bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of CD137/4-1BB and Its Ligand in the NK Cell Mediated Immune Surveillance of Acute Myeloid Leukemia.
Authors: Baessler Tina , Krusch Matthias , Baltz Katrin M. , Schmiedel Benjamin J. , Schmetzer Helga M. , Kanz Lothar , Salih Helmut R. 
Published: October 2019

Abstract
NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies including acute myeloid leukemia (AML). NK cell reactivity is governed by a balance of activating and inhibitory receptors including various members of the TNF receptor (TNFR) superfamily. The TNFR superfamily member CD137/4-1BB has been shown to stimulate proliferation and IFN-γ production, but not cytotoxicity of NK cells in mice. Surprisingly, yet nothing is known regarding the consequences of CD137-CD137 ligand (CD137L) interaction for NK cell reactivity in humans. In this study we demonstrate that CD56dimCD16+ but not CD56brightCD16− NK cells express CD137 upon stimulation with the activating cytokines IL-2 and IL-15 with peak expression between 48 and 60h. Furthermore, we found that 5 of 7 investigated AML cell lines and 16 of 51 (33%) primary AML cells of patients expressed substantial CD137L levels, while no CD137L expression was detected on CD34+ cells of healthy donors (n=5). CD137L expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p<0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via CD137L into AML cells (n=10) significantly induced the release of the immunoregulatory cytokines IL-10 and TNF (both p<0.05, Mann-Whitney U-test). Surprisingly and in contrast to available data regarding the function of murine CD137, we found that in humans blocking CD137-CD137L interaction caused a significant increase in NK cell cytotoxicity and IFN-γ production about 50% (both p<0.05, Mann-Whitney U-test) in coculture assays with CD137L-expressing patient AML cells and AML cell lines. The inhibitory effect of CD137 on NK cell reactivity was further confirmed in cocultures of NK cells with CD137L-transfectants and by triggering CD137 with an agonistic monoclonal antibody. This indicates that CD137 mediates opposite effects in murine compared to human NK cells. Furthermore we conclude that CD137L expression substantially influences tumor immunoediting by AML cells and diminishes NK cell reactivity against AML.
A Novel Therapy of Clofarabine in Combination with Etoposide and Cyclophosphamide Shows Activity in Pediatric Patients with Refractory or Relapsed Acute Leukemia.
Authors: Hijiya Nobuko , Gaynon Paul , Fernandez Manuel , Rytting Michael , Chu Roland , Barry Elly , Thomson Blythe , Cooper Todd , Kadota Richard , Chaleff Stanley , Steinherz Peter , Abichandani Rekha , Carroll William 
Published: October 2019

Abstract
Clofarabine as a single agent has demonstrated activity in childhood acute leukemia. In the current phase I/II study, clofarabine was added to the widely used combination of etoposide and cyclophosphamide. The phase I component of the study is completed. Patients between 1 and 21 years old with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were enrolled in phase I. A standard 3+3 design was followed to determine the safest dose when used in combination. All 3 drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles (depending on the response following cycle 1), followed by consolidation (up to a maximum of 8 cycles, including induction). The initial doses (cohort 1) were: clofarabine 20 mg/m2/day, etoposide 75 mg/m2/day and cyclophosphamide 340 mg/m2/day. Clofarabine was increased to 30 mg/m2/day in cohort 4 and 40 mg/m2/day in cohort 5 after cyclophosphamide and etoposide were escalated to their respective target dose levels (440 mg/m2/day and 100 mg/m2/day) in cohorts 2 and 3. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 cohorts, and response data based on investigator’s assessment are available on the first 22 patients (ALL: 18 patients; AML: 4 patients). The median number of prior induction regimens was 2, and 3 patients had a prior hematopoietic stem cell transplant (HSCT). Data show complete remission (CR) in 7 patients (ALL: 7 patients; AML: 0 patients) and complete remission without platelet recovery (CRp) in 6 patients (ALL: 2 patients; AML: 4 patients) for an overall response rate of 59% (ALL: 50%; AML: 100%). Four patients proceeded to HSCT after treatment. One patient in cohort 4 experienced a dose-limiting toxicity (DLT) that resolved (grade 3 elevation of lipase and abdominal pain). In addition, a second patient in cohort 4 experienced a lipase elevation that did not meet DLT criteria, leading to a cohort expansion to 10 total patients. One patient in cohort 5 (n=6) experienced a DLT of prolonged bone marrow aplasia leading to cohort expansion. Common toxicities observed in ≥20% of patients included febrile neutropenia, abdominal pain, diarrhea, nausea, vomiting, pyrexia, anorexia, hypokalemia, headache, anxiety and rash. As determined by the independent data monitoring committee, the recommended phase II doses of clofarabine, cyclophosphamide, etoposide 40mg/m2/day, 440 mg/m2/day, and 100 mg/m2/day, respectively. Encouraging preliminary efficacy results and an acceptable safety profile of the combination regimen warrants continuation of the phase II portion of the study, which is actively enrolling patients.
Inhibition of Tissue Factor (TF) Pathway Blunts Hepatic Tumor Development in a Rat Colorectal Cancer Model.
Authors: Zerbib Philippe , Grimonprez Alexandre , Corseaux Delphine , Petersen Lars , Jude Brigitte 
Published: October 2019

Abstract
Occurrence of hepatic metastasis (HM) is the leading cause of death in colorectal cancer, making their prevention a major challenge. Tissue factor (TF), the principal initiator of coagulation after binding to its ligand, coagulation factor FVIIa, is expressed by most colorectal cancer cells, and has been demonstrated to be associated to tumor invasion and metastasis. The aim of this study was to analyze the effects of inhibition of the TF pathway in a rat model of HM of colorectal cancer.
Methods DHDK12 Pro B cells (20.106 cells), a tumor cell line established from chemically induced colon carcinoma in BDIX rats, were injected in the portal vein of syngenic rats. Inhibition of TF was achieved in 19 rats (treat ment group) through intraperitoneal injection of active site-inactivated factor VIIa (FFR-FVIIa, Novo Nordisk, Denmark) (10μg/g, once a day from day 3 to day 8 after HM induction). Additionally, 18 rats underwent cancer cell infusion according to the same procedure, without FFR-FVIIa treatment (control group). Rats were sacrificed at day 14.
Results In the control group, infusion of cancer cells resulted in the development of macroscopical hepatic tumors in 17 out of 18 rats. In rats treated by FFR-FVIIa, no macroscopical or histological hepatic tumors were visible on the liver surface in 16 out of 19 rats (p=0.002, versus control group).
Conclusion These results suggest that blockage of TF with proteolytically inactive FFR-VIIa inhibits hepatic tumor development at an early stage of tumoral development and TF is a target for adjuvant therapy in the prevention of HM.
A Chromatin-Associated Histone H3 Dementhylase Promotes the Immortalization of MEFs and the Cycling of HSC-Like Cells in Culture.
Authors: Pfau Raymond , Tzatsos Alexandros , Bear Susan E. , Polytarchou Christos , Kampranis Sotirios , Van Etten Richard A. , Tsichlis Philip N. 
Published: October 2019

Abstract
A common integration site, cloned from MoMuLV-induced rat T cell lymphomas was mapped immediately upstream of Ndy1, a gene expressed primarily in ES cells, hematopoietic stem cells, testis, spleen and thymus. Ndy1 encodes a chromatin-associated nuclear protein. Ndy1 and its homolog Ndy2, which is also a target of provirus integration in retrovirus-induced lymphomas, encode proteins that were recently shown to possess JmjC-dependent histone H3 demethylase activity. Mouse embryo fibroblasts (MEFs) engineered to express Ndy1 or Ndy2 undergo immortalization in the absence of replicative senescence via a JmjC domain-dependent process. Knock down of endogenous Ndy1 or expression of JmjC domain mutants of Ndy1 promotes senescence, suggesting that Ndy1 is a physiological inhibitor of senescence in dividing cells. Infection of bone marrow cells with a high titer MigR1/Ndy1 retrovirus led to the reproducible isolation of immortalized cultures that have the phenotypic characteristics of hematopoietic stem cells. We conclude that Ndy-mediated demethylation of histone H3, promotes cell immortalization, oncogenesis and the cycling of stem cells.
Study of Patients Having Splenectomy Due to Trauma for Long Term Infectious and Vascular Complications.
Authors: Purcell Patricia L. , Crary Shelley E. , Adix Leah , Alder Adam , Buchanan George R. 
Published: October 2019

Abstract
Splenectomy, commonly performed for hematologic conditions, is followed by an increased risk of septicemia and arterial and deep venous thrombosis and pulmonary arterial hypertension. Most recent studies of post-splenectomy vascular complications focus primarily on patients with sickle cell disease, thalassemia, or hereditary stomatocytosis. However, the incidence and pathophysiology of complications in these patients is confounded by persistent hemolysis. Therefore, study of long term post-splenectomy infectious and vascular complications in patients without hemolysis or other serious medical conditions is indicated. Patients having splenectomy for trauma are often young and otherwise healthy so might be good candidates for investigation of post-splenectomy sequelae. To determine the feasibility of conducting a study of infectious and vascular complications following splenectomy for trauma, we retrospectively studied such patients admitted to Parkland Memorial Hospital, a 950 bed public hospital and the site of the Dallas metropolitan area’s primary trauma center. Using appropriate ICD-9 and CPT codes, three separate databases (hospital medical records, trauma registry, and professional billing compilation) were reviewed in order to identify patients ≥ age 18 yr. having total splenectomy for trauma during the past 15 years and to determine whether follow-up data were available in the records regarding subsequent vascular events or surrogate laboratory markers suggesting an increased risk of thrombosis. Between 1992 and 2006, 855 individuals had splenectomy, including 643 (75%) following trauma. The annual number of patients having splenectomy due to trauma did not decline during this period. A comprehensive chart review was performed on the 77 patients having splenectomy for trauma during 2003 and 2004. Records were unavailable in four patients, and 20 died of their injuries shortly after admission. Follow-up records of the remaining 53 patients - 26 (49%) of whom appeared to be discharged in good condition without serious sequelae - were reviewed to attempt to gather data regarding clinical features and laboratory test results. Post hospitalization follow-up occurred in only 9 (17%) of these 53 patients. Six had serious post-trauma complications (e.g., paraplegia); only three seen in follow-up more than six months following splenectomy appeared well. We conclude that complete splenectomy following trauma remains a common procedure. Retrospective review of these patients’ records does not permit evaluation of post-splenectomy complications. However, many patients were discharged shortly following splenectomy without other serious injuries. These patients could potentially be studied prospectively to assess the frequency, timing, and pathophysiology of infection, thrombosis, pulmonary arterial hypertension, and other complications of the post-splenectomy state without the confounder of hemolytic anemia.
Impaired Natural Killer Cells Immune Synapse Formation in Acute Myeloid Leukemia.
Authors: Xing Dongxia , Ramsay Alan G. , Decker William , Li Sufang , Robinson Simon , Yang Hong , Gribben John G. , Shpall Elizabeth J. 
Published: October 2019

Abstract
Abstract 2663
Poster Board II-639
Natural killer (NK) cells are an important component of the innate immune surveillance of tumor cells. Defective NK cell function has been correlated with poor prognosis in acute myeloid leukemia (AML). It is well established that NK cell-mediated cytolytic activity is significantly diminished in AML patients; the mechanisms of this hypo-function are not well understood. Identifying mechanisms of tumor-induced immune suppression of lymphocytes function will aid the development of effective immunotherapeutic strategies. In the present study we examined the molecular basis for impaired NK cell responses in AML and demonstrate impaired NK cell immunological synapse formation. Confocal microscopy was used to visualize F-actin polymerization at the immune synapse between CD56+ CD3- NK cells and autologous AML blasts. We identified a significant reduction in formation of the NK cell immune synapse (NKIS) (p<0.001) from AML patients compared healthy donors (> 70% reduction). This defect was induced by direct tumor contact since NK cell defects were induced in healthy NK cells when they were co-cultured (in direct contact) for 48 hr with allogeneic AML blasts, but not with healthy allogeneic monocytes (P < 0.01). In control transwell co-culture experiments, where the NK cells and AML blast were not in direct contact, we did not observe the induced defect. We examined the molecular nature of the AML blast induced defect by quantifying recruitment of a number of these NK cell adhesion and cytoskeletal signaling proteins to the immune synapse. Following primary co-culture with AML blasts, healthy NK cells showed significantly reduced recruitment of integrin LFA-1, CD2, Lck, WASP, and tyrosine-phosphorylated protein to the NK-AML target interactions synapse (P < 0.001). These studies demonstrate a role for the tumor induced immune suppression of NK cells and will aid in the development of immunotherapeutic approaches targeting AML.

Disclosures:
No relevant conflicts of interest to declare.
Risk of EBV-Positive Hodgkin Lymphoma Varies Over 30-Fold by HLA Class I Genotype and History of Infectious Mononucleosis.
Authors: Jarrett Ruth , Johnson Paul CD , Rostgaard Klaus , Lake Annette , Shield Lesley , Little Ann-Margaret , Ekstrom-Smedby Karin , Adami Hans Olov , Glimelius Bengt , Dutoit Stephen Hamilton , Kane Eleanor , Taylor G. Malcolm , McConnachie Alex , Ryder Lars P , Sundstrom Christer , Andersen Paal Skytt , Chang Ellen T , Alexander Freda , Melbye Mads , Hjalgrim Henrik 
Published: October 2019

Abstract
Abstract 269

Introduction:
Markers in the human leukocyte antigen (HLA) class I locus and infectious mononucleosis (IM) have both been associated with Epstein-Barr (EBV)-positive Hodgkin lymphoma (HL). IM is caused by late infection with EBV. To further explore associations between HLA class I genes and EBV-positive HL and to investigate potential interactions between genetic (HLA) and environmental risk factors in the development of HL, we performed a case-only study of 934 HL cases.

Methods:
HLA-A and B typing were performed by PCR sequence specific oligonucleotide assay. Logistic regression was used to estimate odds ratios (ORs) of EBV-positive HL relative to EBV-negative HL for HLA-A and B genotypes and other known risk factors.

Results:
Increasing age, male sex, HLA-A*01 and a previous history of IM were all associated with a statistically significant increased odds of EBV-positive HL while HLA-A*02 and HLA-B*07 were associated with a protective effect. Significant interactions were detected between HLA-A*01 and HLA-B*07 and between prior IM and HLA-A*02, such that HLA-B*07 abolished the increased odds associated with HLA-A*01 and HLA-A*02 abrogated the increased odds associated with prior IM. In our final model of EBV-positive HL, HLA-B*07 was associated with a dominant protective effect (OR=0.57, 95% confidence interval (CI): 0.34–0.94); HLA-A*02 was associated with a protective effect which was additive (for individuals with no prior IM, ORper allele =0.69, 95% CI: 0.50–0.97); and HLA-A*01 was associated with an increased odds in patients who were HLA-B*07-negative (ORper allele=2.15, 95% CI: 1.54–3.01). Prior IM was independently associated with EBV-positive HL (OR=3.35, 95% CI: 1.67–6.73). This resulted in a >32-fold higher odds of EBV-positive HL in HLA-A*01 homozygotes with IM compared to HLA-A*02 homozygotes without IM.

Conclusions:
We have identified strong associations between both genetic and environmental risk factors and EBV-positive HL. Our findings suggest that HLA class I-restricted, cell-mediated responses to EBV and a prior history of IM play critical roles in the pathogenesis of EBV-positive HL.

Disclosures:
No relevant conflicts of interest to declare.
Nucleostemin Gene Expression in Acute Promyelocytic Leukemia Patients.
Authors: Ashrafi Farzaneh , Nadali Fatemeh , Ghavamzadeh Ardeshir , Alimoghaddam Kamran , Rostami Shahrbano , Ashrafi Mahdi , Keyhani Manoutchehr 
Published: October 2019

Abstract
Abstract 4430

Background
Nucleostemin (NS), a novel p53-binding protein has been shown essential for stem and cancer cell proliferation and implicated in oncogenesis. Nucleostemin expression had been shown in gastric cancer (SGC-7901) cells, human hepatocarcinoma (HepG2) cells, human cervical cancer (Hela) cells, human osteosarcoma (OS-732) cells.

Aim
This work designed to study the NS gene expression in bone marrow cells in acute promyelocytic leukemia (APL) patients and in normal bone marrow specimens.

Materials &Methods
We examined NS gene expression by Quantitative Real Time PCR in bone marrow specimens of 15 cases of APL patients, before treatment and in 4 bone marrow specimens of healthy donors of bone marrow transplantation. In the same samples of bone marrow aspiration morphology of smears was evaluated. Diagnosis of APL was based on morphology and positive PML/RARA in PCR. RT-PCR used to amplify the NS mRNA, and the GAPDH primer sets used for normalizing. For comparison of NS gene expreesion in 2 groups Mann-Whitney U test was used.

Results
15 patients enrolled in this study, 11(73%) newly diagnosed APL and 4(27%) relapsed cases. Mean age of patients was 28.67±9.56 year. NS gene expressed in all bone marrow samples of APL patients. NS gene expressed in normal bone marrow specimens too. NS gene expression in bone marrow of APL patients was significantly higher than normal bone marrows(p value =0.002) Fig 1. There was no significant difference in NS gene expression between newly diagnosed and relapsed APL cases.

Discussion
According to the results of this study it seems that NS gene expressed in normal marrow. NS expression in adult bone marrow hematopoietic stem cells had been reported in previous reports and it had been shown that NS does not express in granulocytes and B lymphocytes. It seems that stem cells and proliferating cells in the normal marrow are the source of NS expression detected in normal marrow. NS expreesion in bone marrow of APL patients was significantly higher than normal marrow. In these patients before treatment marrow is replaced by undifferentiated blasts and promyelocytes. We concluded that NS expression in these cells were high. It had been shown that NS down regulation may lead to cell cycle exit. High expression of NS in APL patients can be used in future researches for finding new targeted therapies in this disease.

Disclosures:
No relevant conflicts of interest to declare.
An Essential Role of the RNA Editing Enzyme ADAR1 in T Cell Development.
Authors: XuFeng Richard , Yang Qiong , Yuan Youzhong , Lu Binfeng , Cheng Tao , Wang Qingde 
Published: October 2019

Abstract
Abstract 917
Post-transcriptional regulation such as RNA editing in hematopoiesis and lymphopoiesis is poorly understood. ADAR1 (adenosine deaminase acting on RNA-1) is a RNA editing enzyme essential for embryonic development. Disruption of the ADAR1 gene was shown to cause defective embryonic hematopoiesis (Wang Q et al, Science 2000). Moreover, we have recently obtained direct evidence for the preferential effect of ADAR1 deletion on adult hematopoietic progenitor cells as opposed to the more primitive cells via a RNA-editing dependent mechanism by different conditional gene deletion strategies (Xufeng R et al PNAS 2009, in press). To further determine the role of ADAR1 in T cell development, we generated a mouse model in which ADAR1 was deleted specifically in T lymphocytes by interbreeding ADAR1lox/lox mice with Lck-Cre transgenic mice. In our current study, we report that ADAR1 is essential for T cell differentiation at the late progenitor stage in the thymus, coincident with T cell receptor-α/β expression. In ADAR1lox/loxLck-Cre mice, mature T cells decreased dramatically in peripheral blood, spleen and lymph nodes in comparison to littermate controls. In the thymus, the production of CD4+/CD8+ double positive cells was severely impaired and massive cell death was observed in pre-T cell populations. Within the pro-T cells, ADAR1 deletion resulted in a significant decrease of late progenitor cells but not early progenitor subsets. In both pro-T and pre-T cell stages, defective T cell development preferentially occurred in the beta chain positive cells, but was not apparent in gamma/delta T cells. Our data demonstrated an indispensable role of ADAR1 in early T cell differentiation that correlated with T cell receptor beta chain expression, thereby indicating that RNA editing by ADAR1 is an essential event in T cell development.

Disclosures:
No relevant conflicts of interest to declare.