bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infliximab Drives Gamma-Delta T Cell Expansion In Crohn's Disease – a Predictor of Lymphoma Risk?
Authors: Kelsen Jens , Schwindt Heinrich , Dige Anders , d'Amore Francesco , Pedersen Finn Skou , Agnholt J∅rgen , Christensen Lisbet Ambrosius , Dahlerup Jens Frederik , Hvas Christian Lodberg 
Published: October 2019

Abstract
Abstract 4131

Background:
Due to the widespread use of combined immunosuppressive therapy in the management of Crohn's disease (CD), the risk of malignant lymphoproliferation, including the fatal hepato-splenic T cell lymphoma (HSTCL), has become a major concern. We investigated dynamic changes of peripheral gamma-delta (γδ)-T cells during CD treatment with the anti-TNF-α-antibodies infliximab (Remicade®) and adalimumab (Humira®).

Methods:
Forty-six patients with active CD and nine healthy volunteers were analysed. Patients delivered blood samples before and 1, 7, and 42 days after infliximab 5 mg/kg (20 patients) or adalimumab given as induction with 160 mg and 80 mg after 2 weeks and subsequently 40 mg every other week (26 patients). The γδ-T cells were analysed using FACS analysis. Patients with high percentages of peripheral γδ-T cells were characterized by PCR-assessment of γδ-T cell clonality.

Results:
Of 46 patients included in the analysis, 35 (76%) had γδ-T cell levels comparable to those of healthy individuals (mean: 1.6%; 95% CI: 1.3–2.0%). Higher γδ-T cell levels from 5% up to 15% occurred in 11 patients (24% of the total cohort). A high γδ-T cell level was associated with non-smoker status and young age. In 18 patients receiving thiopurines or methotrexate, the mean baseline γδ-T cell percentage was 4.4% (95% CI: 2.1–6.7%). In three male CD patients with high baseline values, the γδ-T cell percentage doubled within 24 hours following infliximab therapy. Another male patient on infliximab monotherapy presented with a predominantly clonal baseline γδ-T cell population as high as 20%, further increasing to 25% shortly after infliximab treatment.

Conclusion:
One fourth of the CD patients treated with immunomodulators had constitutive high levels of circulating γδ-T cells, and infliximab aggravates this γδ-T cell expansion. We raise the hypothesis that such patients may be at increased risk of developing a malignant γδ-T cell lymphoproliferation.

Disclosures:
No relevant conflicts of interest to declare.
The BCL11B Tumor Suppressor Is Mutated In Human T-Cell Acute Lymphoblastic Leukemia
Authors: Gutierrez Alejandro , Kentsis Alex , Sanda Takaomi , Etchin Julia , Protopopov Alexei , Zhang Jianhua , Chin Lynda , Silverman Lewis B. , Winter Stuart , Hunger Stephen , Sallan Stephen E. , Zha Shan , Alt Frederick , Look A. Thomas 
Published: October 2019

Abstract
Abstract 4177
The BCL11B transcription factor, previously identified as a central player in normal α/β T-cell development, has recently been found to play critical roles in the maintenance of T-cell identity, with biallelic Bcl11b inactivation in T-cell precursors severely impairing their continued development into the T-cell lineage. Previous work has demonstrated that Bcl11b haploinsufficiency accelerates the onset of thymic lymphomas in p53-mutant mice, as well as T-lymphoid blast crisis in a mouse model of chronic myeloid leukemia induced by BCR-ABL. Furthermore, we have recently identified recurrent monoallelic Bcl11b deletions in 91% of T-cell acute lymphoblastic leukemias (T-ALL) arising in Atm-deficient mice, further supporting a role for Bcl11b haploinsufficiency in T-cell leukemogenesis. In order to determine whether BCL11B inactivation plays a role in the molecular pathogenesis of human T-ALL, we analyzed BCL11B status in primary T-ALL patient samples by array CGH and sequencing analysis. Monoallelic BCL11B deletions were identified in 6% of cases (n = 3 of 47) analyzed by array CGH, including one microdeletion within the BCL11B locus, one small deletion involving BCL11B and 6 additional genes, and one large 26 Mbp deletion of the distal arm of chromosome 14. BCL11B sequencing revealed heterozygous missense mutations in an additional 9% (n = 4 of 43) of primary T-ALL patient samples and in 19% (n = 3 of 16) of T-ALL cell lines. Structural homology modeling revealed that many of the mutations identified, including 3 of the 4 in the primary patient samples, disrupted key amino acids within BCL11B zinc finger domains that are involved in DNA recognition or structural stabilization required for zinc finger domain-mediated transcriptional activity. Analysis of TCRγ rearrangement status and gene expression data revealed that most cases with BCL11B inactivation were characterized by biallelic TCRγ rearrangements together with an early thymocyte precursor (ETP) gene expression signature, indicating developmental arrest at a prethymocyte stage of T-cell development, which we and others have shown confers an increased risk of treatment failure (Coustan-Smith et al. Lancet Oncol 2009; Gutierrez et al. J Clin Oncol 2010). Given that BCL11B expression during normal T-cell development increases markedly at the prethymocyte stage, our findings suggest that BCL11B inactivation may be directly responsible for developmental arrest at a prethymocyte stage during thymocyte transformation. Our findings provide compelling evidence that BCL11B is a tumor suppressor in a subset of human T-ALLs with a high risk of treatment failure.

Disclosures:
No relevant conflicts of interest to declare.
Endogenous Oncogenic Nras Mutation Initiates T-Cell Leukemia/Lymphoma In a Dose-Dependent Manner
Authors: Wang Jinyong , Li Zeyang , Wang Zhongde , Liu Yangang , Ryu Myung-Jeom , Meline Benjamin , Du Juan , Young Ken H , Chang Qiang , Zhang Jing 
Published: October 2019

Abstract
Abstract 4183
The oncogenic NRAS mutations are frequently identified in myeloid diseases but rare in lymphoid diseases. They occur in 4% of acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) patients and 22% of human T-ALL cell lines. Its differential roles in myeloid versus lymphoid disease development remain unclear. Here we examine the tumorigenic potential of oncogenic Nras in T-cells using two conditional Nras G12D murine knock-in models that either hypomorphically (NrasG12D Hypo) or normally (NrasG12D Norm) expresses oncogenic Nras G12D from its endogenous locus. Mice expressing monoallelic or biallelic NrasG12D Hypo develop normally and are tumor free. However, NrasG12D Norm leads to acute T-cell leukemia/lymphoma (TAL/L) in a bone marrow transplantation model, with a low incidence (∼8%) when expressing one allele (TAL/L-het) and a complete penetrance when expressing two alleles (TAL/L-homo). TAL/L-het tumors are associated with spontaneous up-regulation of oncogenic Nras in ∼67% of animals, and tumor cells are TdT positive, suggesting that they are transformed at an immature stage. In contrast, TAL/L-homo tumors express comparable levels of Nras to control thymocytes, and tumor cells are TdT negative, suggesting that they are transformed at a more mature stage. Both TAL/L-het and TAL/L-homo tumors are oligoclonal or polyclonal. Above 70% of these tumors contain clonal Notch1 mutations and are sensitive to gamma-secretase inhibitor. These data indicate that Notch1 mutations are acquired at an early stage and play an important role in the development of TAL/L-het and TAL/L-homo tumors. Together, our results show that engdogenous oncogenic Nras mutation leads to TAL/L in a dose-dependent manner, and thus explain the low incidence of oncogenic NRAS mutations in human T-cell diseases.

Disclosures:
No relevant conflicts of interest to declare.
JAK2 Germline Genetic Variation In Budd-Chiari Syndrome and Portal Vein Thrombosis
Authors: Smalberg Jasper , Koehler Edith , Murad Sarwa Darwish , Plessier Aurelie , Garcia-Pagan Juan-Carlos , Seijó Susana , Langlet Philippe , Trebicka Jonel , Primignani Massimo , Maat Moniek De , Valla Dominique , Janssen Harry , Leebeek Frank 
Published: October 2019

Abstract
Abstract 4212
Primary Budd-Chiari syndrome (BCS) and non-malignant, non-cirrhotic portal vein thrombosis (PVT) are rare disorders with a considerable overlap in etiology. Myeloproliferative neoplasms (MPN) are the most frequent underlying prothrombotic factor in both entities. The JAK2 V617F mutation (VF) has been identified in over half of the individuals with MPN. Recently, a JAK2 haplotype, designated ‘46/1’, has been described. Previous studies suggest that the JAK2 46/1 haplotype represents a disease susceptibility to MPN, independent of VF status. The aim of this study was to determine the role of the JAK2 46/1 haplotype in the etiology of BCS and PVT. Patients were recruited from the EN-Vie cohort, consisting of 163 BCS and 138 PVT patients, consecutively enrolled in nine European countries between October 2003 and October 2005. DNA was available from 116 BCS patients (50 males and 66 females; median age 38.1), 97 PVT patients (47 males and 50 females; median age 49.8) and 104 healthy controls (43 males and 61 females; median age 36.8). The JAK2 46/1 haplotype was tagged by the rs12343867 single nucleotide polymorphism. Frequency of the JAK2 haplotype 46/1 was higher in BCS (36%, p=0.06) compared to controls (27%), while similar in PVT patients (28%, p=0.89). When stratified for VF status, haplotype 46/1 frequency was higher in VF positive BCS (44%, p=0.01) and VF positive PVT patients (40%, p=0.06) compared to controls. Haplotype 46/1 frequency was similar in VF negative BCS (33%, p=0.29) and PVT patients (24%, p=0.47) compared to controls. VF negative BCS patients with a proven MPN also showed increased frequency of the 46/1 haplotype (56%, p=0.07). Logistic regression, adjusted for age and sex, showed an association between the 46/1 haplotype and risk of VF positive BCS (OR: 2.10; 1.16–3.80), VF positive PVT (OR 2.07; 0.95–4.52) and VF negative BCS patients with a proven MPN (OR 3.04; 1.02–9.06). We conclude that the JAK2 46/1 haplotype may be associated with BCS and that this was limited to patients with a proven MPN, independent of VF status. In PVT, the 46/1 haplotype was only associated with patients who were VF positive.
This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie).

Disclosures:
No relevant conflicts of interest to declare.
Clearance of Platelet Microvesicles by Endothelium. the Role of Developmental Endothelial Locus–1 (Del-1)
Authors: Dasgupta Swapan Kumar , Le Anhquyen , Thiagarajan Perumal 
Published: October 2019

Abstract
Abstract 4303
Activation of platelets with certain agonists induces release of small submicron size membrane-enclosed compartments of platelet content called microvesicles. During microvesiculation, phosphatidylserine, an anionic phospholipid, moves from the inner to the outer leaflet of membrane bilayer accounting for the procoagulant effect of microvesicles. Microvesicles circulate in the blood with a short half-life of less than 5–10 minutes and the exposure of phosphatidylserine may mediate its rapid clearance. Developmental endothelial locus–1 (del-1) is a 52kDa glycoprotein secreted by endothelial cells. It contains three epidermal growth factor (EGF)-like repeats in amino terminus and two discoidin I-like domains in carboxy terminus, similar to the macrophage opsonin lactadherin. The second EGF like repeat contains the canonical Arg-Gly-Asp (RGD) motif that enables Del-1 to bind integrin αVβ3 and αVβ5. Here, we tested the role of Del-1 in endothelial uptake of platelet-derived microvesicles.
In vitro, resting human umbilical vein endothelial cells engulf BODIPY-labeled phosphatidylserine expressing platelets microvesicles avidly. Evidence of uptake was obtained by confocal microscopy and by flow cytometry. Following uptake, the microvesicles were distributed throughout the cytoplasm of the endothelial cells. We quantified the internalization of fluorescent microvesicles by measuring the intracytoplasmic fluorescence associated with endothelial cells in a flow cytometer after quenching cell surface fluorescence with Trypan Blue. A monoclonal antibody to Del-1 inhibits (p=0.03) the uptake while exogenous Del-1 promotes the uptake by endothelial cells. Abciximab inhibited -dependent phagocytosis to about ∼40 % while under similar conditions an irrelevant control antibody had no effect (p=0.016). In addition, annexin A5 also inhibited the uptake of platelet-derived microvesicles by endothelial cells (p=0.002). These results show Del-1 mediates phosphatidylserine and integrin-dependent uptake of microvesicles by endothelial cells. To assess the in vivo significance, we infused BODIPY labeled platelet-derived microvesicles into the inferior vena cava of the mouse and harvested endothelial cells from the pulmonary circulation. Microvesicles were detected within the endothelial cells. In Del-1 deficient mice has impaired uptake of microvesicles compared wild type littermate controls (P=0.02). We also measured the levels of microvesicles six after administration lipopolysaccharide. Del-1 deficient mice have increased microvesicles compared to their littermate controls (p=0.02).
These studies show a physiological role for Del-1 in the clearance of microvesicles by endothelium.

Disclosures:
No relevant conflicts of interest to declare.
Genetic Determinants of Plasma Von Willebrand Factor Antigen Levels: A Target Gene SNP and Haplotype Analysis of the ARIC Cohort
Authors: Campos Marco , Sun Wei , Yu Fuli , Barbalic Maja , Chambless Lloyd , Wu Kenneth , Ballantyne Christie , Folsom Aaron , Boerwinkle Eric , Dong Jing-fei 
Published: October 2019

Abstract
Abstract 4310

Background and Objectives:
Von Willebrand factor (VWF) is an essential component of hemostasis. It is known that multimer size and the amount of circulating VWF impact its hemostatic function. Genetic factors play a major role in regulating VWF synthesis and clearance and are reported to contribute to 66% of the variation in plasma VWF antigen level. We have analyzed 78 SNPs distributed throughout the VWF gene and haplotypes constructed from those SNPs for an association with VWF antigen level in 7,856 subjects of European descent in the Atherosclerosis Risk in Communities cohort. Methods and Results: Blood was drawn after an 8 hour fasting period and VWF antigen level was determined by a commercial ELISA kit. All subjects underwent analysis for 78 SNPs available from Affymetrix 6.0 chip in the region encompassing the VWF gene. We used the fastPHASE 1.2 program to resolve haplotypes from the unphased SNP genotype data. Using Haploview we determined SNPs in strong linkage disequilibrium (LD), their co-segregation rates and underlying haplotypes. Linear models were used to evaluate the association of actual or log VWF antigen levels with each SNP and haplotypes derived from those SNPs. Eighteen (16 are intronic) of the 78 SNPs were found to significantly associate with levels of VWF antigen (Table 1). All are clustered in a 50 kb region of the VWF gene in spite of the fact that the 78 SNPs studied are distributed throughout the VWF gene without apparent clusters. All 78 SNPs are co-segregated in 9 LD haplotype blocks, but a majority of positive SNPs (88.9%) are located in Block 5 and 6, which significantly correlate with VWF antigen level. The O blood type contributes to ∼ 15% of variation in VWF antigen levels. The association for SNPs and Haplotypes grows stronger after ABO effects are removed. Among non-genomic factors, age and BMI are the most significant factors and contribute to 4.8% and 1.4% of variation in VWF antigen level. Conclusions: We have found a strongly positive association between VWF level and SNPs and haplotypes from a strikingly concentrated region of the VWF gene. This region encodes the D2, D' and D3 domains of VWF, including the propeptide and multimerization and Factor VIII binding sites. The physiological significance of these clustered SNPs on VWF synthesis or clearance remains to be further investigated. Our data suggest that this region plays an important role in regulating VWF antigen level and support the idea that combinations of SNPs in LD can provide additive affects.

Disclosures:
No relevant conflicts of interest to declare.
A Study of the Proliferative Effect on Acute Lymphocytic Leukemia Cell Lines by G-CSF and Synergetically Anti-Leukemic Effect on These Cell Lines by G-CSF Plus Cytotoxic Agent
Authors: Xue Shengli , Dai Lan , Chen Yan , Qiu Qiaocheng , Chen Suning , Tang XiaoWen , Sun Aining , Depei Wu 
Published: October 2019

Abstract
Abstract 4330

Objectives
To observe the proliferative effect on acute lymphocytic leukemia (ALL) cell lines caused by G-CSF, and to evaluate the synergetically anti-leukemic effect on these cell lines produced by Ara-C combined with G-CSF.

Methods
With fluorescence quantitation kit and flow cytometry, G-CSFR expression density of 5 ALL cell lines were detected, and expression density changes due to G-CSF stimulation were evaluated. After treatment by G-CSF of various concentrations, changes of cell cycle and cell proliferation in ALL cell lines were examined by DNA-PREP-TM kit and Cell Counting Kit (CCK-8), respectively. After treatment by different concentration's Ara-C combined with different concentration's G-CSF, ALL cell lines’ existing cell viability were detected by CCK-8.

Results
All 5 ALL cell lines expressed G-CSFR, 2 ALL cell lines including CCRF-CEM and 697 exhibited G-CSFR expression density up-regulation tendency after G-CSF's stimulation, while 3 T-ALL cell lines including MOLT-4, Jurkat,Clone E6-1, A3 showed G-CSFR expression density down-regulation tendency after G-CSF's stimulation, which was similar in neutrophil. Cell cycle analysis showed that S phase cell proportion in MOLT-4, Jurkat,Clone E6-1, A3 cell lines had a growing tendency after G-CSF’ treatment, while no similar tendency was observed in CCRF-CEM, 697 cell lines. A relatively proliferative advantage was found in MOLT-4, Jurkat,Clone E6-1, A3 cell lines after G-CSF's treatment, but only in MOLT-4 there was a statistically significance after 10ng/ml G-CSF's stimulation. A synergetically anti-leukemic effect was observed in MOLT-4, Jurkat,Clone E6-1, A3 cell lines after Ara-C's treatment combined with G-CSF.

Conclusions
The biological characteristics of ALL cell lines expressing G-CSFR was different from each other. Synergetically anti-leukemic effect produced by cytotoxic agent and G-CSF could occur in ALL cell lines which showed a growing S phase cell proportation after G-CSF's treatment. ALL cell's response to G-CSF, which means down-regulation of G-CSFR expression density, seems a promising indicator that a synergetically effect could be produced by Ara-C plus G-CSF. Before this indicator could be applied for guiding ALL patients’ management, clinical researches are needed to confirm it.

Disclosures:
No relevant conflicts of interest to declare.
Treatment of Primary Granulocytic Sarcoma of the Uterine Cervix: Reports of Three Cases
Authors: Jie Zhang , Jian Meng Xiao , Jin Ye Xiu , He Jing-Song , Huang He 
Published: October 2019

Abstract
Abstract 4346

Background:
Granulocytic sarcoma is a rare event with a poor prognosis which may herald, accompany or signal acute myeloid leukaemia. While many advances in diagnosis have been made, dilemmas remain concerning the diagnosis and treatment of this disease particularly when it arises in an unusual site such as the uterine cervix.

Case:
We describe here three female cases of primary granulocytic sarcoma in the cervix uteri who were 39, 44 and 41 years old, respectively. All the patients presented with irregular vaginal discharge or bleeding and postcoital pain. Biopsy of the vaginal wall or cervix was performed and multiple immunohostochemical analyses were obtained. Myeloid markers were strongly positive whereas lymphoid markers, epithelial markers as well as neuroendocrine markers were all negative, which confirmed the diagnosis of granulocytic sarcoma. The induction chemotherapy including homoharringtonine in combination with cytarabine (homoharringtonine, days 1–3; cytarabine days 1–7) or idarubicin with cytarabine (idarubicin, days 1–3; cytarabine days 1–7) was given followed by consolidation therapy. All the patients achieved complete remission after induction and two of whom remain in complete remission with normal complete blood counts, physical examination, abdominal ultrasonography and magnetic resonance imaging. One patient relapsed locally after six cycles of chemotherapy and progressed to acute myeloid leukemia after one year follow-up.

Conclusion:
Granulocytic sarcoma of the cervix is a rare entity and even in its localized form, early intensive therapy appears to be appropriate. Although this experience is confirmed to three patients, it may contribute to the design of prospective therapeutic studies in patients with this rare disease.

Disclosures:
No relevant conflicts of interest to declare.
Survival Outcomes of Adults with Acute Myeloid Leukemia – A Study of Native American, Hispanic, and Non-Hispanic Whites Treated In New Mexico (1986 to 2006)
Authors: Rivera Nancy , Armijo Beeling , Quintana Dulcinea , Abdul-Jaleel Maryam , Lee Sang-Joon , Wiggins Charles , Libby Edward 
Published: October 2019

Abstract
Abstract 4365

Purpose of study:
The three largest ethnic populations in New Mexico are Caucasians, Native Americans, and Hispanics. As the largest tertiary care center in the state, our institution offers treatment to significant numbers of all three groups. In addition, many residents of the state live in rural areas. The goal of this study is to identify potential differences in outcome between ethnic groups from urban or rural areas in patients with newly diagnosed acute myelogenous leukemia (AML) treated at this center from 1986–2006.

Methods:
A retrospective chart review was performed on patients identified through a New Mexico tumor registry search of all adult patients (≥ 18 years of age) with a new diagnosis of AML treated at this center from 1986 through 2006. The search identified 150 cases. Of those patients, 144 charts were available for review. Six charts could not be located. Electronic, microfilm and paper-based medical records were reviewed. Data was collected for race/ethnicity, sex, zip code, age at diagnosis, pathologic diagnosis, date of diagnosis, cytogenetics, treatments received, total number of chemotherapy cycles, achievement of complete remission, and overall survival from time of diagnosis and from achievement of remission after induction chemotherapy. Date of death was determined from the chart or from New Mexico tumor registry data. Cancer cases who resided in New Mexico counties with large population centers were designated as urban residents and the remaining cases were designated as rural residents. Statistical analysis was performed to examine the effect of the variables mentioned above on overall survival.

Summary of results:
The analysis included 144 patients (mean age 49.98, range 18–85). For those patients who received chemotherapy the standard treatment was 7+3 followed by high dose cytarabine (1-4 cycles) or similar regimen. There were no statistical differences between survival rates when comparing the three ethnic groups, Caucasians 78 (52%), Hispanics 43 (28%), and Native Americans 23 (15%) (P=0.2496). In agreement with previous reports, statistically significant differences were seen for treatment versus palliative care, cytogenetics and age. The study included 61 urban patients with a mean survival of 426 days and 83 rural patients with a mean survival of 278 days. Analysis revealed a statistically significance in survival for urban versus rural patients who achieved complete remission after induction chemotherapy (P=0.0443).

Conclusions:
Survival was improved for urban patients who achieved a complete remission after induction chemotherapy versus rural patients (P= 0.0443). Further study should be undertaken to identify the causes of this disparity.

Disclosures:
No relevant conflicts of interest to declare.