the incidence of heart failure and arrhythmias in TM patients according to baseline T2* values. The aim of this study was to establish prospectively the risk of cardiac complications in a large cohort of well-treated TM patients.

Methods:
We considered 527 TM patients (252 males, mean age 30±9) for who clinical data relative to a period of 5 years after the first MRI were collected in a central data base. At time of the first scan mean ferritin levels were1653±1559 ng/l, global heart was 27±13 ms, and excellent/good level of compliance were present in the 96% of the study population.

Results:
At 5 years of follow-up, we recorded 24 cardiac events: 4 episodes of cardiac failure, 15 of arrhythmia, 1 of pulmonary hypertension and 4 of other cardiac complications. The majority of these events (21/24) happened within the first 24 months subsequent to the MRI, so we considered this follow-up period. At the first MRI scan, in patients with cardiac complications the global heart T2* was 22.5 ±12.4 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of cardiac complications associated with global heart T2* values <20 ms (HR= 2.028 P=0.09) (see figure). In the heart failure patients the global heart T2* was 19±12 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of heart failure associated with global heart T2* values <20 ms (HR=1.9 P=0.524) or <10 ms (HR=2.6 P=0.443).
In the arrhythmic patients the global heart T2* was 25±13 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of arrhythmia associated with global heart T2* values <20 ms (HR=2.1 P=0.179) or <10 ms (HR=0.8 P=0.824). During the follow up changes in the chelation therapy (type and/or dose-frequencies) were found in > 25% of the study population.

Conclusion:
We detected very few cardiac events, almost all concentrated in the first 24 months. In a large cohort of well-treated TM patients heart T2* lost its power in predicting cardiac events probably due to a patient-specific adjustment of the chelation therapy MRI-guided.

Disclosures:
No relevant conflicts of interest to declare.
Increased Expression of Secretory Leukocyte Protease Inhibitor (SLPI) In Mononuclear Cells From Patients with Deep Vein Thrombosis
Authors: Santiago-Bassora Fernanda Dutra , Barnabé Aline , Santos Andrey dos , Carazzolle Marcelo F , Pereira Gonçalo AG , de Andrade Orsi Fernanda Loureiro , de Paula Erich V , Annichino-Bizzacchi Joyce M 
Published: October 2019

Abstract
Abstract 1232
Deep venous thrombosis (DVT) is a common and potentially fatal condition affecting 1% to 2% of the population worldwide, with an annual incidence of 1 in 500. Several studies have demonstrated the association between inflammation and DVT. In this study, we performed a comparative analysis of gene expression from mRNA extracted from leukocytes of 20 patients with previous DVT of the lower limbs (14F/6M; mean age: 39.7 years). An array of inflammation-related genes was selected for this study. Patients were divided in subgroups: (1) spontaneous DVT (n=10; 7F/3M). (2) risk factor-associated DVT (n=6; 4F/2M), in whom risk factor included oral contraceptive, pregnancy, protein C or S deficiencies, and FV Leiden heterozigosity. (3) Patients with antiphospholipid syndrome (APS)-associated DVT (n=4; 3F/1M). Nine healthy volunteers (7F/2M) were used as controls. Using bioarray technology, 60 upregulated (UR) and 56 downregulated (DR) genes were found in DVT patients when compared to healthy volunteers. UR genes were related to immune response, inflammation and proteolysis, and DR genes were related to transcription regulation, signal transduction and inflammation. Gene expression of the SLPI, Caspase-4 precursor (CASP4), Cartilage-associated protein precursor (CRATP) and eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) presented the most significant differences in expression and were then analyzed by qPCR for validation of the results. Statistical analysis was performed by the Mann-Whitney test. No significant differences were confirmed in the expression of CASP4, CRTAP and EEF1A2 between patients and controls. However, a three-fold increased in the expression of SLPI was confirmed in DVT patients compared to controls (p=0.0381). Secretory leukocyte protease inhibitor (SLPI) is synthesized and secreted by mononuclear cells to the site of inflammation in response to cytokines and TNF. Increased SLPI expression could be a result of the inflammatory response that follows DVT. SLPI, a protease inhibitor, could function as a protective mechanism that could neutralize any excess protease load and protect host tissue. Further studies to investigate the role of SLPI in the pathogeneis of DVT and its complications are warranted.

Disclosures:
No relevant conflicts of interest to declare.
Transforming Growth-Interacting Factor (TGIF) Modulates Hematopoietic Stem Cell Functions
Authors: Yan Ling , Womack Bethany , Brandt Stephen J. , Hamid Rizwan 
Published: October 2019

Abstract
Abstract 1279
We have shown that quantitative expression of the stem cell expressed Transforming-growth-interfering factor (TGIF) is a predictor of patient survival in acute myelogenous leukemia (AML). By Kaplan-Meier analysis, patients whose leukemic cells expressed decreased levels of TGIF RNA had a mean survival of 12 months, while patients whose leukemic cells expressed TGIF at a higher level had a mean survival of 60 months (p=0.00001).
TGIF is a homeobox transcriptional repressor and although it has been implicated in holoprosencephaly (HPE), whether it has a direct role in hematopoiesis is not known. It is known, however, that TGIF is expressed in hematopoietic stem cells (HSCs) and that it can down-regulate both TGF-b and retinoic acid (RA) signaling, and there is incontrovertible evidence that both of these pathways play an important role in hematopoiesis.
To understand the biological basis for our clinical finding, we hypothesized a role for TGIF in hematopoiesis and in particular HSC function. We then proceeded to test this hypothesis in a Tgif knockout mouse model. Flow cytometric analysis of non-lineage depleted bone marrow (BM) cells showed that Tgif-null mice had statistically increased numbers of long-term HSCs (LT-HSCs) as defined by CD34-Flk2-Lin-ckit+Sca1+ status or by CD150+CD48-Lin-cKit+Sca+ status and decreased numbers of multipotent progenitors (MPP) as defined by CD34+FlK+Lin-ckit+Sca1+ status. The short-term (ST) HSC (defined by CD34+Flk2-lin-ckit+Sca1+ or by CD150-CD48-lin-ckit+Sca+) populations were not statistically different between the null and the WT-type mice. Tgif-null BM cells produced statistically significant higher total colony number in methylcellulose colony forming unit (CFU) compared to the WT-mice though the percentages of specific colonies types remained the same. We then compared the Tgif-null BM cells with WT-BM cells in competitive repopulation assays (CRA). These experiments showed that Tgif-null BM cells were more competitive and showed higher engraftment compared to the WT-BM cells.
In conclusion, our data suggest that Tgif has an important role in hematopoietic stem cell function and may play a role in determining the balance between quiescence and self-renewal. One hypothesis to explain these data is that HSCs with no or low Tgif are more quiescent and if so this provides one biological explanation of how might TGIF affect AML prognosis; increased quiescence of HSCs or the Leukemic stem cells derived from these HSCs may make them more resistant to myelotoxic injury following chemotherapy, increasing the likelihood of relapse and/or poor long-term survival. These hypotheses continue to be an active area or research in our laboratory.

Disclosures:
No relevant conflicts of interest to declare.
Sequence Specific Single Stranded DNA Binding Protein 2 (SSBP2) Is a Regulator of Hematopoietic Stem Cell Activity
Authors: Li June , Klumpp Sherry , Amin Hesham M. , Liang Hong , Brandt Stephen J. , Nagarajan Lalitha 
Published: October 2019

Abstract
Abstract 1384
Interstitial deletions of chromosome 5q are common, non-random anomalies in myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). While most deletions are large, spanning 5q13–33, a subset of patients deletes only the 5q11–14 region. We isolated SSBP2, a candidate gene from a critical region of loss at 5q14. SSBP2 expression is undetectable in AML cell lines, primary AML and MDS samples with chromosome 5q deletions. Decreased Ssbp2 expression due to viral integration has been reported in a case of primate AML resulting from HOXB4 retroviral transduction1. We have established SSBP2, to be a member of Lim Domain Binding Protein (LDB1)-Lim Only 2(LMO2)- TAL1/LYL1containing transcriptional complexes. SSBP2-LDB1, interactions promote gene expression by protecting LDB1 from proteosomal degradation2,3. LDB1-LMO2-bHLH complexes are also critical regulators of hematopoietic stem cells (HSC), a target of transformation in MDS and AML. The transcriptional cofactor LDB1 is required for hematopoiesis as part of an autoregulatory loop, which maintains the expression of TAL1, LMO2, E2A and GATA14.
Since Ssbp2 is a candidate gene from 5q and an in vivo regulator of LDB1 stability3, we sought to determine its role in hematopoietic stem cell homeostasis. In normal marrow, Ssbp2 expression is highest in Lin−, Sca1+, c-Kit+ (LSK) cells and decreases during lineage commitment. Ssbp2−/− mice are apparently normal upto six months of age although multiple hematopoitic tissues exhibit modest hypoplasia. However, hematopoietic recovery from 5-Fluoro uracil treatment is considerably delayed in these mice. Furthermore, competitive repopulation assays reveal significantly reduced short and long-term engraftment with Ssbp2−/− bone marrow. Enforced expression of Ssbp2 rescues the competitive repopulating activity. Increased expression of E2A and its' transcriptional target CDKN1A in Ssbp2−/− LSK cells appears to underlie the impaired stem cell activity. Our results identify SSBP2 to be a novel regulator of HSC function by maintaining the LDB1 mediated regulatory loop. Furthermore, these findings suggest defective stem cell homeostasis in the absence of SSBP2, when combined with mitogenic signals might contribute to the evolution of MDS/AML in a subset of patients.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Implications and Clinical Characteristics Associated with Bone Marrow Fibrosis in Patients with Myelofibrosis
Authors: Nazha Aziz , Estrov Zeev , Cortes Jorge E. , Pierce Sherry , Kantarjian Hagop M. , Verstovsek Srdan 
Published: October 2019

Abstract
Abstract 2824

Background:
Myelofibrosis (MF) is a heterogeneous, hematopoietic stem cell malignancy characterized by abnormal proliferation of myeloid cells with varying maturity and function. Bone marrow fibrosis (BMF), which results from abnormal deposition of stromal reticulin and collagen fibers, plays a major role in the pathophysiology of MF.

Objectives:
To investigate the characteristics associated with the extent of BMF and its implications on the clinical manifestation, overall survival (OS), event-free survival (EFS), and transformation to acute leukemia in patients with primary or secondary myelofibrosis.

Methods:
We conducted a retrospective chart review analysis of 514 patients who were diagnosed with myelofibrosis according to World Health Organization criteria (353 patients with primary myelofibrosis, 82 with post polycythemia vera [Post-PV] MF, and 79 with post essential thrombocythemia [Post-ET] MF) and were referred to MD Anderson Cancer Center between February 2005 and December 2009. Results of the first bone marrow biopsy done at MD Anderson were reviewed. BMF was documented according to the European consensus grading system (MF 0–3), in which MF-3 is the most severe grade of fibrosis.

Result:
Of 514 patients, 7 (1%) had MF-0, 44 (9%) had MF-1, 171 (33%) had MF-2, and 292 (57%) had MF-3. Table 1 summarizes patient characteristics and outcomes by grade.

Conclusion:
Severe bone marrow fibrosis was associated with lower Hgb, lower WBC count, larger spleen and abnormal cytogenetics. There was no association between JAK2 mutation and the severity of BMF. The OS, EFS and transformation to leukemia were similar among patients with various degrees of fibrosis. Similar results were achieved in patients with primary, post-PV MF, and post-ET MF. This might explain the heterogeneity of the disease course and its prognosis. Longer follow-up is needed to further investigate the impact of BMF on OS, EFS and PFS.

Disclosures:
No relevant conflicts of interest to declare.
3D Telomeric Profiles of MGUS, MMN and Relapsed MM
Authors: Olujohungbe Ade B , Klewes Ludger R , Rubinger Morel , Mai Sabine 
Published: October 2019

Abstract
Abstract 2899
Multiple myeloma (MM) is recognized as the second most common cancer of the blood. It is a malignant disorder of plasma cells and commonly affects adults past the age of 50. Although risk factors have been established, it is currently not possible to assess the individual risk to cancer progression. Moreover, the causes of disease progression from its precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to full-blown MM and its progression to relapsed MM remain elusive. We have performed previous studies on the three-dimensional (3D) nuclear organization of telomeres and found that normal and tumor cells display significant differences in their nuclear organization. These differences were objectively quantified with two software programs, TeloView and TeloScan developed by our group.
We now report on a new double blinded preliminary study with 36 patients, including 20 MM, 12 MGUS and 4 relapsed MM. Using blood- and bone marrow-derived plasma cells from the respective patient groups, we have examined 3D nuclear telomeric profiles of the above patients. Plasma cells from MM, MGUS and relapsed MM exhibit specific 3D telomeric signatures. MM have the highest telomere numbers, followed by MGUS, while relapsed MM presents with the lowest numbers of telomeres and the shortest telomeres. Additional telomere parameters, such as cell cycle distribution profiles (a/c ratio), telomere aggregate numbers, distances from nuclear centre and also exhibited significance (p< 0.001).
Within the MGUS and MM patient groups we studied are patients whose 3D telomeric profiles indicate the beginning of a new signature that resembles signatures of MM and relapsed MM respectively. Blood and bone marrow gave us comparable results opening the future opportunity to base diagnostics and monitoring on blood samples, sparing the patient form invasive bone marrow sampling with potentially adverse effects. Based on our current preliminary data, we propose the following 3D telomeric criteria that define individual signatures of MGUS and MM and progression within each of the groups: telomere numbers, telomere sizes, presence of telomeric aggregates, telomeres per nuclear volume, and a/c ratios. The clinical significance of these findings is the early identification of individuals with high risk of progression. This opens the possibility for better monitoring and early intervention with newer treatments with an acceptable efficacy and low toxicity ratio.

Disclosures:
No relevant conflicts of interest to declare.