bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Nup98-HoxA9 Leukemogenic Fusion Protein Blocks Xpo1 and Tap-Mediated Nuclear Export
Authors: Dogan Yildirim , Sahay Sutapa , Dorn David C , Franceschino Anna , Xu Michael , Moore Malcolm A.S. 
Published: October 2019

Abstract
Abstract 5228
In leukemia Nup98 fusion genes are found as a product of the reciprocal translocation between Nucleoporin 98 (nup98) and homeobox-cluster genes. Nup98-HoxA9 (NHA9), the product of the t(7;11) translocation, is detected in acute myeloid leukemias (AMLs) and as a secondary abnormality in blast crisis of chronic myeloid leukemia (CML). The role of NHA9 in leukemogenesis is complex and incompletely understood. Here, we show an abrogation of nucleocytoplasmic shuttling of the nuclear export receptor Xpo1 and Tap in NHA9-expressing cells by using retroviral nuclear trafficking as a model. Lentiviral Rev, the prototype for nuclear export signal (NES)-containing proteins is shuttled through the nucleopore by Xpo1. NHA9 sequestered Xpo1 from the nuclear rim into nuclear aggregates resulting in deficient Xpo1-dependent nuclear exit of Rev and its mRNA substrates. Tap is involved in mRNA nucleocytoplasmic shuttling and is also responsible for the nuclear export of D-type retrovirus CTE-mRNAs. By using Tap/CTE-mRNA nuclear export as a model we also found that Tap colocalized in NHA9 nuclear aggregates leading to impaired Tap-mediated nuclear exit of CTE-mRNA substrates. Leukemogenicity of Nup98 fusion proteins may be accounted for in part by defects in Tap and Xpo1-mediated export of their substrates.

Disclosures:
No relevant conflicts of interest to declare.
Molecular and Pathological Analysis of DOCK Family Proteins in Hematopoietic Malignancy
Authors: Nishihara Hiroshi , Wang Lei , Nishio Mitsufumi , Endo Tomoyuki , Fujimoto Katsuya , Obara Masato , Tanaka Shinya 
Published: October 2019

Abstract
Abstract 5230
Crk, originally identified as an oncogene product v-Crk encoding in a chicken retrovirus CT10 in 1988, is a signaling adaptor protein mostly composed of SH2 and SH3 domains, and has been shown to play a pivotal role in cell proliferation, differentiation, and migration in various human cancers. Crk SH3 domain binds to DOCK180 which has been reported to activate Rac regulating cytoskeletal reorganization leading to the enhancement of cell motility and engulfment. In 1999, we identified DOCK2, a hematopoietic cell-specific homolog of the DOCK family protein, and revealed that DOCK2 regulated cell motility and cytokine production through the activation of Rac in human hematopoietic cells (1–3). Recently, we demonstrated the prominent expression of DOCK2 in human B cell lymphoma, and DOCK2 regulated cell proliferation through Rac and ERK activation in B cell lymphoma cell lines (4). Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD chimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. In addition, we confirmed the elevated expression levels of DOCK2 in various types of hematopoietic tumor cell lines as well as in the primary cells from the patients with leukemia and lymphoma. Interestingly, we also found the expression of DOCK180, not DOCK2, in Hodgkin/Reed-Sternberg cells of Hodgkin lymphoma tissue specimens as well as in three cell lines derived from Hodgkin lymphoma. We are currently analyzing the tumorigenic roles of DOCK2 and DOCK180 using the suitable cell lines derived from various hematopoietic neoplasms.
Here we summarize the results of our molecular and pathological analysis for the DOCK family proteins in various human hematopoietic malignancies such as lymphomas and leukemia. Our results suggest the possible target molecules of DOCK family proteins including DOCK2 and DOCK180, and also Rac for lymphoma and leukemia therapy.

Disclosures:
No relevant conflicts of interest to declare.
Loss of Heterozygosity (LOH) of PTPRJ in Non-Hodgkin`s Lymphoma (NHL)
Authors: Aya-Bonilla Carlos A , Green Michael R , Camilleri Emily , Marlton Paula , Lea Rod , Gandhi Maher , Griffiths Lyn R 
Published: October 2019

Abstract
Abstract 5231
The identification of Tumor Suppressor Genes (TSGs) in tumor tissue lacking of its normal germ-line counterpart has been limited due to the absence of proper statistical approaches that allow inferring the specific germ-line heterozygous status of a patient. Nonetheless, the implementation of Hidden Markov model (HMM) or cohort heterozygosity comparisons (CHC) approaches in the analysis of SNP array data from un-paired tumor DNA samples have permitted the detection of LOH regions and possible TSGs that might be implicated in the origin and development of cancer. Non-Hodgkin's Lymphoma (NHL) is the most common type of lymphoma. Nevertheless, its aetiology and pathogenesis remain unclear because of heterogeneity in biology, genetics and chemoresponse.
Here, we employed high-density SNP array analysis of tumors from two of the most frequent subtypes of NHL, Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region of 11p11.2, containing the gene encoding the receptor-type protein tyrosine phosphatase, PTPRJ. LOH of this gene has been previously described in colorectal, lung, thyroid and breast cancer and the gene product regulates key survival pathways in B-cells, such as MAPK, PLCγ1, Scr and BCR signalling.
We validated LOH of the PTPRJ region by microsatellite analysis of an extended cohort of NHL tumors and found significantly increased rates of homozygosity compared to a patient-matched control population. Furthermore, sequencing of NHL cases revealed a strong association between LOH and the presence of a non-synonymous SNP in the PTPRJ coding region. Together, these results show the utility of LOH screening in identifying novel tumor suppressor genes, and implicate LOH of the PTPRJ gene as a potential lymphomagenic mechanism.

Disclosures:
Aya-Bonilla: Cancer Council of Queensland: Research Funding.
The AG Genotype of the Wilms Tumor-1 rs16754 SNP Is Associated with Poor Outcome in Pediatric AML Patients Treated with Stem Cell Transplantation but Not in Adults
Authors: Abalkhail Hala , El-Solh Hassan , Alseraihy Amal , Ayas Mouhab , Al-Ahmari Ali , Belgaumi Asim F , Al-Jefri Abdullah , Altombakty Ola , Toulimat Mohammed , Almhareb Fahed , Chaudhri Naeem A. , Walter Claudia Ulrike , Aljurf Mahmoud , Albitar Maher 
Published: October 2019

Abstract
Abstract 5237
The synonymous single nucleotide polymorphism rs16754 in the Wilms Tumor-1 gene (WT1) has been reported to correlate with outcome in adult patients with acute myeloid leukemia (AML) when treated with intensive chemotherapy. Specifically the GG genotype is significantly associated with favorable outcome, but also the AG genotype has been reported to be associated with better outcome as well. The clinical relevance of the rs16754 SNP in pediatric AML patients is far from clarified. In addition, it is not known whether allogeneic hematopoietic stem cell transplantation (HSCT) can modify the role of this SNP and its association with outcome.

Methods:
Genotyping of the SNP by direct sequencing of the exon 7 was performed on bone marrow samples from 86 AML patients (38 pediatrics and 48 adults). All patients were treated with HSCT. Most patients (39 adults and 28 pediatrics) were transplanted in first remission (CR1). The median age was 25 years (range: 14–54) for adults and 8 years (range: 8 months–14 years) for the pediatric group.

Results:
In pediatric AML, we detected the AA genotype in 22 patients (53%), the GG genotype in 2 patients (5%) and the remaining (42%) had AG genotype. In the adult patients, the AA genotypye was present in 26 patients (54%), GG genotype in 3 (6%) patients, and the AG genotype in the remaining patients (39%). A similar distribution was observed in the normal population (58%, 12%, 30%, for AA, GG, and AG, respectively). In pediatric patients, the AG genotype significantly correlated with shorter overall survival (OS) (P=0.04) and event free survival (EFS) (P=0.04) when compared with the patients with AA genotype. In contrast, in adult AML, groups with AG and AA geneotypes completely overlapped for OS and EFS. When only patients treated with HSCT in CR1 were considered, the pediatric patients showed the same trend (P=0.07), but there was no correlation with survival in the adult group. This analysis included patients with intermediate and adverse risk cytogenetics. AG genotype was not a predictor of outcome in multivariate model incorporating cytogenetics and the WT1 genotype. The patients with the GG genotype were too few for analysis.

Conclusion:
This data supports the concept that the biology of AML in pediatric patient is different from that in adults. The role of this synonymous SNP in AML needs further exploration, especially investigating the potential that this SNP may have some effects on the host and not only the disease.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation of ADAMTS13 Activity and Inflammatory Markers in Deep Venous Thrombosis Patients
Authors: de Moraes Mazetto Bruna , Orsi Fernanda A. , Barnabé Aline , de Paula Erich V , Annichino-Bizzacchi Joyce M 
Published: October 2019

Abstract
Abstract 5246

BACKGROUND:
The role of inflammation on the pathophysiology of arterial thrombosis has been extensively studied. However, the relationship between inflammation and deep vein thrombosis (DVT) is not completely understood. Conflicting reports have been published about the levels of proteins involved in the inflammatory response in the context of DVT. Changes in ADAMTS13 levels have been reported in other inflammatory conditions such as sepsis, and this protease could be involved in the interplay between hemostasis and inflammation.

OBJECTIVE:
To evaluate ADAMTS13 activity in DVT patients and its association with inflammatory markers (IL-6, IL-8, CRP, TNF-α), D-dimer and von Willebrand Factor (VWF) levels.

METHODOLOGY:
Thirty-eight DVT patients, from 6 months to five years after the diagnosis of DVT, followed at the outpatient unit of thrombotic diseases from University of Campinas and 38 healthy volunteers selected as controls were included in the study. ADAMTS13 activity was determined by the residual binding of VWF to collagen. VWF, IL-6, IL-8 and TNF-alpha levels were determined by ELISA, and D-dimer levels was determined by a turbidimetric method.

RESULTS:
In this study population DVT was triggered by transient risk factors, particularly the use of oral contraceptives. No patient presented renal, hepatic or malignant disease. Median ADAMTS13 activity was not statistically different between patients (median: 98.2%; range: 70–146) and controls (median: 96.1%; range: 66–117; p=0.35). IL-6 and TNF-alfa levels were also higher in patients (median: 1.0pg/mL and 2.3pg/mL) compared to controls (median: 0.64pg/mL and 1.7pg/mL, p=0,01 and p=0,009). In addition, VWF and D-dimer levels were also significantly higher in patients (all P<0.01). No significant difference could be demonstrated between IL-8 and CRP levels from patients and controls. No significant correlation between ADAMTS13 levels and other inflammatory markers could be demonstrated. VWF levels correlated significantly with IL-8 (r=-0.4635, p< 0.0001).

CONCLUSIONS:
This study reinforces the role of inflammation in the pathogenesis of DVT. The correlation of VWF and IL-8 supports the notion that IL-8 stimulates the secretion of VWF. The role of ADAMTS13 in the context of DVT is yet to be determined.

Disclosures:
No relevant conflicts of interest to declare.
Analysis of the Genetic Expression of Inflammatory Mediators From Patients with Spontaneous Deep Venous Thrombosis
Authors: Barnabé Aline , Santiago-Bassora Fernanda Dutra , dos Santos Andrey , Carazzolle Marcelo Falsarella , Pereira Gonçalo AG , de Andrade Orsi Fernanda Loureiro , de Paula Erich V , Höehr Nelci Fenalti , Annichino-Bizzacchi Joyce M 
Published: October 2019

Abstract
Abstract 5251
Deep venous thrombosis (DVT) is a multifactorial disease and in about 30% of patients no risk factor can be identified. Association of inflammation and hemostasis is thought to play a significant role in the pathogenesis of DVT. We hypothesized that distinctive patterns of expression of inflammatory mediators in mononuclear cells from patients with previous DVT could be relevant to the pathogenesis of DVT. cDNA microarray technology (CodeLink Bioarrays) was chosen to study the gene expression profile of inflammatory mediators in DVT patients with clinical characteristics of a high penetrance of any putative hereditary risk, and their healthy siblings. These microarrays were hybridized with synthesized probes from pooled samples collected from patients and control siblings. Patients were divided into two clinical groups: (1) patients with one spontaneous DVT (n=2), and (2) patients with recurrent spontaneous DVT episodes (n=1). Preliminary analysis showed that 2% of approximately 55,000 transcripts contained in the array had significant (higher than 2-fold) differences in expression in spontaneous and recurrent spontaneous DVT relative to their asymptomatic siblings. In group 1, 738 genes were upregulated and 504 genes were downregulated. In group 2, 1229 genes were upregulated and 87 genes were downregulated. Genes with different expression compared to controls were associated to immune and inflammatory response, motility, cell adhesion, cell-cell signaling, defense response, signal transduction and apoptosis. Genes that presented the highest differences compared to controls were interleukin 8 (43-fold increase), chemokine (C-X-C motif) ligand 2 (11-fold increase), major histocompatibility complex, class II, DR beta 5 (8-fold increase), major histocompatibility complex, class II, DQ alpha 1 (29-fold decrease), caspase recruitment domain family, member 15 (7-fold increase), carboxypeptidase A5 (11-fold decrease), cathepsin G (8-fold decrease), and azurocidin 1 (3-fold decrease). A comprehensive list of these genes was generated. Evaluation of the significance of these distinctive gene expression profiles between patients with spontaneous and recurrent DVT compared to their asymptomatic siblings could reveal novel insights into the pathophysiology of the first DVT episode and of DVT recurrence, as well as new biomarkers or therapeutic targets.

Disclosures:
No relevant conflicts of interest to declare.
No Thrombotic Risk in Patients with Asymptomatic Antiphospholipid Antibodies
Authors: Zawilska Krystyna M , Kopydlowska Agata M 
Published: October 2019

Abstract
Abstract 5254

Aim of the study.
Antiphospholipid antibodies (APA) are well known risk factor for thromboembolic events and/or obstetric complications. They may be found incidentally in patients without thrombotic complications (asymptomatic APA), and they often lead to an incorrect suspicion of hemorrhagic diathesis, as well as to an unnecessary disqualification from surgical procedures or withdrawal from a proper antithrombotic prophylaxis during these procedures. The aim of the study was to register venous and/or thrombotic events in a group of patients with asymptomatic APA, diagnosed according to the international guidelines (Myakis et all. 2006).

Material and methods.
The study group consisted of 25 patients (18 women and 7 men) of the mean age of 46 years (20 – 75 years). Concomitantly 9 of them had other autoimmune disorders (no systemic lupus erythematosus) and 4 had neoplasms. Among risk factors for arterial thrombosis 5 patients had hypercholesterolemia, 5 – hypertension, 4 were smokers and 4 were obese (BMI >30 kg/m2). None of the patients had hereditary thrombophilia (antithrombin, protein C or protein S deficiency, factor V Leiden, prothrombin G20210A mutation, increased activity of factor VIII). Family history of venous thromboembolic disease has been noticed in 4 patients and of arterial thrombosis in 6 patients. The observation lasted for 3 to 127 months (mean 35 months).

Results.
The number and percent of patients (n = 25) with abnormal results 997337of different laboratory diagnostic assays for APA:
aPTT-activated partial thromboplastin time; dRVVT - diluted Russell viper venom time; ACA-anticardiolipin antibodies; β2-GPI – anti-β2–glycoprotein I antibodies
Abnormal results of more than one assay in any combination were found in 16 patients, lupus anticoagulant alone in 9 patients. Only 4 out of 25 patients have taken aspirin - 75mg daily, in the other 4 a prophylactic dose of low molecular weight heparin was administered temporarily because of surgery.
During observation time no venous or arterial thrombotic events occurred in the study group. On a basis of a limited number of previous studies that predominantly included systemic lupus erythematosus patients, aPL-positive patients without previous thrombosis have a 0% to 3.8% annual incident thrombosis risk (Barbhaiya M, Erksan D. Curr Rheumatol Rep. 2011; 13: 59–69).
In two patients asymptomatic APA disappeared.

Conclusion:
independently of the type and quantity of asymptomatic antiphospholipid antibodies, there were no venous or arterial thromboembolic events in the group of patients observed for meanly 35 months.

Disclosures:
No relevant conflicts of interest to declare.
The Risk of Malignancy Following Idiopathic Venous Thromboembolism: A Population-Based Cohort Study
Authors: Kondal Dimple , Kahn Susan R. , Tagalakis Vicky 
Published: October 2019

Abstract
Abstract 5255

Background:
Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), can be the earliest manifestation of an occult malignancy.

Objectives:
We used the hospital discharge (MED ECHO) database of the province of Quebec, Canada to determine the risk of a new cancer diagnosis in patients with idiopathic VTE.

Methods:
Using data from Med-Echo which systematically records information on all hospital admissions in Quebec, we constructed a cohort of all individuals with a first-time diagnosis of DVT or PE between January 1, 1996 and December 31, 2004 and no cancer diagnosis preceding the VTE. Subjects were excluded if there was a surgical procedure, pregnancy, trauma or hospitalization in the 3 months prior to the VTE. Subjects were followed for 12 months after VTE for a first diagnosis of cancer (except non-melanoma skin cancer). VTE and cancer were defined using the 9th edition International Classification of Diseases codes.

Results:
In all, 20 740 patients with idiopathic VTE and without previous cancer were identified. The mean age was 65.9 years (SD 12.6) and 58% were female. Overall, 696 (3.4%) patients were diagnosed with cancer in the 12 months following VTE. The risk was lowest among subjects aged 50 years or less (1.0%) and highest among patients aged 80 years or more (5.5%). Lung (25%) and gastrointestinal tumours (21%) were the most common diagnoses.

Conclusions:
In this large population of patients with idiopathic VTE we found that 3.4% of patients were diagnosed with cancer in the first year following VTE, and that older patients had a higher risk of cancer compared to younger patients. This risk is less than previously reported estimates of 4–12%. The value of occult cancer screening in patients with idiopathic VTE is uncertain.

Disclosures:
Tagalakis: Sanofi Aventis: Research Funding; Pfizer: Research Funding.
Insulin-Like Growth Factor and Platelet Activation the Role in Arterial Injury and Restenosis
Authors: Corinaldesi Giorgio 
Published: October 2019

Abstract 5267
Insulin-like growth factor (IGF-1) is an activator of the PI3K/AKT (serine/threonine protein kinase) signalling pathway. It can also stimulate cell growth (PDGF, PDAF, VEGF, TGF-alfa and beta), and cellular proliferation, and is a powerful stimulator of directed migration of VSMC (vascular smooth muscle cells). The deregulated action of IGF-1 influences coronary artery disease (CAD) by promoting neo-intimal hyperplasia and leukocyte recruitment, pro-mytotic activity (MAPK: mitogen-activated protein kinases, serine/threonine kinase), and extracellular matrix synthesis in atherosclerotic lesions; it also increases platelet activity, and the expression of P-selectin, IL-6 and platelet CD62. This growth factors may also promote chemotaxis, LDL-cholesterol uptake, and the release of pro-inflammatory cytokines, finally it is a strong inhibitor of apoptosis (BAX, Fas/FasL); in other words, a high level of IGF-1 is a strong risk marker for ischemic heart disease.
We have studied a group of 140 patients (92 males and 48 females, mean age was 58 years, range 46–68 years); 72 patients with CAD in early stage of restenosis and 68 control. Patients with arterial restenosis have significantly high levels of IGF-1 (142.8 ng/ml +/− 24.2 ng/ml) that appear closely related to recurrence, than control subjects (mean level of IGF-1: 98.6 ng/ml +/− 14.4 ng/ml).
Additional investigations are needed to determine the exact weight of IGF-1 from a slightly clinical point of view, as this marker showed interestingly to have a key role in the pathogenesis of atherosclerosis.

Disclosures:
No relevant conflicts of interest to declare.