bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Expression of EIF2S3 in Acute Myeloid Leukemia and Its Prognostic Significance
Authors: Lu Jielun , Xu Lihua , Luo Xiaodan , Chen Shuyi , Zou Yawei , Tan Huo 
Published: October 2019

Abstract
Background: Eukaryotic translation initiation factor 2 subunit gamma (EIF2S3) is a component of eIF2 ,which functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA and binding to a 40S ribosomal subunit. The preliminary research suggested that in multiple malignant carcinomas, the expression level of EIF2S3 between the normal tissue and malignant one is Significantly different.It indicated that EIF2S3 might play an important role in the occurrence and development of malignant tumors .The purpose of this study is to investigate the expression status of EIF2S3 and its prognostic significance in AML patients.
Methods:Total RNA was extracted from bone marrow of 42 patients. The expression of EIF2S3 was examined by Realtime quantitative PCR. The relationship of EIF2S3 expression and other clinicopathological charactors and itsprognosis significance were statistically analyzed.
Results:The relative expression of EIF2S3 was much higher in patients who had achieved CR (median value 0.088, range: 0.0179-0.238;) compared with newly diagnosed AML patients(median value 0.037, range: 0.003-0.203),p value was 0.020.Furthermore, the expression of EIF2S3 was markedly associated with Complete Remission (P = 0.012) and outcome(P=0.029). Patients with lower EIF2S3 expression had a relatively poor overall survival(OS) (P = 0.016) and short disease-free survival(DFS) (P = 0.001). Moreover, EIF2S3 expression was an independent prognostic factor for both OS (P = 0.001) and DFS (P <0.001).
Conclusions:Patients who had achieved CR usually had a higher level of EIF2S3 expression compared with newly diagnosed AML patients. The over-expression of EIF2S3 is associated with good prognosis in AML patients, and was an independent prognostic factor for both OS and DFS.

Disclosures
No relevant conflicts of interest to declare.
Yearly Percent Incidence of Suspected Novel Oral Anticoagulant Interference on Thrombophilia Testing: A Nine Year Experience at a Reference Coagulation Laboratory
Authors: Wong Edward C.C. , Worfolk Laura A. , Dlott Jeffrey S. 
Published: October 2019

Abstract
Introduction: With the recent FDA approval of novel oral anticoagulants (NOACs) for anticoagulation, the diagnosis of thrombophilia risk factors, such as protein S deficiency, protein C deficiency and presence of lupus anticoagulant, has become problematic, especially when clot-based assays are utilized in the presence of Xa and direct thrombin inhibitors. Falsely elevated protein S and C activities and false positive lupus anticoagulant testing may occur with NOAC use. Little is known about the yearly incidence of such interference during the time period when these NOACs were introduced in the United States (dabigatran, 10/2010; rivaroxaban, 7/2011; apixaban, 12/2012; edoxaban, 1/2015). To answer this question, we undertook a retrospective study that examined interference before and after NOACs were introduced to the US market.
Materials and Methods: Retrospective review of venous thrombophilia testing from January 2008 to December 2016 at a major coagulation reference referral laboratory. To identify potential NOAC interference, samples were tested with both a dilute Russell Viper Venom test (dRVVT), which is a lupus anticoagulant test, and a protein C activity test. NOAC interference was strongly suspected when dRVVT testing demonstrated an inhibitor pattern and elevated protein C activity (>200%). The annual percentage of thrombophilia tests with strongly suspected NOAC interference was determined and compared to that of tests with elevated protein C activity and without a dRVVT inhibitor pattern (less strongly suspected interference).
Results: The percentage of suspected NOAC interference increased annually from 2008 to 2016, which corresponds to the introduction of NOACs to the US market. From 2008 to 2016, test results of suspected NOAC interference increased from 0.21% to 3.45% (16.4-fold increase), peaking in 2015 (24.1-fold increase); test results of elevated protein C activity without a dRVVT inhibitor pattern increased from 0.48% to 7.22% (15.0-fold increase), peaking in 2014 (31.5-fold increase). Suspected interference decreased between 2015 and 2016, which may be related to education efforts by our laboratory in 2014 and 2015, when we notified practitioners of possible interference.
Conclusions: Suspected NOAC interference, which can potentially cause false-positive test results for lupus anticoagulant and protein C activity, increased when NOACs were introduced into the US market. Further education of licensed independent practitioners may help prevent these interferences and provide more accurate assessment of thrombophilia risk factors.
Figure. Figure.

Disclosures
Wong: Quest Diagnostics: Employment, Other: stock . Worfolk:Quest Diagnostics: Employment. Dlott:Quest Diagnostics: Employment, Other: stock.
Improved Pharmacokinetic Profile for BAY 81-8973 Due to Increased Branching and Sialylation of N-Linked Glycans of Recombinant Factor VIII
Authors: Teare John M. , Kates David S. , Shah Anita , Garger Stephen 
Published: October 2019

Abstract
The circulatory half-life of recombinant factor VIII (rFVIII) products is affected by glycosylation of the FVIII protein, including N-linked glycan branching and terminal sialic acid occupancy, primarily through receptor-mediated hepatic clearance (eg, asialoglycoprotein receptor [ASGPR] and lipoprotein receptor-related protein [LRP]). BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA) is an unmodified full-length rFVIII for treatment of hemophilia A. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of branching and sialylation of N-linked glycans. This study evaluated whether a relationship exists between N-linked glycosylation patterns and pharmacokinetic (PK) characteristics of BAY 81-8973 and 2 other rFVIII products (sucrose-formulated rFVIII [rFVIII-FS; Kogenate® FS, Bayer] and antihemophilic factor (recombinant) plasma/albumin-free method [rAHF-PFM; Advate®, Shire, Westlake Village, CA]).
N-linked glycans or terminal carbohydrates were enzymatically removed from immobilized BAY 81-8973, rFVIII-FS, and rAHF-PFM proteins and analyzed using high-performance liquid chromatography to determine the percentage of individual N-linked glycan structures and degree of sialylation of each structure. PK data were available from 2 separate phase 1 crossover studies in which the PK profile of BAY 81-8973 was compared with that of rFVIII-FS (n=26) and rAHF-PFM (n=18) in patients with severe hemophilia A who received a single 50-IU/kg dose of each product.
BAY 81-8973 and rFVIII-FS had increased N-linked glycan branching with higher levels of sialylation compared with rAHF-PFM. Levels of trisialylated glycans were 29.0% for BAY 81-8973 versus 11.5% for rFVIII-FS and 4.8% to 5.5% for rAHF-PFM; tetrasialylated glycans were 12.0% versus 2.8% and 0.6%, respectively. Degree of sialylation was 96% for BAY 81-8973, 94% for rFVIII-FS, and 78% to 81% for rAHF-PFM. Based on chromogenic assay results from the single-dose phase 1 PK studies, BAY 81-8973 half-life was 15% longer than that for rFVIII-FS and 16% longer than rAHF-PFM.
Increases in the percentage of sialylated tri-antennary and tetra-antennary N-glycans correlated well with longer half-life of rFVIII in humans (adjusted R2=0.978 and 0.892 for tri-antennary and tetra-antennary N-glycans, respectively). Higher percentages of sialylation (ie, sialic acid capping) correlated with a longer half-life (adjusted R2=0.697), but the relationship was not as strong as that between glycan branching and half-life. Improved PK for BAY 81-8973 relative to rFVIII-FS and rAHF-PFM as seen in single-dose crossover PK studies might be related to this greater level of branching and sialylation, which may prolong the time BAY 81-8973 remains in the circulation.

Disclosures
Teare: Bayer: Employment. Kates:Bayer: Employment. Shah:Bayer: Employment. Garger:Bayer: Employment.
RDW Is a Prognostic Marker for Patients with Aggressive Peripheral T-Cell Lymphoma
Authors: Beltrán Brady E. , Castro Denisse A. , Huerta- Collado Yesenia M. , Sotomayor Eduardo , Castillo Jorge J. 
Published: October 2019

Abstract
Introduction: Red blood cell distribution width (RDW) has emerged as a potential prognostic factor in solid tumors and lymphomas. Previous studies have shown an association between increased levels of RDW and inflammatory diseases, being a surrogate marker of inflammation and a predictor of poor outcome. Data on the impact of RDW in outcomes of patients with aggressive peripheral T-cell lymphoma (PTCL) are scarce.
Methods: We performed a retrospective study on consecutive patients with a de novo diagnosis of aggressive PTCL diagnosed and treated at our institution between 2010 to 2016. All patients included were treated with chemotherapy with a curative intent. The RDW was collected from the hemogram of PTCL patients at diagnosis. RDW-CV >14% and RDW-SD >49 fL were our cut-offs for the categorical analysis. We fitted univariate and multivariate Cox proportional hazard regression models for overall survival (OS). P<0.05 were considered statistically significant.
Results: A total of 101 patients with de novo aggressive PTCL were included. This study included 53 patients (52%) with PTCL, not otherwise specified, 16 patients (16%) with extranodal natural killer/T-cell lymphoma,15 (15%) with adult T-cell lymphoma/leukemia,14 patients (14%) with anaplastic large cell lymphoma, 2 patients (2%) with angioimmunoblastic T-cell lymphoma, and 1 patient (1%) with enteropathy-associated T-cell lymphoma. Median age was 57 with a male predominance (69%). Clinically, 45 patients (45%) were 60 years or older, 41 patients (34%) had ECOG ≥2, 63 patients (65%) had increased LDH levels, 68 patients (67%) had > 1 extranodal site, 65 patients (64%) had stage III/IV disease, and 55 patients (54%) had B symptoms. RDW-CV was >14% in 64 patients (64%). RDW-SD was >49 fL in 35 patients (35%). 38% of patients received CHOEP, 29% received CHOP, and 33% received other regimens. The overall response rate was 68%; 50% had a complete response and 18% had a partial response. At 5 years, median overall survival (OS) was 46%. In the univariate Cox regression analysis, ECOG ≥2 (p<0.001), high RDW-CV >14% (p<0.001), high RDW-SD >49 fL (p=0.007) and high neutrophil-lymphocyte ratio (NLR >4) (p=0.002) were associated with a worse survival. In the multivariate Cox regression analyses, ECOG ≥2 (HR 3.1 CI 1.6-6.0; p=0.001) and high RDW-CV >14% (HR 2.7, 95% CI 1.2-6.0; p=0.01) were independent predictors of poor survival. RDW-CV was an independent factor of survival when was compared with IPI and NCCN-IPI score.
Conclusions: RDW is an independent marker for adverse prognosis in aggressive patients with aggressive PTCL treated with curative intent.
Figure. Figure.

Disclosures
Castillo: Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Millennium: Research Funding.
Morning Vs Bedtime Aspirin Intake in Patients with Essential Thrombocythemia
Authors: Cacciola Emma , Gentini Cacciola Elio , Vecchio Veronica , Cacciola Rossella Rosari 
Published: October 2019

Abstract
The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombotic risk. The treatment with aspirin (ASA) is recommended in ET patients at risk of first-time or recurrent thrombotic events. An unexplored topic is the optimal timing of once daily ASA intake. On the basis of the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of ASA is not sustained during the usual 24-hour (h) dosing interval and that 3) a higher gastric mucosal resistance in the evening, we evaluated platelet count, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot formation/firmness. We studied 60 patients (20 men, 40 women; mean age 51 years, range 32-70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of these, 30 took ASA on awakening and 30 took ASA at bedtime. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. CT, CFT and MCF were measured by ROTEM delta. The mean platelet count was 455±200x109/L. The awakening ASA patients had normal β-TG and PF4 (12±5 IU/ml and 4±1 IU/ml), normal CT (CT, unit: s. n.v. 100-240 s) ( 110±20 s), normal CFT (CFT, unit: s, n.v. 30-110 s) (45±5 s) and normal MCF (MCF, unit: mm, n.v. 50-72 mm) (61±2 mm), whereas the bedtime ASA patients had high β-TG and PF4 (200±15 IU/ml vs 20±11 IU/ml and 170±50 IU/ml vs 6±2 IU/ml, respectively) (p<.0001 and p<.0001, respectively), shortened CT (CT, unit: s. n.v. 100-240 s) ( 80±10 s), CFT (CFT, unit: s, n.v. 30-110 s) (15±5 s) and MCF (MCF, unit: mm, n.v. 50-72 mm) (40±2 mm). These findings suggest that in ET patients the optimal timing of once daily ASA intake is in the morning.

Disclosures
No relevant conflicts of interest to declare.
CD25 (IL2RA) Is a Direct Transcriptional Target of PRDM1 in Activated Human Natural Killer Cells
Authors: Akman Burcu , Kursun Deniz , Hatipoglu Tevfik , Hu Xiaozhou , Chan Wing C , Kucuk Can 
Published: October 2019

Abstract
Background: PRDM1 is a transcription factor that regulates differentiation and/or homeostasis of B and T lymphocytes. It may also play a role in natural killer (NK) cell homeostasis, and it is frequently inactivated in NK cell-derived lymphomas. Many target genes of PRDM1 have been reported; however, there is little insight into genes directly targeted by PRDM1 in NK cells. IL2 receptor signaling is crucial for many features of NK cell activation including sustained proliferation and survival. Here we evaluated whether CD25 (IL2Rα), a critical gene involved in NK cell activation, is transcriptionally repressed by PRDM1 in activated human NK cells.
Methods: ChIP-Seq was applied on normal primary NK cells activated using a special co-culture system that involved genetically engineered NK cell target cells (i.e. K562-Cl9-mb21) to determine genomic locations occupied with PRDM1. PRDM1 binding site screen in CD25 was computationally performed using two different ChIP-Seq peak callers. Two malignant NK cell lines (NK92 and KHYG1) were transduced with a retroviral construct that co-expresses PRDM1α and GFP. CD25 transcription expression was evaluated with DNA microarray, RNA-Seq and RT-qPCR on GFP-sorted NK cells 48h post-transduction. CD25 expression was stably knocked-down with two different shRNAs in NK92 and KHYG1 cell lines. CD25 was ectopically expressed in primary human NK cells activated through coculturing with K562-Cl9-mb21. GFP competition assays were performed on CD25 shRNA-transduced NK cell lines or primary NK cells with ectopic CD25 expression in limiting IL2 concentrations, respectively.
Results: PRDM1 occupancy on the 1st intron of CD25 was detected with CisGenome and MACS softwares in activated primary NK cells. Direct binding of PRDM1 on CD25 was further validated by ChIP-qPCR in normal activated NK cells. Two PRDM1α-transduced PRDM1-nonexpressing NK cell lines showed significant transcriptional repression of CD25 by DNA microarray and RNA-Seq, the repression of which was cross-validated with RT-qPCR. Stable knock-down of CD25 inhibited growth of two NK cell lines cultured in limiting IL2 concentrations. By contrast, ectopic expression of CD25 resulted in positive selection of ex vivo cultured primary NK cells.
Conclusions: Altogether these results establish CD25 as a direct transcriptional target of PRDM1 in human NK cells. These observations provide additional support for the role of PRDM1 in termination of NK cell activation and growth, with implications on neoplastic transformation or NK cell function when it is deregulated.

Disclosures
No relevant conflicts of interest to declare.
Gene Mutation Profile and Risk Stratification in AML1-ETO-Positive Acute Myeloid Leukemia Based on Next-Generation Sequencing
Authors: Yu Guopan , Yin Changxin , Wu Fuqun , Jiang Ling , Zheng Zhongxin , Xu Dan , Zhou Jiaheng , Jiang Xuejie , Liu Qifa , Meng Fanyi 
Published: October 2019

Abstract
Gene mutations play a critical role in leukemogenesis of AML1-ETO-positive acute myeloid leukemia (AE-AML). Nevertheless, gene mutation profile in this subtype leukemia remains unclear, and their clinical effect might be underestimated. In this study, we detested gene mutations at diagnosis and relapse with next-generation sequencing in 64 newly diagnosed AE-AML patients, and verified the results with Sanger sequencing at the same time. Our results showed that 68.8% patients presented recurrent mutations at diagnosis and 6/11 cases underwent genetic alterations at relapse. C-KIT mutation was the most common event at diagnosis, with an incidence of 42.2%, followed by ASXL1 (15.6%), MET (12.5%), MLH1 (9.4%) , TET2 (7.8%), and FBXW7, TP53 and DNMT3A (7.8%), etc. Also, C-KIT mutation was the most common molecular event associated with relapse (7/11, 63.6%). No significant difference in the clinical characteristic between the gene mutation and wild type (WT) groups was observed, except of higher incidence of additional cytogenetic abnormalities (ACAs) (P=0.025) in TP53 mutation patients. C-KIT (exon 8, 17) mutation but not exon 10 adversely affected on survival. Also ASXL1 and TP53 mutation were poor for the RFS (P<0.05), and ASXL1, MET, FBXW7 and TP53 mutation negatively impacted on the OS (P<0.05). Multivariate analysis showed C-KIT (exon 8, 17) and ASXL1 mutations were the independent adverse factors for survival. Further, co-mutation of these two genes showed even worse effect on survival. Taking together, additional gene mutations are critical in the development and progression of AE-AML. C-KIT and ASXL1 mutations are the two most common molecular events in this subtype leukemia. Single mutation of C-KIT (exon 8, 17) or ASXL1 poorly affects on survival, even worse in the co-mutation.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Newly Identified Metabolites Connect Colon Cancer to Thrombosis
Authors: Belghasem Mostafa , Roth Daniel Michael , Walker Joshua Aaron , Richards Sean , Spencer Cheryl , Tashijan Joseph Yeghishe , Arinze Nkriuka , Andry Chris , Ravid Katya , Chitalia Vipul 
Published: October 2019

Abstract
Patients with cancer are at 4-to-7-fold higher risk of venous thromboembolism (VTE). The risk of cancer-associated VTE varies with the type of cancer, underscoring the presence of cancer type-specific drivers and a need for appropriate animal models, both of which have been understudied. Here, we generated a colon cancer-specific mouse model and probed for the development of VTE and factors that might induce it. To this end, a group of athymic animals injected with human colon adenocarcinoma cell line (HT-29) underwent inferior vena cava (IVC) ligation, a validated model of venous thrombosis. Compared to corresponding controls (age- and gender-matched), mice on regular chow diet with xenografts exhibited significantly higher IVC clot weights. Plasma analysis of metabolites led us to identify the tryptophan metabolites, Kynurenine and Indoxyl Sulfate, which are known activator of the Aryl Hydrocarbon Receptor (AHR), as significantly elevated in the cancer model (2-3 fold; p<0.05). Plasma from these animals activated the AHR pathway and augmented both tissue factor (TF) and Plasminogen Activator Inhibitor 1 (PAI-1) levels in venous endothelial cells. PAI-1 is a known target of AHR pathway in other cells. Using an AHR inhibitor, we showed that the above effects of the plasma depended on AHR activation. Consistent with these findings, immunostaining of the endothelial layer of IVC in animals with xenografts revealed predominantly nuclear AHR (sign of activation) and clear increases in TF and PAI-1 expression- telltale signs of an activated AHR-TF/PAI-1 axis. As TF augments thrombogenesis and PAI-1 inhibits thrombolysis, these results may explain the enhanced thrombogenicity in this model. While this model represents a novel tool to mechanistically probe mediators of cancer-associated VTE, it links for the first-time cancer-associated VTE to a set of metabolites. Our data raise a possibility of AHR-TF/PAI-1 axis as a mediator of VTE in other tumors, worthy of exploration given its potential as a biomarker and a therapeutic target.

Disclosures
No relevant conflicts of interest to declare.
Rafoxanide, an Organohalogen Drug, Triggers Apoptosis and Cell Cycle Arrest in Multiple Myeloma By Enhancing DNA Damage Responses and Suppressing the p38 MAPK Pathway
Authors: Shi Jumei , Xiao Wenqin , Xu Zhijian , Chang Shuaikang , Gao Lu , Tao Yi , Wang Yingcong , Wu Xiaosong , Zhu Weiliang 
Published: October 2019

Abstract
Rafoxanide is used in veterinary medicine for the treatment of fascioliasis. We previously repositioned the drug as the inhibitor of B-Raf V600E, but its anti-tumor effect in human cancer has never been reported. In this study, we investigated the effects of rafoxanide in multiple myeloma (MM) in vitro and in vivo. We found that rafoxanide inhibited cell proliferation and overcame the protective effect of the bone marrow (BM) microenvironment on MM cells. Rafoxanide induced cell apoptosis by reducing mitochondrial membrane potential (MMP) and regulating the caspase pathway, while having no apparent toxic effect on normal cells. Rafoxanide also inhibited DNA synthesis and caused cell cycle arrest by regulating the cdc25A-degradation pathway. In addition, rafoxanide enhanced the DNA damage response by up-regulating the expression of γ-H2AX. Importantly, as a potent B-Raf V600E inhibitor, rafoxanide could suppress activation of the p38 MAPK pathway. Rafoxanide treatment inhibited tumor growth, with no significant side effects, in an MM mouse xenograft model. Finally, combination of rafoxanide with bortezomib or lenalidomide significantly induced synergistic cytotoxicity in MM cells. Collectively, our results may provide a rationale for use of this drug in MM treatment. This study was supported by grants from the National Natural Science Foundation of China (Nos. 81570190; 81670194 and 81529001).
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.