bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Gene-Environment Interactions with Venous Thromboembolism (VTE): A Merged/Imputed Genome-Wide Scan/Candidate-Gene Case-Control Study
Authors: Heit John A. , Armasu Sebastian M. , Matsumoto Martha E. , Petterson Tanya M. , Rider David N. , Cunningham Julie M. , Asmann Yan W. , de Andrade Mariza 
Published: October 2019

Abstract
Abstract 2295

Background:
While interaction between Factor V Leiden and other VTE risk exposures compound VTE risk, whether other gene-environment interactions are associated with VTE is largely unknown.

Objective:
To test novel gene-environment interactions for an association with VTE.

Methods:
Genome-wide scan (Illumina 660Q [557,112 SNPs]) and candidate gene (12,551 SNPs in 764 genes within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways) genotypes from 1270 non-Hispanic adults of European ancestry with objectively-diagnosed VTE (cases; no cancer, venous catheter or antiphospholipid antibodies) and 1302 controls (frequency-matched on case age, gender, race, MI/stroke status) were merged and imputed to 2.5 million SNPs with MACH using HapMap Phase 2 (60 CEU). We tested pairwise interactions between these SNPS and each of 7 exposures (“stress” [defined as ever hospitalized, ever surgery, ever trauma, ever transfemoral procedure or ever leg paresis], ever surgery, ever neurosurgery, ever orthopedic surgery; and among women, ever pregnant, ≥3 pregnancies and ever oral contraceptives/hormone therapy), adjusted for age, gender, MI/stroke status and state of residence, using logistic regression.

Results:
The mean ± standard deviation case and control ages were 54.4 ± 16.2 and 55.6 ± 15.8 years, respectively and 51% were female. Among the 7 models, a significant interaction was found between stress and A2BP1 (rs735919, OR=0.2, p=2.8E-07), ever surgery and ABCG8 (rs6709904, OR=0.27, p=2.1E-07), orthopedic surgery and SLC24A3 (rs6081599, OR=0.53, p=2.8E-07), neurosurgery and TBC1D4 (rs17064485, OR=8.5, p=3.5E-07), every pregnant and MICALCL (rs11022321, OR=0.17, p=8.3E-07), >3 pregnancies and KLRB1 (rs2536929, OR=0.31, p=1.1E-07) and ever oral contraceptives/hormone therapy and LINGO2 (rs10969259, OR=2.02, p=4.9E-07). A2BP1 plays a role in RBC shape and size, ABCG8 is associated with severe hypercholesterolemia, SLC24A3 is important for intracellular calcium homeostasis, TBC1D4 participates in cell signaling in CD4+/CD45RO+ memory T-cells, MICALCL is an extracellular signal-regulated kinase 2-binding protein, KLRB1 regulates natural killer cell function, and LINGO2 encodes a leucine-rich repeat signaling protein. Our observed interaction of VTE risk factors with these genes to compound the risk of VTE requires replication in future studies. If confirmed, functional studies will be important to determine the roles of these gene products in the causal pathway to VTE.

Conclusion:
VTE risk factors and SNPs within several novel genes may interact to compound the risk of VTE.

Disclosures:
Heit: Daiichi Sankyo: Consultancy, Honoraria.
Physical Interaction of the Proto-Oncogene EVI1 with Hypermethylated in Cancer 1 (HIC1) Deregulates EVI1 Mediated Apoptosis in Cancer Cells
Authors: Pradhan Anjan Kumar , Chakraborty Soumen 
Published: October 2019

Abstract
Abstract 2449
The ecotropic viral integration site I (EVII) gene has attracted considerable attention in recent years because of its reported involvement in chronic myeloid leukemia, high risk myelodysplastic syndrome and a very high percentage of acute myeloid leukemias. The most recent World Health Organization classification has designated AML with inv (3) or t(3;3) and associated RPN1/EVI1 fusion, as a distinct AML subgroup associated with an unfavorable prognosis. Studies also indicate that EVI1 may be overexpressed in a subset of human colon cancers, and that EVI1 might affect disease progression and/or sensitivity to chemotherapy. The presence of zinc finger domains that are able to bind to specific sequences of DNA suggests that EVI1 is a transcriptional regulator; however, few target genes of EVI1 have been functionally identified. In the present study, we demonstrate by co-immunoprecipitation assay that the proximal zinc finger domain of EVI1 binds to HIC1, which abolishes the ability of EVI1 to induce expression of Bcl-xL. HIC1, is an epigenetically regulated transcriptional repressor that functionally cooperates with p53 to suppress age dependent development of cancer in mice. Inactivation of HIC1 results in up regulation of SIRT1, which deacetylate and inactivates p53; allowing cells to bypass apoptosis and DNA damage survival., Our study also demonstrates via indirect immuno fluorescence analysis that EVI1 and HIC1 proteins are colocalized in speckles in the nucleus. We recently reported that EVI1 not only binds the Bcl-xL promoter but also up regulates its transcriptional activity and protein expression. We now demonstrate by EMSA and luciferase assays that physical interaction between EVI1 and HIC1 releases the binding of EVI1 from the Bcl-xL promoter, and hence promotes apoptosis. Thus by directly binding to EVI1, HIC1 displaces EVI1 from its DNA consensus site leading to down regulation of Bcl-xL. Also we observed that posttranslational modification of EVI1, mainly acetylation plays a critical role in this EVI1-HIC1 protein-protein interaction. Further elucidation of the counteracting effects of HIC1 and EVI1 on Bcl-xL expression may provide new insights in EVI1 mediated disease progression.

Disclosures:
No relevant conflicts of interest to declare.
The Accuracy of PET in the Detection of Posttransplant Lymphoproliferative Disorder (PTLD)
Authors: Dierickx Daan , Verhoef Gregor , Gheysens Olivier , Tousseyn Thomas , Wolf-Peeters Christiane De , Wlodarska Iwona , Brepoels Lieselot 
Published: October 2019

Abstract
Abstract 2657

Introduction.
PET scan has emerged as a powerful tool in the diagnosis and staging of both Hodgkin and different subtypes of aggressive non-Hodgkin lymphoma. We investigated the accuracy of PET scan in 170 patients with suspected posttransplant lymphoproliferative disorder (PTLD).

Material and methods.
We retrospectively reviewed all patients in our center between 2003 and 2010 for whom a PET-scan was requested for the indication PTLD. 170 PET-scans in 150 patients were eligible for evaluation. In 45 cases, the patient had already a biopsy proven PTLD before PET-scanning and PET was considered a staging tool in these patients. In the remaining 125 PET-scans, PLTD was only suspected at the time PET was performed. In 73 (43%) and 97 (57%) cases PET scan without CT and combined PET/CT scan were ordered respectively. Because the aim of this study was to determine the accuracy of PET scan in diagnosis of PTLD, we evaluated only results of the PET scans. PET-scans were blindly scored on a four-point scale. Results were compared with biopsy as the gold standard.

Results.
The majority of PET scans were performed in kidney transplant recipients (35%), followed by liver (15%), lung (15%), heart (15%), hematopoietic stem cell (15%), combined (5%) and bowel (1%) transplantation. In 119 (70%) patients a biopsy was available. We found a sensitivity of PET of 89%, specificity of 89%, positive predictive value (PPV) of 91% and negative predictive value (NPV) of 87%. In a subanalysis of the 125 scans performed for differential diagnosis PTLD versus other diseases, sensitivity, specificity, PPV and NPV were 90%, 89%, 85% and 93% respectively. FDG-uptake in PTLD was generally high with a median mean and maximal standardized uptake value (SUV) of 9.0 and 17.4. False positive results were mainly due to infectious or inflammatory conditions, whereas false negative results were mainly reported in limited stage PTLD. Atypical extrandodal presentation was a frequent finding including diffuse pulmonary involvement and gastro-intestinal lesions.

Conclusions.
From these data, we can conclude that PET is highly sensitive for the detection of lesions of PTLD, and that PET has an excellent ability to differentiate PTLD from other diseases.

Disclosures:
No relevant conflicts of interest to declare.
SF1126, a Pan-PI3K Inhibitor Has Superior Preclinical Activity to CAL-101 a PI3K Delta-Specific Inhibitor in Aggressive B-Cell Non-Hodgkin's Lymphoma
Authors: Mahadevan Daruka , Qi Wenqing , Stejskal Amy , Cooke Laurence , Garlich Joseph R 
Published: October 2019

Abstract
Abstract 2720
The PI3K pathway is constitutively active in B-cell non-Hodgkin lymphomas (B-NHL). PI3K pathway targeted therapies have focused on inhibiting mTORC1 (rapalogs) with a ∼20–48% response rate due to inactivation of mTORC1 resulting in G1 cell-cycle arrest or apoptosis. A mechanism of resistance to rapalogs is that mTORC2 is unaffected resulting in undesirable Akt activation. Strategies to block Akt up-regulation require novel agents that simultaneously block PI3K, mTORC1 and mTORC2. SF1126 is a novel pan-PI3K/mTORC1/mTORC2 inhibitor conjugated to an integrin targeted peptide RGD with potent anti-tumor activity in multiple solid tumor types. Here, we demonstrated SF1126 had potent anti-B-NHL activity and is superior to CAL-101 a PI3K delta-isoform specific inhibitor in a panel of aggressive B-NHL cell lines. Cells treated with SF1126 exhibited >90% decrease in pAkt and pGSK-3β confirming the mechanism of action of a pan-PI3K inhibitor. Moreover, SF1126 induced apoptosis in a dose and time dependent manner confirmed by flow cytometry, PARP cleavage and with an IC50 < 4μM. In contrast, CAL-101 was less active compared to SF1126 in inducing apoptosis (12% versus 25% in SUDHL-4 and 15% versus 23% in TMD-8) and cell proliferation (5.62μM versus 3.28μM SUDHL-4 and 5.31μM versus 1.47μM in TMD-8). SF1126 induced G1 cell cycle arrest at 2μM which contributes to suppression of cell proliferation. The cell cycle protein cyclin D1 is downstream of mTORC1, and the over-expression of cyclin D1 is a hallmark of mantle cell NHL (MCL). Consistent with this, cyclin D1 was significantly decreased by SF1126 compared to CAL-101. Lastly, the addition of Rituximab to SF1126 or CAL101 increased the apoptosis over single agent therapy in B-NHL cell lines. In conclusion, we demonstrate that SF1126 potently inhibits the constitutively activated PI3K/mTORC/Akt pathway in aggressive B-cell NHL cell lines with consequent suppressive effects on cell cycle progression, cell proliferation and induction of apoptosis. These findings provide a rationale for SF1126 in combination with rituximab as a novel therapeutic strategy for aggressive B-NHL and warrant early phase clinical trial evaluation [Funded by the Lymphoma SPORE 1 P50 CA 130805 01A1].

Disclosures:
Garlich: Semafore Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Slit2/Robo4 Signaling Modulates HIV-1 Gp120-Induced Lymphatic Hyperpermeability,
Authors: Zhang Xuefeng , Yu Jinlong , Kuzontkoski Paula M. , Li Dean Y. , Groopman Jerome E. 
Published: October 2019

Abstract
Abstract 3225
Dissemination of HIV in the host involves transit of the virus and virus-infected cells across the lymphatic endothelium. HIV may alter lymphatic endothelial permeability to foster dissemination, but the mechanism is largely unexplored. Using a primary human lymphatic endothelial cell model, we found that HIV-1 envelope protein gp120 induced lymphatic hyperpermeability by disturbing the normal function of Robo4, a novel regulator of endothelial permeability. HIV-1 gp120 induced fibronectin expression and integrin α5β1 phosphorylation, which led to the complexing of these three proteins, and their subsequent interaction with Robo4 through its fibronectin type III repeats. Moreover, pretreatment with an active N-terminus fragment of Slit2, a Robo4 agonist, protected lymphatic endothelial cells from HIV-1 gp120-induced hyperpermeability by inhibiting c-Src kinase activation. Our results indicate that targeting Slit2/Robo4 signaling may protect the integrity of the lymphatic barrier and limit the dissemination of HIV in the host.

Disclosures:
No relevant conflicts of interest to declare.
Integrin Alpha E (CD103) Beta 7 Expression Marks A Subset of Human Bone Marrow-Derived CD207+ Dendritic Cells Which Induce T Regulatory Cells Via Indoleamine 2,3-Dioxygenase,
Authors: Curti Antonio , Ocadlikova Darina , Trabanelli Sara , Evangelisti Cecilia , Ciciarello Marilena , Baccarani Michele , Lemoli Roberto M. 
Published: October 2019

Abstract
Abstract 3233
Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in tryptophan catabolism along the kynurenine pathway. IDO expressed by different cell subsets inhibits T-cell activation, proliferation and survival and induces regulatory T cells (Tregs), thus mediating immunological tolerance. Although human monocyte-derived dendritic cells (DCs) have been shown to express IDO, little is known about its expression in other subsets of human DCs, including those generated from CD34+ hematopoietic progenitors (CD34+-derived DCs). In particular, no data are currently available for IDO expression in CD34+-derived DC subsets. CD34+-derived DCs were generated from healthy donors from purified CD34+ cells after 7 days of culture with GM-CSF and TNF-a. Then, DCs were separated into CD1a−CD14+ and CD1a+CD14− cells. DCs subsets were analyzed for IDO expression by real-time PCR and western immunoblot, kynurenine production, inhibition of allogeneic proliferation and Tregs induction. CD34+ cells did not express IDO mRNA expression regardless of the progenitor cell sources (cord blood, mobilized peripheral blood, bone marrow). During DC differentiation, IDO expression and function, evaluated by enzymatic and immunological tests, was markedly induced at day 7. Interestingly, the expression of IDO was shown to be 10 times higher in the CD1a+ compartment as compared to CD1a- cell fraction. IDO expression resulted in increased production of kynurenine and in reduced allostimulatory capacity of T-cell proliferation. Moreover, CD1a+ cells were shown to induce a population of CD4+CD25+Foxp3+ which acted as Tregs by inhibiting allogeneic T cell proliferation. This effect was abrogated by the addition of the IDO inhibitor 1-methyl tryptophan. Phenotypically, IDO-expressing CD1a+ cells expressed typical marker of Langerhans cells such as CD207, CD11b, CD1c, as well as CD103, which has been recently identified as a marker for tolerogenic DCs. Importantly, IDO expression was mainly detected in the CD103+ CD207+ fraction, which induces Tregs through an IDO-dependent manner. In conclusion, DC differentiation of CD34+ cells results in the expression of a functionally active IDO protein in CD103-expressing DCs. Given the role of IDO in regulating immune tolerance, a subset of bone marrow-derived DCs, expressing CD103, may be intrinsically committed to function as regulatory DCs. These data point toward IDO expression as part of a tolerogenic signature during DC development.

Disclosures:
No relevant conflicts of interest to declare.
Desialylated Platelets Are Cleared From the Circulation by the Hepatic Asialoglycoprotein Receptor,
Authors: Grozovsky Renata , Giannini Silvia , Hoffmeister Karin M. 
Published: October 2019

Abstract
Abstract 3257
The regulatory mechanisms of platelet homeostasis remain elusive. We investigated here the role of hepatic asialoglycoprotein receptor (a.k.a. Ashwell-Morell receptor) in platelet clearance. Mice lacking the hepatic asialoglycoprotein receptor Asgpr2 subunit had increased platelet survivals (T1/2 = 49.5±2h) when compared to wild type (WT, T1/2 = 31±4h) mice. Consequently, Asgpr2−/− mice had platelet counts increased by ∼20%, compared to WT, with increased terminal galactose exposure, as demonstrated using the galactose specific lectin RCA1. Bone marrow and spleen megakaryocyte numbers were reduced by ∼15% and ∼20% in Asgpr2−/− mice, compared to WT mice. Sialidase (NA, Clostidium perfringens, 50mU/mice) maximally desialylated circulating platelets when injected intravenously, as evidenced by increased RCA1 binding. Sialidase injection resulted in a ∼60% depletion of circulating platelets after 24h in Asgpr2−/− mice, compared to >90% in WT mice, indicating that desialylated platelets were partially removed by Asgpr1/2. In contrast to platelets, red blood cell counts were unaffected by sialidase treatment. Sialidase injection for 72h resulted in a 2.3-fold and 1.2-fold increase in megakaryocyte numbers in the spleen and bone marrow of WT mice, respectively, but not in Asgpr2−/− mice. In contrast to sialidase treatment, injections of rabbit anti-mouse platelet serum (RAMPS) depleted >95% of circulating platelets and increased by 70% bone marrow, but not spleen MK numbers in both WT and Asgpr2−/− mice. The data shows that removal of desialylated, i.e, senescent, platelets by the hepatic Ashwell-Morell receptor differs to that of antibody-mediated platelet clearance.

Disclosures:
No relevant conflicts of interest to declare.
Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response in a Rat Model of Peptidoglycan Polysaccharide - Induced Arthritis,
Authors: Garcia Analia E , Mada Sripal R , Rico Mario C , De La Cadena Raul A. , Kunapuli Satya P. 
Published: October 2019

Abstract
Abstract 3287
Clopidogrel is a widely used anti-thrombotic drug that prevents platelet activation by irreversibly antagonizing P2Y12 receptor. This drug could be co-administrated in patients afflicted with inflammatory conditions, such as rheumatoid arthritis and lupus. Hence it is of importance to determine if blocking P2Y12 receptors has any therapeutic benefit during the inflammatory response. Therefore, we evaluated the effect of clopidogrel using an animal model of chronic inflammation. Genetically susceptible Lewis rats were injected intraperitoneally with peptidoglycan polysaccharide (PGPS) to develop arthritis and followed for 21 days. Interestingly, we noticed an increased level of inflammation in induced arthritis animals treated with clopidogrel compared with induced arthritis animals alone, including a) increased in joint diameter between day 15 and 21 (p<0.0001) with augmented clinical manifestations of inflammation, b) an elevated neutrophil blood count and an increased circulating platelet count (926 ± 195 × 103 vs. 561.25 ± 97 × 103 mL; p<0.05). Furthermore, microscopic differences were observed at the site of joint inflammation namely: a significant increase in leukocyte infiltration, pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in induced arthritis animals. Plasma levels of pro-inflammatory cytokines, namely IL-1 beta, interferon (IFN) gamma, and IL-6, were significantly increased in the induced arthritis animals treated with clopidogrel when compared to induced arthritis animals alone (p<0.05). In contrast, plasma levels of IL-10 were significantly lower when animals were treated with clopidogrel compared to induced arthritis animals alone (p<0.05). Plasma levels of platelet factor 4 (PF4) were increased in all animals treated with PGPS, however PF4 levels show not difference with clopidogrel treatment. This last finding suggests that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. In summary, according to clinical observations, histopathology measurements and cytokine results, the antagonism of the P2Y12 receptor has a pro-inflammatory effect in this model of erosive arthritis, which might not be mediated only by platelets. These data provide new insights into the role that thienopyridine metabolites play during chronic inflammation distant from their action on platelets and with a detrimental outcome in this model of erosive arthritis

Disclosures:
No relevant conflicts of interest to declare.
Dose-Finding Study: Rational Proceeding in Patients with VWD,
Authors: Halimeh Susan , Rott Hannelore , Nowak-Gottl Ulrike 
Published: October 2019

Abstract
Abstract 3326
In patients with von Willebrand's disease (VWD) replacement therapy with factor VIII/VWF concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes were diagnosed with VWD. In all patients, decision for initiating prophylaxis was based on a bleeding score >2 prior to diagnosis, concomitant with recurrent bleedings associated with anemia in patients with on-demand therapy. We report results on secondary prophylactic VWF replacemment therapy applied 13 children, 7 adolescents and 4 adults (n=24) with VWD type 1 (n=4), 2 (n=12) and the severe type 3 (n=8).
Based on individual 24h VWF:RCo recoveries [aim: 0.01 to 0.02 IU/ml > baseline] median dose was 40 [min. 20- max. 47] IU/kg, 15 patients were give substitution therapy semiweekly, 7 patients thrice weekly and 2 children four times per week. Within a 12-months-period hemoglobin conentrations returned to normal values. Median duration of prophylaxis was 3 years. Recurrent bleeding episodes stopped in 23/24 patients. One female type 3 patient additionally needed locally applied tranexamic acid [tooth bruising]. Following a 12-months observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre-prophylaxis/ pre-diagnostic values.

Conclusion:
The use of secondary prophylactic VWF replacement therapy with FVIII/VWF concentrate is an effective tolerated treatment modality, highly benefical for patients with VWD, who present recurrent bleeding events during an on-demand therapy.

Disclosures:
No relevant conflicts of interest to declare.
Results of a Prospective, Open-Label Trial to Assess the Efficacy, Safety and Immunogenicity of Wilate® in Children Under 6 Years of Age with Inherited Von Willebrand Disease,
Authors: Nowak-Gottl Ulrike , Russo Alexandra , Kruempel Anne , Jansen Martina , Knaub Sigurd 
Published: October 2019

Abstract
Abstract 3330

Introduction:
Wilate® is a new-generation plasma-derived concentrate of von Willebrand factor (VWF) and factor VIII (FVIII) developed for treatment of patients with von Willebrand disease (VWD) and haemophilia A. The objective of this study was to assess efficacy, safety and immunogenicity of Wilate in children below 6 years of age with inherited VWD.

Methods:
The prospective, multi-centre trial included patients with inherited VWD of any type below 6 years of age with insufficient response to DDAVP. Any clinical event requiring VWF/FVIII concentrate treatment within 1 year was treated with Wilate. Efficacy was recorded by using a 4-point VRS and in vivo recovery of FVIII:C and VWF:RCo was analyzed. Immunogenicity was assessed by determination of inhibitors against VWF and FVIII. Safety was measured by monitoring of adverse events. Tolerability was rated as “very good” or “good” for all cases by the investigator.

Results:
Fifteen subjects (6 type 3) were analyzed. Dosing regimens were dependent on specific clinical situations of each subject. The mean incremental in vivo recovery was 1.2 IU/dL per IU/kg for VWF:RCo and 1.6 IU/dL per IU/kg for FVIII:C (n = 7). Forty five bleeding episodes required treatment with Wilate. In all cases the overall haemostatic efficacy ratings by the investigator were “excellent” or “good”. The mean dose was 35.9 IU VWF:RCo/kg. Nine surgical procedures (3 major) were performed in 7 subjects, requiring 2 to 12 infusions/procedure with a mean dose per exposure day of 61.7 VWF:RCo/kg. Haemostatic efficacy for a total of 419 infusions was rated as “excellent” for 362, “good” for 54, “moderate” for 2 (1 missing) infusions. No notable changes in thrombogenicity markers and no thromboembolic events occurred. No inhibitors against VWF or FVIII were detected.

Conclusion:
This study demonstrates the efficacy, safety and tolerability of Wilate® in treatment of VWD in patients below 6 years of age.

Disclosures:
Jansen: Octapharma: Employment. Knaub:Octapharma AG: Employment. Off Label Use: the product, Octanate, is approved in many countries worldwide but is not currently approved in the US.