bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association Between SERPINC1 C.883G>a and VT in the Chinese Population
Authors: Liu Jingdi , Tang Liang , Zeng Wei , Hu Yu , Liu Han 
Published: October 2019

Abstract
Background: Antithrombin(AT) is a major anticoagulation molecule in vivo and is encoded by the gene SERPINC1. AT plays a key role as an inhibitor of physiological haemostasis by inhibiting the procoagulation factors, especially the factor Xa and thrombin.
Objectives: To explore the variations of SERPINC1 gene associated with venous thrombosis in the Chinese population.
Methods: SERPINC1 gene sequencing was carried out. A case-control study involving 1335 patients diagnosed with VT and 1315 Age- and sex-matched control individuals without a history of thrombosis were further carried out. Furthermore, plasma AT activity, AT antigen, and thrombin generation tests (TGT) were performed to evaluate the influences of the mutations.
Results: Four different missense mutations were identified in an unreported hot spot region of SERPINC1. They were c.880C>T(p.Arg294Cys), c.881G>T(p.Arg294Leu), c.881G>A(p.Arg294His) and c.883G>A(p.Val295Met). All of the affected individuals were heterozygotes. In addition, c.883G>A was found to be a predominant mutation. In the case-control study, the mutation was proved to be a strong risk factor for venous thrombosis with an OR of 10.92(p<0.01, 95%CI 1.41-84.68). Functional assays showed that both the activities and antigens of plasma AT decreased mildly.
Conclusion: A hot spot mutation region of SERPINC1 gene was discovered. The predominant mutation of SERPINC1 c.883G>A is the most frequent cause of AT deficiency and is associated with an increased risk of venous thrombosis in the Chinese population.

Disclosures
No relevant conflicts of interest to declare.
Incidence of Catheter-Related Venous Thromboembolism Events in Acute Leukemia patients; A Comparative, Retrospective Study of the Safety of Peripherally-Inserted Vs Centrally-Inserted Central Venous Catheters
Authors: Refaei Mohammad , Fernandes Bruna , Brandwein Joseph , Goodyear M. Dawn , Wu Cynthia M 
Published: October 2019

Abstract
1. Background
Central venous catheters (CVCs) are a leading cause of upper extremity deep vein thrombosis (UE DVT). There is little data on patients with acute leukemia (AL). Long term CVCs are required for chemotherapy in AL. Concomitant severe thrombocytopenia makes anticoagulation for CVC related thrombosis a challenge. Incidence of UE DVT has been reported to be increased in those with peripherally inserted central venous catheters (PICC lines) vs those with centrally inserted lines.
2. Aims
Our objective is to compare the incidence rate of VTE in leukemia inpatients with a PICC vs centrally-inserted CVC.
3. Methods
We reviewed 420 charts for AL inpatients requiring a PICC line admitted to Hematology at the University of Alberta Hospital between 2003-2013. Baseline patient characteristics were recorded. All venous thromboembolic events were objectively confirmed on imaging studies. Incidence of catheter associated thrombosis was calculated.
4. Results
420 patients were identified. We present the preliminary results of the 337 patients that met our inclusion criteria, and received at least one PICC line insertion. 305 (90%) had AML, 144 (43%) were smokers, 126 (37.4%) had cardiovascular risk factor, and only 14 (4.2%) had previous VTE. Overall, there were 634 PICC line insertions, with the 5FR dual lumen being the most commonly used PICC line (80%). Out of the 634 insertions, there were 65 (10%) new ipsilateral upper extremity DVTs, 54 (83%) of which developed acutely (<1month), and 44 (68%) in thrombocytopenic patients (platelet<50). 7 (1.1%) and 15 (2.4%) patients developed recurrent and concurrent VTEs, respectively. There was an incidence of 1.85 DVT per 1000 catheter days.
5. Conclusions
The incidence rate of DVT in our AL patients is higher than predicted for a general cancer patient population. This data will be compared to a similar cohort of AL inpatients presently being reviewed, who received a centrally-inserted CVC. Updated results will be included accordingly. Determining factors that are associated with a lower risk of DVT in this high bleeding risk population will be important to optimize patient care.

Disclosures
Wu: Leopharma: Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Membership on an entity's Board of Directors or advisory committees.
Outcome of BONE Marrow Transplantation in Congenital Diskeratosis: Preliminary DATA from the European Group for BONE Marrow Transplantation (EBMT)
Authors: Fioredda Francesca , Korthof Elisabeth T , Iacobelli Simona , Knol Cora , Veelken Joan H , Veys Paul , Yoshimi Ayami , Mellegren Karin , Fagioli Franca , Zecca Marco , Maschan Alexey , O'Brien Tracey , Diaz Miguel Angel , Smith Owen , Socie Gerard , Josue de la Fuente , Or Reuven , Dufour Carlo 
Published: October 2019

Abstract

Hematopoietic Stem cell Transplantation (HSCT) is the definitive treatment for bone marrow failure in diskeratosis congenita (DC). Organ dysfunction (mainly lung and gastrointestinal tract) are often part of the disease and may be a limiting factor for or may affect the final outcome of HSCT. Scarce data or relatively small cohort studies are available in current literature on outcome of HSCT in this disease. We analyzed the outcome of 87 patients diagnosed with DC reported in the data base of the European Society for Blood an Bone Marrow Transplantation (EBMT) who underwent HSCT from 1979 to 2014. In particular we analyzed data on type of HSCT, characteristic of donors, source of cells, incidence of acute and chronic GvHD. Males were 76%. Median age at diagnosis of DC was 5.7 years (0-33 yrs), median age at HSCT was 11.2 years (range 0.56-41 yrs). Median time from diagnosis to HSCT was 19 months (0.62-304 mo). The cell source was bone marrow (BM) in 67%, peripheral blood (PB) in 22% and cord blood (CB) 11%. Twenty six percent of patients were engrafted from a matched related and 53% from a matched unrelated donor. Twenty one percent of subjects were engrafted from a mismatched (both related and unrelated) HSCT. Engraftment was documented in 95% of subjects: 4 % had primary graft failure and 10% lost the graft. Overall 35 patients (40%) died, and 52 were alive (60%) at last follow-up. Causes of death were: infections (43%), multi-organ failure (26%), rejection/oss of graft (14%), GvDH (8.5%) undefined (8.5%). In 32% of cases death was related to transplant. Lung injury was present in 17% of subjects who died. Acute GVDH (mainly grade 2-4) and chronic GvHD occurred in 39% and 30% of cases. Five year OS was 60 %. OS was not significantly different by calendar period (before and after year 2000: 50% vs 67% respectively, p=0.424), by age at transplant (below and above age of 12 years: 64% vs 55% respectively ; p= 0.564) and by source of cells (marrow 60%, cord blood 68%, and peripheral cells 46%; p= 0.687). Conversely, OS in HSCT from mismatched donor was inferior to that of transplants from matched donor (38% vs 65% respectively; p= 0.045). The use of radiotherapy or busulfan (any dose) in the conditioning vs other regimens did not impact on 5 y-OS ( 58% vs 62% respectively; p=0.898). HSCT from HLA matched donor can be considered a treatment option in DC. Transplant related mortality looks rater high. Multi organ failure and lung injury are amongst the main causes of death thus pointing to pre-transplant organ status as important determinant of HSCT outcome.

Disclosures
Dufour: Pfizer: Consultancy.
Identification of Novel Drug Targets in T-Cell Acute Lymphoblastic Leukemia
Authors: Laukkanen Saara , Liuksiala Thomas , Nykter Matti , Heinäniemi Merja , Lohi Olli 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the leading causes of death in children with tumors. Genetic changes in T-cell acute lymphoblastic leukemia (T-ALL) are relatively well known, but the underlying molecular processes driving the disease remain insufficiently understood. Better knowledge of molecular events in T-ALL would improve our understanding of the development and maintenance of the disease and could also lead to the development of targeted and more effective treatments.
We have compiled a large gene expression data-set from microarray studies of various hematological and lymphoid malignancies and healthy tissues that use a uniform technical platform (Affymetrix HG U133 Plus 2.0) (see abstract by Liuksiala et al). Data-set includes 1302 healthy samples and 4418 leukemia samples: 1713 acute myeloid leukemias, 1648 precursor B-ALLs, 801 chronic lymphocytic leukemias, 385 T-ALLs, and 215 chronic myeloid leukemias. From this data-set, we identified a number of transcription factors (TFs) that were differentially expressed in T-ALL, including high expression of NOTCH1 and BCL11B as previously reported (Weng et al Science 2004; Gutierrez et al Blood 2011). Several novel candidate TFs with specific expression in T-ALLs were also discovered, including strong expression of two poorly characterized TFs, SIX6 and PCBP3. These findings were validated using real-time quantitative PCR (RT-qPCR) in a cell line panel consisting of T-ALL and pre-B-ALL cell lines as well as healthy controls.
We next sought to identify novel drug targets in T-ALL by comparing our leukemia expression data-set with the therapeutic target database (TTD). TTD is a database providing information about the known and explored therapeutic protein and nucleic acid targets, and the corresponding drugs aimed at these targets. We identified high expression of a nicotinic acetylcholine receptor (nAChR) subunit CHRNA3 (cholinergic receptor, nicotinic, alpha 3), which is a target of nAChR inhibitor bupropion. RT-qPCR confirmed the high expression of CHRNA3 in T-ALL cell lines but not in pre-B-ALL cells or healthy controls. The effect of bupropion was tested in Jurkat cells which represent T-ALL cell line with high expression of CHRNA3. Increasing concentrations of bupropion (1-100µM) resulted in dose-dependent decrease in proliferation of Jurkat cells as measured by cell viability assay AlamarBlue. As a control, cell lines with low level of CHRNA3 expression (CCRF-CEM and REH) were treated as well but these cells did not show any changes in the rate of proliferation.
In summary, we have identified several candidate transcription factors which could have a leukemic role in T-ALL. Furthermore, we identified high expression of CHRNA3 in T-ALL, suggesting a role for the cholinergic system in T-cell leukemia, and thus a novel avenue in search of putative therapeutic options.

Disclosures
No relevant conflicts of interest to declare.
Varying Responses of PML-Rara with Different Genetic Mutations to Arsenic Trioxide
Authors: Liu Jiangying , Zhu Hong-Hu , Jiang Hao , Jiang Qian , Huang Xiao Jun 
Published: October 2019

Abstract
Resistance to arsenic and/or ATRA is a challenging problem in the clinical management of acute promyelocytic leukemia (APL). Acquired genetic mutations in the PML moiety of the PML-RARA fusion gene have been found to exist virtually in APL patients at relapse. While C212/C213 mutations in the PML B2 domain of PML-RARA were shown to be capable of abolishing the effect of arsenic on target proteins in vitro, A216V and L218P mutations in the PML portion of PML-RARA were detectable in two APL patients resistant to arsenic therapy. More recently, we identified a panel of point mutations (including previously reported A216V and, newly identified S214L, A216T, L217F and S220G) from nine of 13 APL patients with arsenic resistance. These findings indicated the existence of a mutational hotspot (S214-S220) within the PML-RARA oncoprotein among APL patients at relapse. Whether each of the identified point mutations plays a role and functions distinctly in the mechanism underlying the resistance to arsenic therapy is of particular interest.
Here, we performed in vitro functional analyses in both the hematopoietic irrelevant and relevant cells, and a retrospective analysis of APL patients to investigate the effect of PML-RARA mutations on mediating the resistance to arsenic trioxide. Among the five point mutations in the PML part of PML-RARA identified in patients with relapsed APL, we found that A216V, S214L and A216T mutations could attenuate the negative regulation of arsenic on PML-RARA, which resulted in the retention of oncoproteins. In contrast, L217F and S220G mutations function weakly in this context. Furthermore, we demonstrated that high concentration of As2O3could overcome the primary arsenic resistance driven by the indicated point mutations in PML-RARA. In addition to providing more evidence to reinforce the correlation of genetic mutations in PML-RARA with arsenic efficacy, we provide a novel insight into the functional difference of acquired mutations of PML-RARA both in vitro and in the clinical setting. Our findings may help predict the prognosis and select more effective strategies during APL therapy.

Disclosures
No relevant conflicts of interest to declare.
The Impact of Breastfeeding on the Childhood Acute Leukemia Risk Among Children Attending Alexandria University Children's Hospital
Authors: Massoud Mohamed NZ , Hassab Hoda MA , Ali Aida M M , Mohamed Doha N 
Published: October 2019

Abstract
Objective: The present study was conducted to investigate the impact of breastfeeding on the risk of development of acute leukemia among children Admitted to Alexandria University Children's Hospital.
METHODS: A case control study included 134 ALL&AML cases & 134 matched controls for age & sex from the same family relatives to evaluate socioeconomic & genetic causes of the disease. The mothers were interviewed for the completion of interview format that included: duration & patterns of breastfeeding.
RESULTS: lower proportion of acute leukemia cases 59.7% were exclusively breast-fed babies as compared to 89.6% of the control subjects. However, higher proportions of index children were either predominant breast-fed 19.4% or complementary-fed 10.4%. Nearly 10.4% were bottle-fed babies as compared to none of their controls. The differences between cases & controls as regards pattern of breast feeding were statistically significant where p<0.001. As regards duration of breastfeeding 75.4% of index children were breast-fed for more than 6 months as compared to vast majority of their controls (97.8%). The difference between cases & controls was statistically significant where p <0.001. The association also was statistically significant when 2 groups (standard & high risk) were considered as regards pattern of breastfeeding where x2=13.055, p =0.004. The multivariate logistic regression analysis indicated that bottle feeding had the odds of 7.76 of being at high risk level for acute leukemia (OR=7.76, 95% CI 1.9-33.8).
CONCLUSION: Exclusive breast-feeding and breast-feeding for one year are protective against acute childhood leukemia.
Table 1. Bivariate and multivariate analysis for pattern & duration of breastfeeding of the studied children with acute leukemia and their controls. Pattern and duration of breastfeeding Bi variant variable Multivariate variable Type of feeding during the first 6 month of life. Cases (n=134) Control (n=134) Significance OR (95% CI) Significance No. % No. % X2 = 37.6 P>0.0001* 1 Exclusive BF 80 59.7 120 89.6 Predominant BF 26 19.4 13 9.7 1.67 (1.26 - 2.2)* X2 = 9.4 P=0.002* Complementary feeding 14 10.4 1 0.7 21 (2.8 - 436.4)* X2 = 16.13 P>0.0001* Bottle feeding 14 10.4 0 0 2.5 (2.1 - 2.9)* X2 = 19.12 P>0.0001* Duration of breastfeeding 0-≤ 3 month 2 1.7 0 0 X2 =15.331 MC P=0.0001* AN- FEP=0.18 =13.06 P=0.0003* X2=0.38 P=0.537 3-≤ 6 month 17 14.2 3 2.2 7.6 (2.1 - 33.8)* 6-12 month 16 13.3 17 12.7 1.26 0.6-2.8 More than 12 month 85 70.8 114 85.1 1 - X2: Chi-Square test FEP: Fisher's Exact test -NA-: Not Applicable *significant at P≤0.0

Disclosures
No relevant conflicts of interest to declare.
Monoamine Oxidase a (MAO A) Is Expressed Selectively in Reed-Sternberg Cells of Classical Hodgkin Lymphoma
Authors: Li Pei-Chuan , Siddiqi Imran N , Loo Eric Y. , Kong Yinfei , Cozen Wendy , Wu Chieh-Hsi , Shih Jean Chen 
Published: October 2019

Abstract
Monoamine oxidase A (MAO A) is a mitochondrial enzyme, which catalyzes oxidative deamination of neurotransmitters or dietary amines and produces H2O2. Recent work indicates that MAO A is overexpressed in prostate cancer. Inhibiting its activity suppresses tumorigenesis and metastasis. In this study, we showed that Hodgkin lymphoma (HL)-derived L1236 cells express high MAO A activity, while other human lymphoma cell lines examined, including both Hodgkin and non-Hodgkin lymphoma, do not express MAO A. We also analyzed MAO A expression by immunohistochemistry in formalin-fixed paraffin-embedded classical Hodgkin (n=88), nodular lymphocyte predominant Hodgkin (n=8) and non-Hodgkin lymphoma (diffuse large B-cell lymphoma, n=54; follicular, n=33; Burkitt lymphoma, n= 19; mantle cell lymphoma, n= 13). We found that 60% of the classical Hodgkin lymphoma (cHL) cases demonstrated at least some MAO A expression by the neoplastic Reed-Sternberg cells and 30% of the tumors show strong/uniform expression. In contrast, no MAO A activity was seen in normal lymphoid tissue, nodular lymphocyte predominant Hodgkin lymphoma or non-Hodgkin lymphomas. The MAO inhibitor clorgyline inhibited MAO A activity (IC50 of 8.3×10-9 M) and was cytotoxic (IC50 of 30 μM) to L1236 cells. In addition, clorgyline reduced the cell proliferation, colony formation, and invasion of L1236 cells in vitro. Taken together, we have shown for the first time that MAO A is expressed selectively in Reed-Sternberg cells of cHL. Our results suggest that MAO A may be a biomarker for classical Hodgkin lymphoma Reed-Sternberg cells and may provide biological insights as well as a potential therapeutic target.

Disclosures
No relevant conflicts of interest to declare.
Smoothened (SMO) Is an Adaptor Protein That Recruits TRAF6 and Phospholipase C Gamma 2 (PLCg2) to Enhance the Activation of NF-Kb Signaling Pathway
Authors: Agarwal Nitin , Kim Chae Hwa , Kunkalla Kranthi , Yang Gloria , Tjendra Youley , Liu Yadong , Qu Changju , Vega Francisco 
Published: October 2019

Abstract
Background: Constitutive activation of NF-κB signaling is a hallmark of DLBCL. Activation of NF-κB is a multifactorial process resulting from oncogenic mutations (CARD11, MYD88…), chromosomal abnormalities, chronic activation of B-cell receptor signaling (BCR) as well as stimuli from the microenvironment. Chronic activation of BCR is not only the result of gene mutations (e.g.CD79B) but also is the result of stimuli generated from the lymphoma microenvironment.
We previously found that smoothened (SMO), transducer of hedgehog (Hh) signaling, enhanced NF-κB activation in lymphoma cells, independently of the presence of oncogenic mutations (Changju et al., Blood 2013). Hh ligands are provided by the lymphoma microenvironment (e.g. stromal cells) to activate SMO in the lymphoma cells. Activated SMO, recruits and activates trimeric-G-coupled proteins to activate PKCβ/CARMA1/TRAF6/NEMO axis, followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO resulting in NF-κB activation. Now, we reveal an additional mechanism by which SMO further contributes to the activation of NF-κB in DLBCL.
Summary of results: We explored if recombinant Hh ligand can activate NF-κB signaling in the presence of the BTK inhibitor (PCI-32765). Hh stimulation resulted in phosphorylation of PLCg2 (downstream of BTK) and partially rescued the inhibitory effect of the BTK inhibitor on phosphorylation of PLCg2 suggesting a crosstalk between SMO and BCR receptor signaling. We identified that SMO forms a complex with TRAF-6 and PLCg2 using immunoprecipitation and Duolink in situ proximity ligation assays. We found that SMO stabilizes and protects TRAF-6 from proteosomal degradation. SMO-dependent TRAF6 stabilization is mediated by the ubiquitin-specific protease-8 (USP-8) by removing ubiquitin from K48-linked lysine of TRAF6.
Conclusions: Collectively, our data reveals multilayer crosstalk between Hh and BCR/NF-κB pathways and provide significant insights into how SMO contributes to chemotolerance and progression of DLBCL. We expect that our results will delineate novel molecular mechanisms involved in the pathobiology of DLBCL that may serve as therapeutic targets.

Disclosures
Vega: Seatle Genetics: Honoraria; NIH: Research Funding.
Increasing Use of Social Media at Annual ASH Meetings
Authors: Dahiya Saurabh , Kansagra Ankit J. , Ali Syed S. 
Published: October 2019

Abstract
Background: The use of social media is expanding in medicine. More and more healthcare professionals, patients and advocates are using social media as a common platform to enhance communication.
Methods: Each year American Society of Hematology (ASH) creates a hashtag (#) followed by year of the annual meeting (e.g. ASH 2014 had this hashtag: #ASH14) on Twitter. We conducted a retrospective study of annual meeting's hashtag use on Twitter for past 4 annual meetings using data from Symplur, LLC. Symplur is an online forum offering analytics of the global Twitter based conversations. Following hashtags were used for analysis, #ASH11, #ASH12, #ASH13 and #ASH14.
Results: Overall there is an increasing trend for use of annual meeting's hashtag (see table 1). Last year's meeting generated over 72 million impressions. Number of tweets being sent out is doubling every year. More twitter users are engaging in conversations than the year before using annual meeting's hashtag. Last year almost 4000 individual twitter accounts were used during the annual meeting. Number of tweets per participant has stayed relatively constant over past four years. @ash_hematology remains the most commonly mentioned twitter handle every year since 2011. In 2014 itself, @ash_hematology was mentioned over 2000 times.
Conclusion: Twitter is a very powerful tool that amplifies the content of scientific meetings. Use of twitter using meeting's hashtag is increasing every year at annual ASH meetings. This analysis provides a snapshot of twitter activity at the conference. Avenues for further research are: trend identification, "influencer" identification, and qualitative analysis. Interdisciplinary research should focus on evaluation methods that can assess the quality, value, and impact of tweeting.
Table 1. Year Impressions Tweets Participants Average tweet per participant 2011 12,255,646 3123 606 5 2012 18,153,786 5,094 870 6 2013 30,018,580 12,233 1942 6 2014 72,433,270 24,185 3977 6

Disclosures
No relevant conflicts of interest to declare.