bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a Non-Invasive Hemoglobin Estimation in Patients with Sickle Cell Disease
Authors: Al-Khabori Murtadha K. , Al-Hashim Abdulhakeem , Jabeen Zeba , Farsi Khalil Al , Al-Huneini Mohammed , Al-Riyami Arwa Z. , Al-Kemyani Nasser , Daar Shahina 
Published: October 2019

Abstract
Abstract 4770

Introduction:
The care of patients with Sickle Cell Disease (SCD) is frequently complicated by difficult venous access complicating blood sampling for laboratory investigations including hemoglobin (Hb) measurement. Non-invasive hemoglobin concentration monitoring is a potential solution, albeit not validated yet in patients with SCD. The primary objective of this study was to validate non-invasive pulse CO-oximetry based hemoglobin estimation in this patient population.

Methods:
We conducted a prospective observational study on patients with SCD admitted to the inpatient wards over 4 weeks in a tertiary care hospital. We estimated a spot Hemoglobin (Sp Hb) measurement using Masimo Pronto-7 Pulse CO-oximetry device (two measurements per patient) and compared it to a venous sample Hb (Reference Hemoglobin; Ref Hb) measured using Abbott CELL-DYN Sapphire hematology analyzer. We calculated Pearson correlation coefficient and coefficient of determination (R2). The multivariable linear regression model of predicting the estimation differences included age, gender, weight, height, blood pressure and reference hemoglobin.

Results:
We enrolled 98 patients (45 males, 53 females) with a mean age of 26 years (SD 8.8; 14–75) and a mean Ref Hb of 9.2 g/dL (SD 1.5; 5.3–13). The mean Sp Hb was 10.1 g/dL (SD 2.0; 5.3–14.5). The correlation coefficient between the Sp Hb and Ref Hb was 0.54 (R2 = 29%) with a mean difference of 0.9 g/dL (SD 1.7; −4.8 to 4.5). In the multivariable model, gender (p =0.042) and Ref Hb level (p=0.001) were statistically significant predictors for the difference in measurement. A strong correlation between the two CO-oximetry Hb measurements was obtained (correlation coefficient = 0.81, R2 = 65%).

Conclusions:
Our study demonstrated the validity of the CO-oximetry Hb measurement in adult patients with SCD. Larger prospective studies are needed to confirm our results.

Disclosures:
No relevant conflicts of interest to declare.
Study On the Expression of 14-3-3ζ in Acute Myeloid Leukemic Cell Lines
Authors: Liang Rong , Xiong Hua , Wang Zhe , Chen Qun xie , Gao Xun guang , Dong Xia bao , Zhang Liang 
Published: October 2019

Abstract
Abstract 4820

Objectives:
It is known that one of main reasons of refractory and relapsed acute myeloid leukemia (AML) is multidrug resistant (MDR). Despite it was showed that 14-3-3ζ was over- expressed in HL-60/VCR MDR cells than in HL-60 sensitive AML cells by examining the difference of gene expression profile with Affymetrix GeneChip Human Genome U133 set A. Yet, the understanding on role of 14-3-3ζ in the survival of AML cells remains poor.

Methods:
Semi-quantitative RT-PCR method was used to examine the expression of mdr1 mRNA in AML cell lines to validate the results of microarray. Western blot was performed to investigate Pgp#x2610;A14-3-3ζ#x2610;ABCL-2#x2610;AMCL-1 proteins expression. Immunofluorescence assay was used to detect the subcellular location of 14-3-3ζ protein in HL-60 and HL-60/VCR cells by laser scanning confocal microscope. 14-3-3ζ knockdown cells were obstained by transduction with lentivirus-mediated shRNA to silence 14-3-3ζ in AML cell lines. MTT and cell count method were used to analyze the changes of growth of AML cells.

Results:
mdr1 mRNA and Pgp was not expressed in HL-60 cells, but significantly overexpressed in HL-60/VCR cells(P<0.01). Except 14-3-3σ, the expression of other subtypes of 14-3-3 was higher in HL-60/VCR cells than in HL-60 cells, especially 14-3-3ζ(P<0.01). The higher increased expression of 14-3-3ζ, BCL-2, MCL-1 protein was observed in HL-60/VCR cells than in HL-60 cells. These results were same as gene chip. It was also noticed that14-3-3ζ was located in the cytoplasma and nuclear of AML cell lines, especially over-expressed in HL-60/VCR cells(P<0.05). Furthermore, suppression of14-3-3ζ by RNA interference resulted in inhibition of the proliferation of AML cells with BCL-2 and MCL-1 decreased protein expression, especially in HL-60/VCR cells(P<0.01).

Conclusion:
It was implied that14-3-3ζ played an important role in AML MDR and was associated with BCL-2 and MCL-1 expression. These results suggested that development of therapy targeting 14-3-3ζ may provide novel, effective strategies for refractory and relapsed AML.

Disclosures:
No relevant conflicts of interest to declare.
MiR-146a Expression Level As a Molecular Marker in Acute Promyleocytic Leukemia
Authors: Zhong Hua , Wang Chun , Fangyuan Chen , Xu Lan , Zhong Jihua , Jiong HU 
Published: October 2019

Abstract
Abstract 4821
MiR-146a which is located on chromosomes 5 may be involved in normal hemtopoisis and the pathogenesis of several hematopoietic diseases through inhibiting the expression of its targets. Acute promyelocytic leukemia (APL) cell line NB4 was taken as research model to find out whether miR-146a expression was associated to cell differentiation and proliferation. The miR-146a expression level of NB4 cells decreased after ATRA treatment, meanwhile the expression level of its predicted target gene Smad4 increased simultaneously.
MiR-146a expression plasmid, no related negative control sequence plasmid and recombined luciferase reporter gene vector containing the miR-146a complementary combined site on Smad4 plasmid were constructed by DNA recombination technical. Both recombined plasmids were transiently co-transfected into 293T cells with control plasmid pRL-TK. The interaction between miR-146a and its predicted target gene Smad4 was confirmed by the relative activities of dual luciferase detection.
This interaction relationship was further confirmed by liposome entrapment transfection of miR-146a and its antisense molecular in NB4 cells. The expression level of miR-146a in NB4 cells did no influence on Smad4 gene expression but Smad4 protein expression levels (fig 1).
The changes of NB4 cells on biological behaviors were observed by cell morphology, proliferation curve and flow cytometry methods under different miR-146a expression status. The results showed that cell proliferation ratio decreased and cell apoptosis ratio increased after miR-146a expression suppression in NB4 cells.
The investigation of miR-146a expression levels in mononuclear cells of APL patients' bone marrow and clinical data were carried out. It was showed that the expression levels of miR-146a were higher in APL patients than normal controls. The expression level of miR-146a was positive correlated with peripheral blood white cell count (fig 2). MiR-146a expression level was negative correlated with Th/Ts ratio among these patients (fig 3).
MiR-146a/Smad4 signal pathway is expressed in acute promyelocytic leukemia. The proliferation and apoptosis of the cells are modified by the Smad4 protein expression regulated by miR-146a expression. MiR-146a expression is somewhat associated with acknowledged clinical prognosis factors. It has potential possibility to take miR-146a as prognosis factor.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy and Safety of Linezolid in Immunocompromised Patients with Hematological Malignancy
Authors: Qian Shenxian , Song Hua , Zhang Xuejin , Zhang Xuejin , Zhang Xiaohong , Luo Wenji , Luo Wenji , Huang Qian 
Published: October 2019

Abstract
Abstract 4838

BACKGROUND:
The aim of this study was to determine the safety, tolerance and efficacy of linezolid for the treatment of infections from Gram-positive bacteria in immunocompromised patients with Hematological Malignancy.

METHODS:
This was a prospective non-comparative unblinded and multi-center study in the Hematology Unit over a one-year period, administering combined use of linezolid in patients with Hematological Malignancy.

RESULTS:
Fifth-four adult patients received linezolid (600 mg, iv, q12h per day). Thirty-four children received linezolid (30 mg/kgr: 3 i.v. per day).Mean duration of linezolid administration was 12.8 days (range, 10–23days). Among the evaluable patients, fifty four were adults, the median age was 67(range, 30–101years); thirty four were children (range, 11 months-12.6 years), while the median age was 6 years. Primary diagnosis was acute lymphoblastic leukemia (forty-five patients), lymphoma (twenty-three patients), multiple myeloma (eleven patients), Aplastic anemia(four patients), myelodysplasia syndrome(one patients), leucopenia and hemophagocytic syndrome (two patient each). All patients were immunocompromised, 90% of them in the midst of chemotherapy cycles. The mean base number of platelet was 41×109/L(range, 30 – 138×109/L), platelet count less than 30×109/L patients were 28 cases (33%), among them, less than 10×109/L were 13 cases (14.8%). 27 out of 88 patients had positive blood cultures, methicillin-resistant Staphylococcus aureus, eighteen patients; Enterococcus, seven patients; Methicillin Resistant Staphylococcus Epidermidis and hemolytic streptococcus (one patient each).All patients were considered clinically cured after the end of the linezolid regimen (100% efficacy). The main adverse events were thrombocytopenia. There were 11 cases happened transient thrombocytopenia, Among them, four cases were happened within 4 days, seven cases happened four to seven days after received linezolid. Eliminate the possibility caused by reasons such as severe infection which can also result in thrombocytopenia, Linezolid related thrombocytopenia were only two cases (2.3%). Chemotherapy-induced myelotoxicity (90% patients) was not worsened during linezolid therapy. The platelet recovery time was also not lengthened during linezolid therapy. No bleeding episodes were presented, no Self-limited diarrhea were happened. The total adverse event rate was 2.3%; however, there was no premature cessation of linezolid in any patient.

CONCLUSIONS:
Linezolid may be another effective and safe therapy to treat infections from resistant Gram-positive bacteria in immunocompromised patients, even in children.

Disclosures:
No relevant conflicts of interest to declare.
Brain Lymphoma Treatment with Chemotherapy or Chemoradiotherapy from an Institution
Authors: Jalaeikhoo Hassan , Shafaeean Bahman , Keyhani Manoutchehr 
Published: October 2019

Abstract
Abstract 4859

Background:
Primary Brain Lymphoma (PBL) is an aggressive malignancy arising from the brain parenchyma. It is potentially curable brain tumor, or at least one in which durable remission can be achieved. We examined survival among patients with PBL treated with combination chemotherapy and radiotherapy and/or chemotherapy alone.

Methods:
We conducted a retrospective study of 38 patient diagnosed with PBL and examined long-term survival and morbidity among patients treated with either combination chemotherapy and radiotherapy or chemotherapy alone between July 1, 2004 to July 1, 2012. Patients were eligible for the study if they were between 16 and 80 years of age, HIV negative and had positive pathology and immune- histochemical staining for non Hodgkin's lymphoma of the brain. All patients had CT scan of chest, abdomen and pelvic, total body bone scan and bone marrow aspiration as part of their initial work up.
Enrolled patients were treated with combination of chemotherapy and radiotherapy if they were younger than 60 and with chemotherapy only if they were older than 60 years to reduce cognitive complications related to radiotherapy in older adults. The chemotherapy regimen included Methotrexate 2500 mgs per M2 with Leucovorin rescue (started day two) and Vincristine 1.4 mg per m2 (day two) which was administered every other week for 6 weeks. Chemotherapy in younger patients (<60) was followed by daily radiotherapy for 3 weeks to a total of 4500 rads. Both groups received Cytarabine 3000 mgs per m2 for 2 successive days (3 weeks apart). Intrathecal injection of Methotrexate 15 to 20 mg plus Cytarabine 100 mg were given in all patients in whom spinal fluid was drown on suspicion of meningeal involvement.

Result:
Among the 38 patients 77 % had diffuse large B cell lymphoma and 56% presented with multiple lesions and 44% with a single lesion on MRI. The median age at diagnosis was 53 years (range19 to 75). Two thirds (65.7%) were men. Mean duration of follow-up was 12 months (range 1 to 100 months). Overall (21%) of all patients died from early relapse, 2 patients had disease outside of brain found after relapse one in the liver and another one in mediastinum. The vast majority of deaths were among patients younger than 60 (87.5%). Significant morbidity included memory loss, hemi paresis, blindness, abnormal gate, psychiatric problems and incontinence which persisted or developed in 30% of patients. Among all patients 50% are alive and without significant morbidity. Disease recurrence was noted in 30% of all patients. Relapsed patients have been treated indefinitely with high dose Methotrexate.

Discussion:
Current management of PBL either with chemotherapy alone and/ or combination chemotherapy and radiotherapy has improved long-term survival in these patients. The most troublesome complication of treatment has been memory loss.

Disclosures:
No relevant conflicts of interest to declare.
Hepatosplenic T Cell Lymphoma Mimicking Hemophagocytic Lymphomhistiocytosis: A Case Report
Authors: Ahn Inhye E , Rice Lawrence 
Published: October 2019

Abstract
Abstract 4864

Background.
Hepatosplenic T cell lymphoma (HSTCL) is rare and aggressive extranodal lymphoma characteristically involves young males in third or fourth decade of life. It frequently manifests as pancytopenia with severe thrombocytopenia, hepatosplenomegaly, and much rarely, hemophagocytic lymphohistiocytosis (HLH).

Methods.
Medical records of a patient who presented with HLH as a presenting signs of HSTCL were reviewed. Literature search was performed to identify characteristic demographics and natural course of HSTCL reported to date.

Results.
A 30-year-old male presented after 6 months of constitutional symptoms. Remarkable findings were pancytopenia, mildly elevated LFT, and high ferritin level (89,000). Extensive work up for autoimmune and infectious etiology was negative. Worsening anemia and thrombocytopenia prompted the third bone marrow biopsy, which revealed the first evidence of hemophagocytosis. Despite of Cyclosporine A and Etoposide, pancytopenia worsened which prompted splenectomy and core needle liver biopsy. Sinusoids of spleen and liver were densely infiltrated with atypical lymphocytes consistent with T cell phenotype. Diagnosis of HSTCL was confirmed after PCR detection of gamma delta T cell receptor rearrangement. Previous bone marrow biopsies were retrospectively reviewed, which revealed small clusters of cells staining positive for CD3. The patient underwent three courses of chemotherapy that included high-dose Cytarabine, Etoposide and adriamycin. Post-chemotherapy course was complicated with disseminated Candidiasis complicated with mycortic aneurysm and worsening pancytopenia. The patient expired due to overwhelming septic shock 6 months after the pathologic diagnoses of HSTCL.

Conclusion.
HSTCL causes aberrant expansion of gamma delta T cells and defective innate immunity, and is an important secondary etiology for HLH. Splenectomy has diagnostic significance but little therapeutic benefit. Longer survival was reported in patients who underwent cytarabine-based chemotherapy; however median survivals in anecdotal case series all fall within 2 years regardless of regimen.

Disclosures:
No relevant conflicts of interest to declare.
ACY-1215, a First-In-Class Selective Inhibitor Of HDAC6, Demonstrates Significant Synergy With Immunomodulatory Drugs (IMiDs) In Preclinical Models Of Multiple Myeloma (MM)
Authors: Quayle Steven N , Jones Simon S 
Published: October 2019

Abstract
Histone deacetylase (HDAC) enzymes represent attractive therapeutic targets in multiple myeloma, but unfortunately non-selective HDAC inhibitors have led to dose-limiting toxicities in patients. ACY-1215 is a first generation, orally available HDAC inhibitor that is 11-fold selective for HDAC6, and synergizes in vitro and in vivo with bortezomib in preclinical models of MM without inducing unfavorable toxicities (Blood, 20[210]: 4061). Ongoing Phase Ib clinical trials with ACY-1215 have thus far confirmed an exceptional safety and tolerability profile (Raje, et al, EHA, 2013).
The IMiD class of drugs, including lenalidomide and pomalidomide, exhibit striking anti-myeloma properties in a variety of MM models, and have demonstrated significant clinical activity in MM patients. Prior studies have shown clinical activity of a combination of the non-selective HDAC inhibitor vorinostat with lenalidomide and dexamethasone in myeloma patients (Richter, et al, ASH, 2011). However, many patients experienced significant toxicities with this regimen that significantly limits its clinical utility. In support of our ongoing clinical development program for ACY-1215 in MM, we show here that combining ACY-1215 with either lenalidomide or pomalidomide leads to synergistic decreases in the viability of MM cells in vitro. The relevance of inhibition of HDAC6 to this synergistic effect was validated by demonstrating synergistic interactions of either IMiD molecule with ACY-775, which is more than 300-fold selective for HDAC6 over class I HDAC’s. Further, the combination of ACY-1215, lenalidomide, and dexamethasone was well tolerated in vivo with no overt evidence of toxicity, and combination efficacy studies with this combination are now ongoing in models of MM. By demonstrating that a selective inhibitor of HDAC6 synergizes with IMiD’s while maintaining an improved safety profile, these results provided a rational basis for the clinical development of the orally available combination of ACY-1215 and lenalidomide plus dexamethasone in an ongoing Phase Ib clinical trial (NCT01583283) for the treatment of MM.

Disclosures:
Quayle: Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership.
Common Gamma Chain Cytokines Contribute To Acute GvHD Via Perforin/Granzyme B-Mediated Cytotoxicity Of CD8 T Cells
Authors: Schwarze Vincent , Hechinger Anne-Kathrin , Leonhardt Franziska , Prinz Gabriele , Schmitt-Gräff Annette , Kovarik Jiri , Zeiser Robert 
Published: October 2019

Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an important treatment option for different hematological malignancies, but also for some nonmalignant hematological disorders such as sickle cell anemia, aplastic anemia or thalassemia(1). In the ladder group the graft-versus-leukemia (GvL) effect mediated by donor T cells is less important and prevention of graft-versus-host disease (GvHD), which occurs in 40-50% of allo-HCT patients, is a major priority. The common gamma chain (CD132) is a cytokine receptor sub-unit that is common to the interleukin (IL) receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Since several of these cytokines were shown to be increased in the serum of patients developing acute GvHD, we reasoned that inhibition of CD132 could have a profound effect on acute GvHD by inhibiting the bioactivity of multiple proinflammatory cytokines.
We observed that anti-CD132 treatment reduced GvHD potently with respect to survival, production of TNF, IFN-γ, IL-6, MCP-1 and GvHD histopathology. Protection was only seen when anti-CD132 was applied in a CD8 T cell-dependent GvHD model while no protection was seen when only CD4 T cells were given. Mechanistically, we could show that CD8 T cells isolated from mice treated with anti-CD132 had reduced levels of Granzyme B and that GvHD induced by Perforin-deficient T cells was resistant towards blockade by anti-CD132 treatment. These data indicated a role of the common gamma chain cytokines for the induction of Perforin/Granzyme B in CD8 T cells during GvHD. Compatible with this notion, exposure of CD8 T cells towards IL-2, IL-7, IL-15 and IL-21 alone or in combination induced increased levels of Granzyme B.
Based on these findings, we concluded that CD8 T cells that are activated by common gamma chain cytokines during GvHD produce then Granzyme B which can be blocked by anti-CD132 treatment. This therapeutic approach has particular clinical potential for patients undergoing allogeneic transplantation for nonmalignant indications, since graft-versus-tumor activity is not required.

Disclosures:
No relevant conflicts of interest to declare.
Inhibition Of S100A6 Induces Graft Versus Leukemia Effects In MLL/AF4-Positive ALL In Human PBMC-SCID Mice
Authors: Tamai Hayato , Yamaguchi Hiroki , Dan Kazuo , Inokuchi Koiti 
Published: October 2019

Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL-AF4-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-a) was reported to contribute to the GVL effect. We reported previously that MLL/AF4-positive ALL shows resistance to TNF-a, which is the main factor in GVL effect, by upregulation of S100A6 expression followed by interference with the p53-caspase 8-caspase 3 pathway in vitro. We examined whether inhibition of S100A6 can induce an effective GVL effect on MLL/AF4-positive ALL in a mouse model. To examine the long-term effects of inhibition of S100A6,MLL/AF4-positive ALL cell lines (SEM) transduced with lentiviral vectors expressing both S100A6 siRNA and luciferase (SEM-Luc-S100A6 siRNA) were produced. SEM-Luc-S100A6 siRNA cells and SEM-Luc-control siRNA cells were injected into groups of five SCID mice (1×107/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8×107 human peripheral blood mononuclear cells (PBMCs). Although there were no significant differences between the serum concentrations of human-TNF-a after injection of human PBMCs of SEM-Luc-S100A6 siRNA injected mice and those of SEM-Luc-control siRNA injected mice (P=0.95), SEM-Luc-S100A6 siRNA-injected mice showed significantly longer survival periods than SEM-Luc-control siRNA-injected mice (P = 0.002). SEM-Luc-S100A6 siRNA-injected mice showed significantly slower tumor growth than those injected with SEM-Luc-control siRNA (P < 0.0001). These results suggested that inhibition of S100A6 may be a promising therapeutic target for MLL/AF4-positive ALL in combination with allo-HSCT because it induce effective GVL effectson MLL/AF4-positive ALL which is resistant to GVL effects.

Disclosures:
No relevant conflicts of interest to declare.