bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burden of Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation on Health Care Resource Utilization in the Management of Acute Leukemia and Myelodysplastic Syndrome
Authors: Lachance Silvy , Bibeau Joelle , Lachaine Jean 
Published: October 2019

Abstract
Background: Allogeneic Hematopoietic Stem Cell Transplantation (aHSCT) represents the only curative modality for unfavorable acute leukemia (AL) and myelodysplastic syndrome (MDS). Despite its curative intent, a significant number of recipients relapse. There is no standardized approach for the management of relapse following transplants and therapeutic options vary among centers, which represent a major challenge. Post transplant relapse is usually associated with a poor outcome while the impact of the treatment choice on health care resource utilization and survival is unknown. The objective of this study was to measure the health care resource utilization for the management of relapse following AHSCT and how the treatment choice impacted on survival.
Methods: A retrospective medical chart review was conducted at H™pital Maisonneuve-Rosemont (HMR) after research and ethic committee approval. Patients were selected using the Hematopoietic Stem Cell Transplant (HSCT) program database. Eligible patients were diagnosed with AL or MDS and relapsed following a HLA identical aHSCT between January 1st 2011 and December 31st 2014. Patients' and disease characteristics as well as relapse-related health care resource utilization were collected from the date of transplant relapse diagnosis until death or last follow-up.
Results: During the study period, of the 645 HSCT performed at HMR, 303 were allogeneic. A total of 36 patients who relapsed met the inclusion criteria and were included in the survival analysis. Healthcare resource utilization analysis was conducted on the 25 patients for whom complete records were available. Patients' characteristics at relapse, mean health care resource utilization per patient and survival by treatment choice are presented in tables 1, 2 and 3 respectively. The mean time from relapse to death was 10.6 months (SD=13.2). Relapse-related hospitalization duration represented on average 20.3% of patients' follow-up period (SD=26.0). For a mean follow-up time of 9.5 months (ranged from 6 days to 4.8 years), the mean number of relapse-related hospitalization was 2.2 per patient (SD=2.6). The mean length of stay was 40.4 days per patient (SD=54.5). The mean hematologist consultation number was 32.4 per patient (SD=37.3
Conclusion: Relapse following AHSCT is associated with a poor prognosis and survival and significant use of health care resources. Aggressive treatment rarely leads to a second transplant. Innovative approaches should be developed to address this unmet medical need. Healthcare resources devoted to the care of patients in relapse post AHSCT provide a comparative basis for the development of cellular therapy.

Disclosures
No relevant conflicts of interest to declare.
Decentralized Data Storage to Promote Epidemiological Analysis for Subtypes Non Hodgkin Lymphoma
Authors: Bellesso Marcelo , Centrone Renato , Dias Daniela Ferreira , Santucci Rodrigo 
Published: October 2019

Abstract
Advanced disease means a poor prognosis factor in patients with non-Hodgkin Lymphoma (NHL). There are few Brazilian data about epidemiologic incidence of NHL, however it was observed that high grade B cell Lymphoma is more frequent than in North America, Argentina and Chile, besides that we have deficient information about Brazilian private service care. Such knowledge is essential to plan economic resources to promote the best treatment and diagnosis. Moreover, is fundamental to elaborate electronic data storage to promote a continuous supply flow of information during clinical practice. We have designed an accessible and automated data collection model built into the electronic medical records for patients with NHL. Here, we show some epidemiological parameters and classic risk factors about NHL in a private care institute stocked by continuous electronic data storage.
We evaluated data from patients with NHL during November 2015 to May 2016. Information was obtained by decentralized automated model after each outpatient care. We studied 229 patients with NHL. It was observed 112(48.9%) patients with Diffuse Large B cell Lymphoma not otherwise specified (DLBCL), 65(28.3%) Follicular Lymphoma (FL), 21(9.1%) Mantle Cell Lymphoma (MCL), 12(5.2%) Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue gastric lymphoma (GMALT), 6(2.9%) Extranodal marginal zone lymphoma of nonGastric MALT lymphoma (non-GMALT), 4(1.7%) Splenic B-cell marginal zone lymphoma (SL), 1(0.4%) nodal marginal zone lymphoma (NMZL), 1(0.4%) Sporadic Burkitt Lymphoma (BL), 2(0.8%) peripheral T cell lymphoma not otherwise specified (PTCL), 2(0.8%) anaplastic large T Cell lymphoma, ALK negative (ALTCL), 2(0.8%) Extranodal NK/T-cell lymphoma, basal type and 1(0.4%) mycosis fungoides (MF).
It was evidenced advanced disease stage III/IV in DLBCL, FL and MCL: 70(62.5%), 54 (87.1%), 18 (85.7%); Extranodal infiltration sites in DLBCL, FL, MCL: 35/94 (37.2%), 11/50 (22%) and 5/18( 27.7%); Elevated serum LDH in DLBCL, FL, MCL: 31/74( 43.6%), 10/38 (26.3%) and 4/14 (28.5%), Performance status ≥ 2 in DLBCL, FL, MCL: 18/75(24%), 2/28 (4.1) 12/20 (60%), respectively.
In this study, we have demonstrated that decentralized electronic data storage was useful and could appear an attractive model for clinical practice; moreover, it was possible observed high incidence of DLCBL and FL with advanced disease.

Disclosures
No relevant conflicts of interest to declare.
TCIRG1 Mutations As a Cause for Chronic Neutropenia
Authors: Makaryan Vahagn , Fletcher Breanna , Kelley Merideth L. , Bolyard Audrey Anna , Link Daniel C. , Duncavage Eric J. , Qualls David Augustus , Dale David C. 
Published: October 2019

Abstract
Background: Heterozygous mutations in TCIRG1 are recently associated with congenital neutropenia. [Makaryan et al, Human Mutation, 2014] Recent large scale population study revealed statistically significant association between absolute neutrophil count and variations in TCIRG1 gene. [Rosenthal et al, Genetic Epidemiology, 2016]
Aims: To investigate frequency and reveal possible asymptomatic cases of TCIRG1 associated neutropenia.
Methods: The Severe Chronic Neutropenia International Registry (SCNIR) enrolled and followed 2 multigenerational families with genetic neutropenia of unknown etiology with a clear autosome dominant inheritance. Exome sequencing of selected affected members from these families revealed two previously reported heterozygous single point mutations in TCIRG1. Confirmatory Sanger sequencing ratifies exome sequencing results.
Results:
Family 1: P161L (c.482C>T) single point substitution detected in 3 members of this family. This variant is very rare in population and has relatively low minor allele frequency (MAF) score: 0.08. Proline residue at this position is highly conserved and has a high genomic evolutionary rate profiling (GERP) score: 3.46. PolyPhen-2 analysis suggests this substitution as possibly damaging.
Family 2: I721N (c.2162T>A) single point substitution detected in 3 members of this family. This variant is also very rare in population and has MAF score: 0.07. Isoleucine at this position is relatively conserved and has GERP score: 2.73. PolyPhen-2 analysis suggests this substitution as probably damaging.
Summary/Conclusion: Understanding the genetic, epidemiological and biological basis of TCIRG1 associated neutropenia is critical for improving the diagnosis and treatment of this form of hereditary neutropenia. The pathological mechanisms for TCIRG1-associated neutropenia are not yet known. In our original report [Makaryan et al, Human Mutation, 2014] of the large family with TCIRG1-associated neutropenia, all carriers of the pathogenic variant had neutropenia, with variable severity. Some members have severe neutropenia and associated infections whereas others are mildly affected. The report of these two new variants in these families suggests that there may be other patients and families with neutropenia caused by variants in TCIRG1.

Disclosures
Dale: Amgen: Consultancy, Honoraria, Research Funding.
Platelet Factor 4 Induces Leukocyte Responses through Integrin Mac-1 (CD11b/CD18)
Authors: Podolnikova Nataly P. , Yakubenko Valentin P. , Ugarova Tatiana P. 
Published: October 2019

Abstract
The proteins/peptides secreted from α-granules of activated platelets not only aid in thrombus formation and blood coagulation, but also exert various immune-modulating effects. Among many secreted products, Platelet Factor 4 (PF4), a chemokine that belongs to the CXC family, is one of the most abundant platelet proteins. While PF4 assignment to the chemokine family is based on its structural similarity with other CXC chemokines and chemotactic activity, to date no receptor for PF4 on leukocytes has been identified. Our recent elucidation of the recognition specificity of a major leukocyte integrin αMβ2 (Mac-1) allowed the prediction that PF4 contains several putative Mac-1 recognition motifs and thus could potentially interact with this receptor. Using a peptide library spanning the sequence of PF4, we showed that the αMI-domain of Mac-1 bound several overlapping PF4-derived peptides. The biolayer interferometry analyses demonstrated that PF4 bound recombinant active αMI-domain of Mac-1 in a concentration-dependent manner with a KD of 1.3 ± 0.2x10-6 M. No interaction of PF4 with the inactive αMI-domain (α7 helix extended) or the αLI-domain of a homologous integrin αLβ2 was detected. The full-length recombinant PF4 and the αMI-domain-binding peptide (residues 58-70) identified in the peptide library supported strong adhesion and spreading of Mac-1-expressing cells, including neutrophils, U937 monocytic and Mac-1-transfected HEK293 cells. The cell adhesion to PF4 was partially inhibited by anti-Mac-1 mAbs and completely blocked when anti-Mac-1 antibodies were combined with heparin, suggesting that cell surface proteoglycans act cooperatively with integrin Mac-1. PF4 induced a potent migratory response of wild-type, but not Mac-1-deficient, macrophages in a Transwell system. PF4 also enhanced phagocytosis: coating of E. coli bacteria or latex beads with PF4 enhanced ~ 4-fold their phagocytosis by macrophages, and this process was blocked by different Mac-1 antagonists. Furthermore, PF4 potentiated phagocytosis by wild-type, but not Mac-1-deficient, macrophages. These results identify PF4 as a ligand for integrin Mac-1 and suggest that many immune-modulating effects previously ascribed to PF4 are mediated via interaction with Mac-1.

Disclosures
No relevant conflicts of interest to declare.
Identifying Functional Differences Between Protein S and Gas-6 in Pancreatic Cancer
Authors: Zacarias Cosette , Pilli Vijaya Satish Sekhar , Plautz William E. , Wells A'drianne , Majumder Rinku 
Published: October 2019

Abstract
Introduction: Procoagulants such as Factor IX and thrombin play major roles in cancer cell proliferation and migration; however, a role for anticoagulant proteins in cancer biology has not been elucidated. The anticoagulant Protein S (PS), its homologous protein Growth Arrest Specific protein-6 (GAS-6), and the receptors for these proteins, Tyro-3, Axl and Mertk (TAM), are over expressed in many cancer cells. TAM family receptors regulate functions such as cell survival, proliferation, migration, and apoptosis. The consequences of activation of each of these receptors varies, although the mechanism that leads to different outcomes is unknown. We hypothesized that the PS and GAS-6 ligands are responsible for the variations in the functions of these signaling cascades.
Methods: We used qPCR to analyze the pancreatic cancer cell lines Miapaca-2 and Panc-1 for variations in the expression of GAS-6 and PS. We sequestered PS and GAS-6 with antibodies and used FACS analysis to detect effects on the cell cycle and on cell cycle regulators.
Results: GAS-6 was observed to be highly expressed in proliferating Miapaca-2 cells compared with Panc-1 cells, whereas there was no significant difference in PS mRNA levels between these cell lines. For the cell line Miapaca-2, antibody sequestration of GAS-6 arrested the cell cycle in S-phase and increased p53 phosphorylation; conversely, inhibition of PS reduced p53 phosphorylation.
Conclusion: Our results indicate that PS and GAS-6 act antagonistically in controlling pancreatic cancer cell proliferation, and we hypothesize that the ratio of GAS-6 to PS expression is key to this regulation. We will further confirm our hypothesis by overexpressing and knocking down PS and GAS-6 in the pancreatic cancer cell lines.

Disclosures
No relevant conflicts of interest to declare.
Bleeding and Thrombotic Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants in Patients with Prior Venous Thromboembolic Disease
Authors: Shaw Joseph , de Wit Carine , Le Gal Gregoire , Carrier Marc 
Published: October 2019

Abstract

Introduction: The use of Direct Oral Anticoagulants (DOACs) for the prevention and treatment of Venous Thromboembolic Disease (VTE) is increasingly common. Patients on longstanding anticoagulation for the prevention of VTE frequently undergo invasive procedures that necessitate interruption of anticoagulation in order to avoid excessive bleeding during the procedure. There is little evidence surrounding the safety of perioperative DOAC interruption in patients with VTE.
Methods: This study represents a retrospective analysis of adult patients on DOAC therapy for prior VTE, who underwent temporary interruption of anticoagulation therapy for inpatient or outpatient invasive procedures. The timing to hold and resume DOAC anticoagulation was based on the estimated half-life of the DOAC, as well as the bleeding risk of the procedure (Standard vs High). Our primary outcomes included the 30-day thromboembolic complication rate, as well as the 30-day major bleeding rate (ISTH non-surgical and surgical major bleeding criteria). Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and overall mortality.
Results: To date, a total of 87 patients have been included in the analysis, 68% of which were male. The mean age of the cohort was 58.3 years. All patients were on DOAC anticoagulation for acute treatment or secondary prevention of recurrent VTE. A large majority of patients (94%) were anticoagulated with rivaroxaban. Procedures were performed on an inpatient or outpatient basis in 24 and 63 patients, respectively. Forty six patients underwent procedures with standard bleeding risk. Mean time to anticoagulation discontinuation for standard and high bleeding risk procedures was 41.3 (SD = 20.8) and 49.3 (SD = 17.7) hours, respectively. The 30-day thromboembolic complication rate was 1.2% (95% CI: 0.2 to 6.2%), whereas the 30-day major bleeding rate was 0% (95% CI: 0 to 4.2%). The rate of CRNMB was 3.5% (95% CI: 1.2 to 9.7%). Overall mortality was 0% (95% CI: 0 to 4.2%).
Conclusion: The perioperative interruption of direct oral anticoagulation for invasive procedures in patients with prior VTE appears to be associated with a relatively low risk of major bleeding, as well as recurrent VTE. Prospective studies are needed to evaluate the benefits and risks of perioperative interruption of direct oral anticoagulation in patients with prior VTE.

Disclosures
Carrier: BMS: Research Funding; Leo Pharma: Research Funding.
The ALK-2 Inhibitor, TP-0184, Demonstrates High Distribution to the Liver Contributing to Significant Preclinical Efficacy in Mouse Models of Anemia of Chronic Disease
Authors: Peterson Peter , Kim Wontak , Haws Hillary , Whatcott Clifford J. , Siddiqui-Jain Adam , Bearss David J. , Warner Steven L. 
Published: October 2019

Abstract
In individuals with chronic inflammatory diseases, such as cancer or rheumatoid arthritis, constitutive signaling through ALK2, a member of the bone morphogenetic protein (TGFβ/BMP) receptor family, leads to debilitating anemia, commonly referred to as anemia of chronic disease (ACD). Activation of ALK2, like other members of the BMP receptor family, leads to the phosphorylation and activation of SMAD family transcription factors via signal transduction and subsequent activation of gene expression. Activation of ALK2 in the liver induces the SMAD-driven transcription of the peptide hormone hepcidin which, by promoting the degradation of the iron transporter ferroportin, leads to reduced serum iron levels and subsequent functional anemia. Lowering constitutively elevated hepcidin levels by inhibiting ALK2 kinase activity is a potentially viable therapeutic strategy for ACD. Current therapeutic approaches for ACD rely on transfusions, intravenous iron and the use of erythropoietin-based therapies, none of which address the underlying pathological deficit of functionally low iron levels. TP-0184 is a small-molecule, selective inhibitor of ALK2 kinase activity (IC50 = 5 nM). TP-0184 has demonstrated profound preclinical activity in three mouse efficacy models for ACD. In model 1, TP-0184 reversed hepcidin induction in mice treated with turpentine oil. In model 2, TP-0184 abrogated reductions in hemoglobin and total red blood cell counts induced by intraperitoneal injection with heat-inactivated Brucella abortus. In model 3, TP-0184 reversed elevated hepcidin levels in TC-1 tumor bearing mice. Plasma and liver pharmacokinetics in mice revealed that TP-0184 has a high volume of distribution (Vd = 30.8) and accumulates at high concentrations in the liver (Cmax of 292 mM following a single oral dose of at 20 mg/kg). In rat multi-dose tolerability studies, TP-0184 caused no adverse effects when dosed at 200 mg/kg for 7 days, far exceeding the dose levels required to produce efficacy (25 mg/kg). These data suggest that favorable distribution to the liver may play a significant role in the preclinical efficacy of TP-0184 and provide evidence of a significant therapeutic window. Collectively these studies support the clinical evaluation of TP-0184 as an alternative treatment for ACD.

Disclosures
Peterson: Tolero Pharmaceuticals: Employment. Kim:Tolero Pharmaceuticals: Employment. Haws:Tolero Pharmaceuticals: Employment. Whatcott:Tolero Pharmaceuticals: Employment. Siddiqui-Jain:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Warner:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties.
Identification of New BMP6 Pro-Peptide Mutations in Patients with Unexplained Iron-Overload
Authors: Piubelli Chiara , Castagna Annalisa , Marchi Giacomo , Rizzi Monica , Busti Fabiana , Marchetti Monia , De Gobbi Marco , Roetto Antonella , Xumerle Luciano , Giorgetti Alejandro , Delledonne Massimo , Olivieri Oliviero , Girelli Domenico 
Published: October 2019

Abstract

Background: Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least 5 different genes (HFE, HJV, TFR2, SLC40A1, and HAMP) involved in the production and function of the liver hormone hepcidin, a key regulator of iron metabolism. Nevertheless, patients with a HH-like phenotype that remains unexplained, despite extensive sequencing of the known genes, are not infrequently seen at referral centres, implicating the role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), a member of TGFb superfamily, whose expression is stimulated by increased iron stores in the liver. BMP6 acts as a major activator of the BMP-SMAD signalling pathway, ultimately leading to the upregulation of hepcidin gene transcription. Indeed, early this year French Authors have described 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with mild to moderate, late onset, unexplained iron overload (Daher R, Gastroenterology 2016).
Methods: we recently updated our next generation sequencing (NGS)-based second level genetic test for the molecular diagnosis of non-HFE HH (Badar S, Am J Hematol 2016), by adding a number of novel potential candidate genes, including BMP6, to the panel of the 5 known HH genes. This test was applied to 38 patients evaluated at our tertiary referral centre for iron disorders, because of an unexplained iron overload phenotype.
Results: we found 3 heterozygous missense mutations in BMP6 gene in 4 patients with unexplained, late-onset, iron overload, from 3 different families. Their relevant clinical data are summarized into Table 1. Of note, 1 mutation (p.Leu96Pro) was the same recently described by Daher et al. and proven to be functional. The other two mutations (p.Glu112Gln, p.Arg257His) were novel, predicted damaging by bioinformatic tools, and both located in the pro-peptide domain, known to be crucial for appropriate BMP6 processing and secretion. They were further studied by in silico modelling, based on the available 3D structure of the TGFb, which also resulted to be consistent with their pathogenetic role.
Conclusions: to the best of our knowledge, our results provide the first independent confirmation of the likely causal role of BMP6 mutations in late onset, moderate iron overload phenotype, unrelated to mutations in the established 5 HH genes.

Disclosures
No relevant conflicts of interest to declare.
Extramedullary Erythropoiesis in Spleen of HIF Prolyl 4-Hydroxylase-2 Deficient Mice Is Mediated By Notch Signaling Downregulation
Authors: Myllymäki Mikko , Määttä Jenni , Dimova Elitsa , Izzi Valerio , Väisänen Timo , Myllyharju Johanna , Koivunen Peppi , Serpi Raisa 
Published: October 2019

Abstract
Erythrocytosis, an increase in absolute red cell mass, is mainly driven by erythropoietin, while hypoxia-inducible factor (HIF) regulates the expression of a number of genes involved in it, including erythropoietin. Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2/PHD2/EGLN1), the major regulator of the stability of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis and premature death. Although bone marrow is the primary site for erythropoiesis, spleen retains a capability for extramedullary erythropoiesis. We studied HIF-P4H-2 hypomorphic mice (Hif-p4h-2gt/gt) which show slightly induced erythropoiesis only upon aging despite no increased erythropoietin levels. Spleen was identified as the site of extramedullary erythropoiesis in these mice. Hematopoietic stem cells (HSCs) from spleens of the Hif-p4h-2gt/gt mice showed increased growth of BFU-Es and the mice were protected against anemia by induced extramedullary erythropoiesis. HIF-1α and HIF-2α were stabilized in the spleens, while the Notch ligands and target Jag1, Jag2, Dll1 and Hes1 became downregulated upon aging dependent on HIF-2α. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased growth of BFU-Es in the Hif-p4h-2gt/gt mice. We conclude that HIFα stabilization can mediate non-erythropoietin-driven extramedullary erythropoiesis in the spleen via altered Notch signaling.

Disclosures
Myllyharju: FibroGen Inc.: Equity Ownership, Research Funding.