bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue Resident Memory Cells
Authors: Kupper Thomas S 
Published: October 2019

Abstract
Tissue resident memory T cells (TRM) are a relatively newly discovered subset of memory T cells. Rather than inhabiting secondary lymphoid tissue, they are lodged in peripheral tissues. While TRM can appear in any tissue, they are most abundant in tissues that abut the environment--skin, lung, gut, oral and vaginal mucosa. They accumulate as a result of T cell mediated inflammatory processes which occur in response to infection or encounter with a non-pathogenic antigen. Strategically, they can respond almost immediately to a subsequent encounter with the antigen for which they are specific, and thus play a critical role in host defense. CD8 TRM specific for pathogenic viruses have been described, as well as CD4 TRM for pathogenic fungi and other microorganisms. While TRM play a role in host defense, inappropriate activation of TRM in response to autoantigen or otherwise innocuous antigen is thought to play a key role in several T cell mediated inflammatory diseases, including psoriasis, spondyloarthritides, multiple sclerosis, type I diabetes, and asthma. Dislodging pathogenic TRM from tissue has proven difficult or impossible, and thus many of these disorders are relapsing even if successfully treated. Their dependence on cytokines such as IL-15, fatty acid metabolism, and expression of CD69 may represent targets of therapeutic opportunity.

Disclosures
No relevant conflicts of interest to declare.
Padi4 Regulates NET Formation and Inflammatory Cell Death Downstream of Mlkl
Authors: D'Cruz Akshay A , Speir Mary , Bliss-Moreau Meghan , Dietrich Sylvia , Chen Alyce A , Gavillet Mathilde , Lawlor Kate E , Vince James E , Kelliher Michelle , Hakem Razq , Pasparakis Manolis , Williams David A , Ericsson Maria , Croker Ben A 
Published: October 2019

Abstract
Neutrophil extracellular trap (NET) formation can generate short-term functional anucleate cytoplasts and can trigger loss of cell viability. We examined the role of non-apoptotic cell death signaling in NET formation by studying necroptotic human and mouse neutrophils. Necroptotic cell death signaling was activated by caspase-8 inhibition and pharmacological targeting of inhibitor of apoptosis proteins (IAPs). The specificity of cell death was confirmed using neutrophils from mice deficient in receptor-interacting protein kinase-3 (Ripk3), Ripk1 kinase activity (Ripk1D138N/D138N), caspase-8, or the plasma membrane-disrupting effector protein mixed lineage kinase domain-like (Mlkl). NETs were investigated with a combination of imaging and quantitative flow cytometry, immunogold electron microscopy, immunofluorescence microscopy, and ex vivo microbicidal assays to demonstrate functionality of NETs.
In response to necroptotic stimuli, Mlkl translocates to the plasma membrane in neutrophils, and is required for downstream NADPH oxidase-independent reactive oxygen species production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. Neutrophils expressing a kinase-dead form of Ripk1 (Ripk1D138N/D138N) were unable to generate Ripk3/Mlkl-dependent NETs, or to undergo necroptosis or caspase-8-dependent apoptosis. NET formation that is triggered by necroptotic stimuli is dependent on TNF production, can be differentially modulated by the actions of G-CSF and IFNγ, and occurs concomitantly with the production, processing and release of IL-1α/β. Human necroptotic neutrophils also release NETs that kill S.aureus. Necroptotic NETs contain components of canonical NETs including dsDNA, hypercitrullinated histones, and neutrophil elastase, but also non-canonical components including Mlkl and membranes.
Peptidylarginine deiminase 4 (Padi4) is required for extrusion of necroptotic NETs but not for chromatin decondensation. Padi4-deficient neutrophils are hypersensitive to necroptotic stimuli despite normal levels of phosphorylated Mlkl, indicating that Padi4 acts downstream of Mlkl activation. The failure of Padi4-deficient neutrophils to generate necroptotic NETs in the presence of membrane-associated Mlkl, suggests that the removal of Mlkl membrane-disrupting complexes by NETs can facilitate membrane repair and control the kinetics of neutrophil necroptosis. This work defines a distinct cell death signaling network downstream of Mlkl that promotes Padi4-dependent necroptotic NET release.

Disclosures
No relevant conflicts of interest to declare.
First Report of α-Thalassemia Genotypes from Transcaucasia
Authors: Aliyeva Gunay , Asadov Chingiz , Mammadova Tahira , Mammadbayov Zaur , Abdulalimov Eldar , Gafarova Surmaya 
Published: October 2019

Abstract
Background: Transcaucasia is a geographical region located on the border of Eastern Europe and Western Asia including territories of Azerbaijan, Georgia and Armenia. The region has long been known for high incidence of thalassemia and previous studies reported the highest prevalence of β-thalassemia in Azerbaijan (AZE - 4-5%, GEO - 3%, ARM - 2%) and an overlapping mutation spectrum within the region. Nevertheless, the characteristic genotypes and mutation spectrum of less recognised α-thalassemia have not been reported by far. In this multicentre cross-sectional study, we analysed the genotypes of α-thalassemia patients from Azerbaijan as representative of the region.
Methods: 45 patients diagnosed with HbH disease, β-thalassemia major with milder clinical manifestations or any other clinical condition with possible inheritance of α-thalassemia mutations were included in the study. Clinically significant deletions as well as point mutations located on the HBA1 and HBA2 genes were identified via reverse dot blot hybridization method.
Results: From total 8 identified mutations, 20.5 kb (45.3%) and 3.7 kb (31.4%) deletions were the most prevalent. Accordingly, -α3.7 /-(α)20.5 genotype was identified in more than half of the patients with HbH disease (N=23). The most common point mutations were α2 Poly A-2 (HBA2:c.*96G>A) - 7.0%, α2 codon 142 [T>C] (HBA2:c.427T>C) - 4.7%, and α2 IVS-I 5nt del (HBA2: c.95+2_95+6delTGAGG) - 4.7%.
Conclusion: Deletions with less severe clinical presentation comparing to point mutations accounted for the majority of the spectrum. The milder phenotype might be the reason why this disease has been undermined in the region by β-thalassemia. The spectrum of mutations were similar of the populations of neighbouring high incidence territories such as Iran and Turkey.

Disclosures
No relevant conflicts of interest to declare.
Correlation of Direct Antiglobulin Test Strength in Umbilical Cord Blood and Hyperbilirubinemia in ABO Incompatible Neonates with Two Methods
Authors: FEI FEI , Marques Marisa B. , Staley Elizabeth M. , Williams Lawrence A. 
Published: October 2019

Abstract
Introduction: The direct antiglobulin test (DAT) detects the presence of IgG and/or C3 on the red blood cell (RBC) membrane and is used to diagnose autoimmune hemolytic anemias as well as hemolytic disease of the fetus and newborn (HDFN). A positive DAT in a neonate occurs when maternal IgG crosses the placenta and binds to fetal RBCs, which may lead to hemolysis and clinical manifestations of HDFN such as hyperbilirubinemia. Historically, DATs in umbilical cord blood samples were performed manually. We have recently switched to using the Ortho Vision Analyzer (gel technology) for this purpose in our institution, and noticed a trend toward stronger positive reactions. The purpose of this study was to compare the DAT results obtained with the conventional tube method and the gel method, and their association with hyperbilirubinemia and/or the need for phototherapy in the neonates tested.
Methods: We retrospectively reviewed all cord DAT results of infants born between January 2016 and June 2018. We included all tests of neonates of blood group A or B born to blood group O mothers who had a positive DAT and performed a retrospective chart review to collect the following data: DAT strength, gestational age, birth weight, hematocrit, blood type, initial and peak serum total bilirubin levels, use of phototherapy, antibody screening results, and transfusion history. Neonates whose mothers had a positive antibody screen were excluded from the analysis.
Results: During the study-period, 100 ABO-incompatible neonates with a positive DAT were tested by the tube and gel methods (50 with each methodology) and met our inclusion criteria. Their demographic information and laboratory results, including the strength of the positive DAT are in Table 1. There was a clear trend toward stronger DAT results since the gel methodology was introduced; the most common result in the Ortho Vision Analyzer was 1+ positive (52%), and 40% of neonates had a 2+ positive result. The latter was only seen in 2% with the tube method. Furthermore, although there were no significant differences in any demographic or laboratory parameters between the two groups of neonates, an increased percentage of those tested with the new methodology (23/50 or 46%) received phototherapy compared with 14/50 (28%) of those tested manually (Figure 1).
Conclusions: We found that the Ortho Vision Analyzer produced stronger DAT results compared to the tube method without evidence of increased hemolysis. It is essential that Transfusion Medicine physicians communicate the change in methodology to neonatologists to make them aware of the reason for the stronger DAT results in order to avoid unnecessary phototherapy.

Disclosures
No relevant conflicts of interest to declare.
Late-Onset Cytopenias and Therapy Related Myeloid Malignancies in a Cohort of Patients with Lymphoproliferative Disorders at Instituto Nacional De Cancerologia- Mexico
Authors: Palacios Campos Adriana , Corona Herrera Judith Monserrat , Fabián Morales Eunice , Candelaria Myrna 
Published: October 2019

Abstract
Background:
The increasing survival rate of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term complications including therapy related myeloid malignancies (t-MDS/t-AML).
Methods:
To determine the frequency of late-onset cytopenias, as well as t-MDS/t-AML in patients with lymphoproliferative malignancies, a cohort followed from Jan 2011-Dec 2016 including patients with either Follicular Lymphoma (FL) or Diffuse Large B Cell Lymphoma (DLBCL) was reviewed. Inclusion criteria: patients that received full treatment at Instituto Nacional de Cancerología (INCAN), who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia (according to the CTCAE v4.0). Exclusion criteria: Follow-up less than 6 months and previous treatment before receiving medical care at INCAN. Initially peripheral causes (vitamin deficiencies, viral infections, liver autoimmune diseases, among others) were discarded. Thereafter, bone marrow aspiration was performed for morphologic analysis (including cellularity), karyotype and FISH panel. Baseline data was compared between groups with cytopenias and without it, with X2 method. A Cox-regression model evaluated the factors involved in the development of cytopenias. Survival was estimated with Kaplan-Meier method.
Results:
Of 840 patients enrolled, 35 developed cytopenias (4.16%) (23-DLBCL & 12-FL). Causes of cytopenia were: medullar hypoplasia (n=4, 11.4%), transitory cytopenia (n=4, 11.4%), t-MDS (n=8, 22.8%), t-AML (n=2, 5.7%) among others. In patients with FL, only hemoglobin <12 g/dL (p=0.032) and >6 nodal areas (p=0.037) at diagnosis were statistically significant factors for the development of cytopenia; no factor was significant in patients with DLBCL. It is of interest that 80% of patients developing t-MDS also received radiotherapy. Anemia was the most frequent cytopenia in patients with DLBCL (22.8%) and pancytopenia was the most frequent in FL (54.5%). For patients with t-MDS or t-AML (table 1), there was a gender predominance in women (66.7%). Patients with complex karyotype were associated with progression to t-AML, those with t(11q23) and -7 had aggressive clinical course and shorter survival. Treatment details and outcomes are summarized in table 1.
Conclusions:
The incidence of t-MN is increasing as more patients survive their primary cancers. It is quite important to get further knowledge on the molecular biology of the group of therapy-related disorders not only for a better diagnostic and classification criteria, which may help in selecting individualized treatments, but also to investigate potential chemopreventive strategies.

Disclosures
No relevant conflicts of interest to declare.
Evaluation of Endocrine Complications in Beta-Thalassemia Intermedia Patients: A Cross Sectional Multi-Center Study
Authors: Karimi Mehran , Zarei Tahereh , Haghpanah Sezaneh , Azarkeivan Azita , Kattamis Christos , Ladis Vassilis , Kilinc Yurdanur , Daar Shahina , Alyaarubi Saif , Yasseen Duaa , Yassin Mohamed A , Soliman Ashraf Tawfiq , Canatan Duran , Obiedat Maha , Remawi Hala , Mariannis Demetris , Christodoulides Constantinos , Christou Soteroula , Tzoulis Ploutarchos , De Sanctis Vincenzo 
Published: October 2019

Abstract
The diagnosis of beta thalassemia intermedia (BTI) is mainly based on the severity of clinical phenotype. It is associated with a wide range of specific complications including extramedullary hematopoiesis, leg ulcers, gallstones, hypercoagulable state, pulmonary hypertension (PHT), endocrine disorders and osteoporosis. The commonest endocrine complication in beta thalassemia major (TM) patients is hypogonadism followed by hypothyroidism and diabetes but the data on endocrine disorders in BTI patients are scarce. The aim of this study is to determine the prevalence of endocrine complications in a large series of BTI patients.
Methods: In this multi-countries cross-sectional study, all BTI patients registered at 12 thalassemic treatment centers in Iran (2 Centers), Italy (2 Centers), Greece, Turkey (2 centers), Oman, Qatar, Jordan, Cyprus and United Kingdom were enrolled during 2017. Non transfusion- dependent beta-thalassemia patients or those who received blood transfusion 3-4 times or less annually, were evaluated. Required information was collected from medical records using a designed questionnaire. Demographic data, clinical characteristics and laboratory data included age, sex, splenectomy, type of treatment (blood transfusion, iron chelation, hydroxyurea), hormonal assays, bone mineral density, calcium -phosphorous metabolism, serum ferritin, liver function tests, fetal and total hemoglobin levels,, platelet and nucleated red blood cell counts, were collected.
Results: A total of 721 BTI patients were enrolled in the survey from 9 countries. The most prevalent disease-related complications were osteoporosis (21.6%) and hypogonadism (12.6%) followed by: central hypothyroidism (8.3%), non-insulin-dependent diabetes mellitus (7.8%), primary hypothyroidism (5.5%), insulin-dependent diabetes mellitus (4.2%), hypoparathyroidism (2.2%), growth hormone deficiency (1.1%), adrenal mass (1%) and thyroid cancer (0.5%).
Conclusion: This study evaluated the largest cohort of BTI patients with endocrine disorders. Although BTI patients are non-transfusion dependent or only occasionally transfused, iron-overload due to increased intestinal iron absorption and enhanced bone marrow activity cause endocrine disorders and osteoporosis. This study demonstrate that although endocrine complications are less common in patients with BTI compared to data reported in literature in TM patients , a regular monitoring with timely diagnosis and proper management underscoring on osteoporosis and gonadal disorders are crucial to prevent endocrine complications in these patients.

Disclosures
No relevant conflicts of interest to declare.
Influence of FLT3-ITD Mutation and Length on the Treatment Response and Prognosis in Cytogenetically Normal AML Patients
Authors: Jiang Xuejie , Yin Changxin , Sun Junya , Cheng Jiaying , Wang Qiang , Yu Guopan , Jiang Ling , Xu Dan , Liu Xiaoli , Feng Ru , Liu Qifa 
Published: October 2019

Abstract
BACKGROUND : Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contributed to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). FLT3 tyrosine kinase inhibitor sorafenib in combination with chemotherapy was applied to treat FLT3-ITD AML patients with limited efficacy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was considered as a potent therapeutic regimen in FLT3-ITD patients, but additional sorafenib maintenance was indispensable to support their long-term survival after allo-HSCT. Studies showed that increasing ITD size may be accompanied with decreasing OS and RFS in AML patients, but it remained controversial about the prognostic implication of ITD mutant lengths, the prognostic influence was important to evaluate in determining the therapeutic strategy for AML patients with different ITD lengths.
METHODS: Total 185 CN-AML patients with and without FLT3-ITD mutations were enrolled in this study. We retrospectively studied the clinical characteristic, treatment response, survival and relapse risk after chemotherapy or allo-HSCT plus sorafenib in these patients. Distribution of ITD lengths detected in AML patients suggested two groups including long (≥70bp) and short ITD length (<70bp). Influence of FLT3-ITD mutation and its length were investigated after chemotherapy or allo-HSCT plus sorafenib.
RESULT: FLT3-ITD mutations were detected in 15 percentage of AML patients, and associated with leukocytosis, high blast percentage in bone morrow (BM) and increased risk of treatment failure. FLT3-ITD mutations indicated decreased complete remission (CR) rate, overall survival (OS) and relapse-free survival (RFS), and increased relapse risk (RR) in AML patients after chemotherapy plus sorafenib. Patients with long ITD length (≥70bp) had worse OS and RFS, and more relapse probability than these with short ITD length (< 0bp) or FLT3-WT, but patients with short ITD length and FLT3-WT had the similar RFS and RR after chemotherapy. Allo-HSCT plus sorafenib maintenance significantly prolonged OS and RFS, decreased RR in FLT3-ITD patients, especially in these with long ITD length instead of those with short ITD length.
CONCLUSION: Our findings indicated that FLT3-ITD mutation and long ITD length had negative effect on treatment response and prognosis in CN-AML patients. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve survival and decrease relapse probability, abrogated disadvantage from long ITD length in FLT3-ITD patients.

Disclosures
No relevant conflicts of interest to declare.
Long-Term Stability of the Adult Sickle Cell Quality of Life Measure (ASCQ-Me)​
Authors: Roach Keesha L. , Yao Yingwei , Suarez Marie L. , Angulo Veronica , Shuey David , Ezenwa Miriam O. , Schlaeger Judith M. , Fillingim Roger B. , Wang Zaijie J. , Molokie Robert E. , Wilkie Diana J. 
Published: October 2019

Abstract
Aim: The Adult Sickle Cell Quality of life Measure (ASCQ-Me) is a relatively new tool with increasing frequency of use, but no published reports of its long-term stability. The aim of this study was to examine reliability of ASCQ-Me in a sample of adults with sickle cell disease (SCD). Evidence of reliability of this new tool is important for credible use in longitudinal studies of SCD, especially those with interventions intended to improve quality of life (QOL) for patients with SCD.
Methods: In a comparative study, 141 adults with SCD (mean age 37±11 years [ranged from 19 to 74 years]; 100% African ancestry; 60% female; 74% SS, 20% SC and 6% Other) provided demographic information and completed the ASCQ-Me questionnaire twice, separated by 1 year so that data were collected in the same season. The 30-item ASCQ-Me has 6 subscales focused on: pain episodes (frequency and severity), pain impact, emotional impact, sleep impact, social functioning impact, and stiffness impact. Its scores range from (0 low QOL) to 100 (high QOL) and are normed at a mean of 50 and SD of 10. Because the scores are reversed for pain episodes (frequency, severity), higher scores indicate more suffering. Descriptive and bivariate statistical analysis were conducted using the R statistical software package.
Results: Table 1 presents the complete findings for the ASCQ-Me subscale domains, mean (SD) scores at baseline and one-year, intra-class coefficients (ICC), and Cronbach's alphas at baseline and one-year. Generally in this sample, the subscale scores across time did not differ by more than 2.4 points (Table 1). The internal consistency alphas at baseline ranged from 0.64 to 0.93 and at one-year ranged from 0.62 to 0.93. The long-term stability (ICC) ranged from 0.43 to 0.64.
Conclusions: Over a one-year time span, the stability of the ASCQ-Me subscale scores was fair to good, with pain severity being less stable as would be expected for a condition known for recurrent pain episodes as well as chronic pain. Mean scores in this sample are similar to published scores associated with moderate to high severity SCD. Several domains showed ICC of 0.53 and higher, suggesting adequate stability for use of ASCQ-Me as a treatment outcome measure. While worsening disease has been associated with an increased number of pain episodes, in this sample, over the one-year period, the quality of life remained relatively stable. ASCQ-Me may be used to help describe chronic pain phenotypes in patients with SCD and as a longitudinal measure of treatment outcomes.

Disclosures
No relevant conflicts of interest to declare.
Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia
Authors: Perez-Salvia Montserrat , Eneko Aldaba , Yosu Vara , Myriam Fabre , Cristina Ferrer , Carme Masdeu , Aizpea Zubia , Eider San Sebastian , Dorleta Otaegui , Pere Llinàs-Arias , Margalida Rosselló-Tortella , Maria Berdasco , Fernando Setien , Catia Moutinho , Alberto Villanueva , González-Barca Eva , Muncunill Josep , Navarro Jose Tomas , Piris Miguel Angel , Fernando Cossio , Esteller Manel 
Published: October 2019

Abstract
Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes.

Disclosures
Eneko: Quimatryx: Employment. Yosu:Quimatryx: Employment. Myriam:Oncomatryx: Employment. Cristina:Oncomatryx: Employment. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando:Quimatryx: Consultancy.