bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Study about the Relationship between Thrombotic Events and Peripheral Neutrophil-to-Lymphocyte Ratio in Patients with Newly Diagnosed Essential Thrombocythemia
Authors: Cheng Hai , Zhou Dian , Cao Jiang , Chen Wei , Qi Kunming , Xu Kailin , Qiao Jianlin 
Published: October 2019

Abstract
To explore the role of neutrophil-to-lymphocyte ratio (NLR) in patients with newly diagnosed essential thrombocythemia (ET) and the relationship with thrombotic events.150 ET patients with ET from January 2013 to December 2017 were retrospectively enrolled in this study to investigate the risk factors of thrombosis and analyse the role of NLR in thrombotic events. The following parameters were evaluated: age, sex, blood routine examination, JAK2V617F mutation, cardiovascular risk factors, history of previous thrombosis, thrombosis during follow-up, examination and biopsy of bone marrow.Age(P=0.001) and JAK2 V617F mutation(P=0.003) were independent risk factors for thrombotic events at diagnosis after Logistic multivariate analysis. WBC count (P=0.047), NLR (P<0.001), age (P=0.037) and thrombosis at diagnosis (P=0.036) were independent risk factors for future thrombotic events and NLR was better for prediction of future thrombotic events than other risk factors in ROC curve. The thrombosis-free survival of thrombotic events in patients with higher NLR(median survival 22.3 months, 95% CI:17.8-26.8) was significantly shorter than that of patients with lower NLR(median survival 55.5 months, 95% CI:53.4-57.5) in Kaplan-Meier analysis (P<0.001). After 60 months of follow-up, patients with lower NLR had a thrombosis-free survival of 97.4%, while patients with higher NLR had a thrombosis-free survival of 46.7%. NLR at diagnosis was a better predictive parameter for future thrombotic events than other clinical parameters in ET patients, but was not associated with thrombosis at diagnosis.

Disclosures
No relevant conflicts of interest to declare.
MXD1 Regulates the Imatinib Resistance of Chronic Myeloid Leukemiacells By Repressing BCR-ABL1 Expression
Authors: Chen Huan , Lou Jin , Wang Heng , An Na , Pan Yuming , Chen Weihong , Du Xin , Zhang Qiaoxia 
Published: October 2019

Abstract
Tyrosine kinase inhibitors have achieved unprecedented efficacy in the treatment of chronic myeloid leukemia (CML), however, imatinib resistance has emerged as a major problem in the clinic. Because the overexpression of BCR-ABL1 critically contributes to CML pathogenesis and drug resistance, targeting the regulation of BCR-ABL1 gene expression may be a novel therapeutic strategy. In this study, we found that the transcriptional repressor MXD1 showed low expression in CML patients and was negatively correlated with BCR-ABL1. Overexpression of MXD1 markedly inhibited the proliferation of K562 cells and sensitized the imatinib-resistant K562/G01 cell line to imatinib, with decreased BCR-ABL1 mRNA and protein. Further investigations using reporter gene analysis showed that MXD1 significantly inhibited the transcriptional activity of the BCR-ABL1 gene promoter. Taken together, these data show that MXD1 functions as a negative regulator of BCR-ABL1 expression and subsequently inhibits proliferation and sensitizes CML cells to imatinib treatment.

Disclosures
No relevant conflicts of interest to declare.
Factor VIII BAR T-Cell Recognition By Antibodies to Different Domains
Authors: Parvathaneni Kalpana , Pohida Katherine , Scott David W. 
Published: October 2019

Abstract
Up to 30% of patients with hemophilia A develop inhibitory antibodies to therapeutic FVIII and these antibodies block the efficacy of this critical protein. To target the B cells specific for FVIII, we previously generated cytotoxic cells expressing the FVIII C2 or A2 immunodominant domains as chimeric receptors. We termed these antigen-expressing engineered T cells, "BARs", for B-cell Antibody Receptor. These could directly interact and kill with A2 or C2 FVIII-specific B cells as well as FVIII-specific hybridomas in vitro and in vivo. To increase the number of B-cell targets that could be killed, we recently engineered human and murine BAR CD8 T cells to express the FVIII light chain (LC), which includes A3 and C1, as well as C2 domains. In addition, since C2-expressing BAR T cells showed tonic signaling, we hypothesized that LC expressing BARs might not. Our data suggest that LC-expressing BAR T cells do not display tonic signaling but they can be stimulated to proliferate by anti-LC monoclonal antibody (mAb 5G12), for example. Flow cytometry data showed that LC-BAR T cells are stained by anti-C2 mAb (3G6) but this mAb did not stimulate them to proliferate. These data reflect the accessibility of different FVIII domains in BAR T cells, and are important in terms of the utility of FVIII domain expressing BARs to target specific B cells in vivo in the presence of inhibitors. (Supported by NIH grant R01 HL126727)

Disclosures
No relevant conflicts of interest to declare.
Efficacy of a Health Care Transition Program for Patients with Sickle Cell Disease
Authors: Saulsberry Anjelica Christina , Podila Pradeep S. B. , Anderson Shiela , Hodges Jason R , Porter Jerlym , Hankins Jane S. 
Published: October 2019

Abstract
Introduction: Unsuccessful transition from pediatric to adult care among youth with sickle cell disease (SCD) contributes to frequent disease complications and early death. The literature is sparse on longitudinal SCD transition program outcomes. The St. Jude SCD Transition to Adult Care Program started in 2007, is a comprehensive, co-located, and interdisciplinary program embedded in a larger SCD medical home. The objective of this study is to describe transfer rates, time to transfer, and maintenance of adult care over a 9-year period.
Methods: With St. Jude IRB approval, we conducted a retrospective review of the rate of matriculation in adult care, the latency time from leaving pediatric care and initiating adult care, and maintenance of engagement in adult care 12 and 24 months later. Eligibility criteria: 1) SCD diagnosis and 2) Completion of pediatric care between 2007 and 2016.
Results: Three hundred and sixty participants transferred to adult care over the study period. Mean age at transfer was 18 years. Matriculation in adult care within 6 months from leaving pediatric care substantially increased: 71% in 2007 to 93% in 2016. We observed a progressive reduction in the latency time from pediatric to adult care, from 12 months in 2007 to 1.5 months in 2016. Fifty-five percent (n=198) of youth who transitioned to the partner Methodist Comprehensive Sickle Cell Center (MCSCC) post-pediatric care continued to be followed by our program. Of these, 77% and 57% remained with the MCSCC 12 and 24 months after transfer to adult care, respectively.
Conclusions: The St. Jude SCD Transition to Adult Care Program demonstrated a gradual increase in transfer rates and a reduction in length of time-to-adult transfer since its creation. Adult care engagement declined over time and warrants future interventions. Improved health care transition outcomes could potentially translate into improved quality of life and greater longevity.

Disclosures
Hankins: bluebird bio: Consultancy; NCQA: Consultancy; Novartis: Research Funding; Global Blood Therapeutics: Research Funding.
Real-World Data on Frontline (FL) Treatments in Multiple Myeloma (MM) Patients across EU5 Countries
Authors: Anjo Joana , Rider Alex , Bailey Abigail , Gaudig Maren 
Published: October 2019

Abstract
Objective
This analysis was conducted to understand the clinical practice on FL treatment in patients with MM across EU5 countries.
Methods
Real world data were collected through Adelphi's Disease-Specific ProgrammeTM - a point in time survey administered to physicians (n=241) in EU5 countries between Nov 2017 - Feb 2018. Stem Cell Transplant eligibility and treatments, including number of cycles and dosage, were collected from patient record forms (n=1952). Summary statistics were reported and analysed descriptively.
Results
Data on FL treatment was collected for 1952 patients; 988 (51%) were still on FL treatment at the time of data collection.
Bortezomib-based regimens were used in more than 70% of patients - in both transplanted/transplant eligible (TE, n=572) and non-transplanted/transplant ineligible patients (TIE, n= 1380).
In TIE patients, bortezomib, melphalan and dexamethasone (VMP) was the most commonly used regimen, covering almost one third of the patients (31%), followed by bortezomib, either in combination with cyclophosphamide and dexamethasone (VCD, 10%) or thalidomide and dexamethasone (VTD, 10%). The other two FL regimens currently approved in Europe - thalidomide, melphalan and dexamethasone (MPT) and lenalidomide and dexamethasone (Rd) have patient shares of 9% each. When analyzing the TIE patients undergoing FL treatment at time of data collection (n=606), VMP remained the most used regimen (29%) and Rd the second (15%), with VTD and MPT being used in 8% of patients.
In TE patients, VTD was the most commonly used induction regimen, being used in 50% of patients, followed by VCD (21%). The numbers remained the same when analyzing the TE patients in FL treatment at time of data collection (n=382), with 54% and 22% using VTD and VCD, respectively.
Conclusions
Collectively these results indicate that bortezomib-based regimens remain the standard of care in FL treatment of MM in EU5, in both transplant and non-transplant settings.

Disclosures
Anjo: Janssen: Employment. Rider:Adelphi Real World: Employment. Bailey:Adelphi Real World: Employment. Gaudig:Janssen: Employment.
Transcriptional and Functional Description of Stem Cell Heterogeneity in Native and Transplantation Hematopoiesis
Authors: Rodriguez-Fraticelli Alejo E , Weinreb Caleb , Klein Allon Moshe , Camargo Fernando 
Published: October 2019

Abstract
The hematopoietic system follows a hierarchical organization, with multipotent long-term repopulating hematopoietic stem cells (LT-HSCs) occupying the top tier. This paradigm, developed mostly through cell transplantation assays, has recently been contested by a series of studies performed under native conditions, without transplantation. Application of systems-level single cell methods in this setting has revealed a heterogeneity of cell states within progenitors and stem cells, prompting a reevaluation of the theories of hematopoietic lineage fate decisions. We have previously described that hematopoietic stem cell fates are clonally heterogeneous under steady state and uncovered that a fraction of LT-HSCs contributes to a significant proportion of the megakaryocytic cell lineage under steady state, while rarely generating other types of progeny in unperturbed conditions. To elucidate the molecular underpinnings of this functional lineage-output heterogeneity, we developed a technique to barcode hematopoietic cells at the RNA level in order to simultaneously capture the lineage relationships and transcriptional states of HSCs. Using a droplet-based massive single cell RNAseq platform, we analyzed thousands of engrafted hematopoietic stem cells together with a sufficiently significant representation of downstream progenitor cells to measure HSC output. Inspection of the resulting "stem cell state-fate maps" revealed a variety of stem cell behaviors, including single cell quiescence, asymmetric and symmetric divisions, and clonal expansion. We also connected these behaviors with some of the previously observed heterogeneity in stem cell outcomes, including lineage bias, lineage output and clonal competition. Importantly, clustering of expression profiles revealed significant differences in the transcriptional programs related with some of these behaviors, which illuminate the molecular machineries that operate at the stem cell level to define this heterogeneity. Thus, our work has identified potential novel mediators for stem cell heterogeneity, which we are functionally analyzing in further detail to understand their molecular mechanisms.

Disclosures
No relevant conflicts of interest to declare.
Tissue Molecular Genotyping Improves Patient Blood Management in Syrian Injured Patients Treated in Israel
Authors: Akria Luiza , Barhoum Masad , Zisman-Rozen Simona , Suriu Celia , Braester Andrei , Shaoul Ety 
Published: October 2019

Abstract
During the last two decades the importance of molecular biology in transfusion medicine has been growing. Reference centers for immunohematology commonly use molecular methods to clarify problems, discrepancies or unusual results in patient serology. Nowadays there are immunohematology reference laboratories that recommend using molecular genotyping for patient blood management. Our blood bank laboratory is not a reference center, but we routinely use molecular genotyping to solve serologic problems. Due to the proximity to the Syrian border, since the beginning of the Syrian civil war, our medical center has received hundreds of injured patients, some of them with unique features concerning the blood type testing. From our previous experience of such a case in Dec 2015, we realized that due to extreme war conditions and lack of medical amenities, severely injured patients are likely to receive unmatched blood transfusions in Syria, sometimes ABO-incompatible blood transfusions. The patients arriving to our medical center are usually in critical condition and without medical records. Serologic tests show double population (DP) blood type. Molecular genotype of blood samples is not helpful, because it can detect the blood type of the unmatched/incompatible donor. In these cases, we use molecular genotyping from a tissue specimen, usually skin. Until we receive the results, which take about 5 hours in our molecular lab, we give only type O blood and AB plasma. Since Dec 2015, 11 injured patients with DP on serologic typing were admitted to our medical center. Tissue genotyping was performed on 8 of these. We determined that seven of the eleven patients previously received ABO-incompatible blood in Syria. With one exception, all patients were transfused in Israel (detailed data not shown), three with incompatible blood upon admission, based on initial serotype (patients 1,3,4 in the table). Tissue genotyping allowed us to transfuse compatible ABO-matched blood components afterward. All patients survived and were released in good condition. Tissue molecular genotyping helps improve patient blood management in the population of injured causalities from Syria.
Table. Table.

Disclosures
No relevant conflicts of interest to declare.
Early Death in Multiple Myeloma. Analysis of Patients in Real-World Practice
Authors: Lakhwani Lakhwani Sunil , Hernández Miguel T , Lorenzo-Barreto Pablo , Cabrera-Brito Deborah , Fernández-González Marta , Machado-Machado Patricia , Díaz-Gómez Maribel , Raya Sanchez Jose Maria 
Published: October 2019

Abstract
Background. During the last years survival of myeloma patients has improve due mainly to the introduction of new drugs. Despite this, there are patients who die early: before two years from diagnosis. There are few data published of this group of patients with early mortality (EM) and most of them analyzing patients included in clinical trials.
Methods. We reviewed myeloma patients from our center from 1990 to 2017 and identified patients with EM. We recorded many clinical and biological variables, both at diagnosis and in evolution. We compared data of patients with EM with the rest and we analyze which variables confer worse prognosis of this group in a multivariate analysis. We also create a predictive model at diagnosis of patients with EM through a discriminant analysis.
Results. We identified 186 patients with less than two years of survival from diagnosis, 87 women and 99 men. Mean age was 70,3 years old (range 42-99). The most common cause of death was infection (42,33%) followed by progession (39,26%). We could compare data of these patients with those without EM from 1990 to 2009 (n=255) and we found that patients with EM were older (p=0,039), with more comorbidities (p=0,004) and worse ECOG (p<0,001). They had a disease more agressive and more evolved with worse bone disease (p=0,019), lower hemoglobine (p<0,001) and albumin (p<0,001); higher calcium (p=0,007), creatinine (p<0,001), LDH (p<0,001), β2microglobuline (p<0,001), immunoparesis (p=0,007) and percentage of plasma cells in bone marrow (p<0,001) and consequently worse Durie-Salmon (p<0,001) and ISS (p<0,001) prognosis score. We also found a worse response to first line treatment (p<0,001).
In a multivariate analysis, variables that confer a worst prognosis (overall survival) of patients with EM myeloma were β2-microglobuline ≥5,5mg/l (HR: 2,251, p=0,004), >4 points in Cumullative Illness Rating Scale (CIRS) (HR: 1,760, p=0,036) and progressive disease to first line tratment (HR: 2,230, p=0,007).
We create a mathematic predictive model at diagnosis through a discriminant analysis using serum calcium, ISS score and CIRS score to identify patients with EM. With this method we could classify correctly 68,4% of our patients.
Conclusions. In our real-world series patients with EM myeloma die mainly because infection or progression. They have worse basal situation (age, comorbidity, ECOG) an a more agressive and evolved disease as wel as worse response to treatment. We present a model to try to identify these patients at diagnosis, which could involve changing the management like giving antibiotic profilaxis to try to improve survival.

Disclosures
No relevant conflicts of interest to declare.
Evaluating Anti-TNF-Alpha Therapy in Patients with Relapsed and Refractory Langerhans Cell Histiocytosis
Authors: Burke Thomas , Legarreta Alejandra , Lin Howard , Scull Brooks , Eckstein Olive S. , McClain Kenneth L. , Allen Carl E. 
Published: October 2019

Abstract
Purpose: Tumor necrosis factor alpha (TNF-alpha) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in active high-risk vs low-risk LCH vs control patient blood, where TNF-alpha has been reported at 12 pg/ml in juvenile rheumatoid arthritis (JRA). Anti-TNF therapeutic etanercept is used in TNF-mediated diseases, such as JRA, and was successfully used in one case of LCH. We therefore conducted phase II study for etanercept therapeutic efficacy for refractory or relapsed LCH patients. Methods: Luminex platform was used to assess patient blood TNF-alpha level. This phase II study was approved by the Baylor College of Medicine IRB with research support from Amgen/Immunex. Eligibility included LCH patients with progressive disease post-initial treatment and ≥1 salvage therapy. Etanercept was injected 0.4mg/kg subcutaneously twice/week for 12 weeks. Therapeutic response were evaluated at 4 and 8 weeks. Results: TNF-alpha is elevated in blood LCH high-risk (average 45pg/ml) vs low-risk (average 13pg/ml) vs control (average 13pg/ml). Five LCH patients (1.6-42 years) with multi-system involvement, 2 with high-risk disease were enrolled. A median of 5 doses of etanercept were administered (range 1-14). One high-risk patient died 18 days after the first dose from disease progression. At week 4 evaluation, one patient had stable disease and 3 progressed and all subjects progressed by week 8. Ultimately 0/5 patients had disease improvement with etanercept. Conclusion: Etanercept therapy, at JRA-effective dose, in this trial did not improve LCH disease. It is possible that this may not be an effective strategy. Alternatively, it is also possible that drug dose or distribution was suboptimal. While anti-TNF therapies, including etanercept, are effective for treatment of RA, etanercept is not effective for granulomatous diseases such as Crohn's, sarcoidosis or Wegner's disease. Additional studies exploring potential efficacy of higher dose or alternative forms of TNF-alpha inhibition in LCH may be warranted.

Disclosures
No relevant conflicts of interest to declare.
Multiple Myeloma Cell-Derived Interleukin-32gamma Increases the Immunosuppressive Function of Macrophages By Promoting Indoleamine 2,3-Dioxygenase (IDO) Expression
Authors: Yan Haimeng , He Donghua , Huang Xi , Fan Zhang En , Huang He , Cai Zhen 
Published: October 2019

Abstract
Background: The interaction of multiple myeloma (MM) cells with macrophages (MΦs) in the bone marrow microenvironment contributes to the pathophysiology of MM. In addition to promoting angiogenesis through vasculogenic mimicry, MM-associated MΦs (mMΦs) protect MM cells from spontaneous and chemotherapy-induced apoptosis. mMΦs therefore represent a potential target for myeloma treatment and it is essential to explore the mechanisms underlying normal MΦ polarization to mMΦs. We previously showed that IL-32 is overexpressed in MM patients and is mainly derived from MM cells. The present study was designed to explore the clinical significance of IL-32 in MM and to further elucidate the molecular mechanisms underlying the IL-32-mediated immune function of MΦs.
Methods: We examined the expression of IL-32 in bone marrow biopsy samples using immunohistochemistry. Quantitative real-time PCR, western blot analysis and immunofluorescence were applied to measure the expression of IL-32, IDO and proteinase 3 (PR3). We obtained the global transcriptional profile of the IL-32γ-treated MΦs by RNA sequencing (RNA-Seq). Immunoprecipitation (IP) and GST pulldown experiments was applied to confirm the binding affinity of PR3 for IL-32. We created IL-32-knockdown MM cells by transfection of IL-32 shRNA and silenced PR3 expression in MΦs using siRNA targeting PR3. CD4+ T cell proliferation and IL-2, IFN-γ and TNF-α production were measured by flow cytometry.
Results: We found that high IL-32 expression in MM patients was associated with advanced clinical stage and high serum β2-microglobulin levels. Several isoforms of IL-32 were detected in MM cells and IL-32γ was the most active subtype. RNA sequencing revealed that IL-32γ significantly induced the production of the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO) in MΦs and this effect was verified at the protein level. Furthermore, IL-32-knockdown MM cells showed less ability than control MM cells to promote IDO expression. As a binding protein for IL-32, PR3 was universally expressed on the surface of MΦs and knockdown of PR3 or inhibition of the STAT3 and nuclear factor κB (NF-κB) pathways hindered the IL-32γ-mediated stimulation of IDO expression. Finally, IDO-positive IL-32γ-educated MΦs inhibited CD4+ T cell proliferation and IL-2, IFN-γ and TNF-α production in response to activation.
Conclusion: Our study showed that MM cell-derived IL-32γ induced IDO production in MΦs through PR3 and the downstream STAT3 and NF-κB pathways, resulting in the suppression of the proliferation and effector function of CD4+ T cells. High IL-32 expression in MM may contribute to an immunosuppressive microenvironment by upregulating IDO production in MΦs and promote MM progression.

Disclosures
No relevant conflicts of interest to declare.