bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconstituted Bay 81-8973 Factor VIII Stability Supports Its Suitability for Continuous Infusion for up to 24 Hours
Authors: Teare John M. , Trefethen Jared , Garger Stephen , Mathew Prasad 
Published: October 2019

Abstract
Continuous infusion (CI) is used in many treatment centers as an option at the time when patients with hemophilia A undergo major surgical procedures. Benefits of CI versus bolus infusion (BI) of factor VIII (FVIII) in patients undergoing surgery include avoiding unnecessarily high peaks and low troughs of FVIII levels and reducing FVIII consumption during and after surgery, partially due to decreased clearance. Stability and long-term potency of FVIII products under CI conditions have been shown to exhibit variability. Thus, it is important to demonstrate stability for each product used in CI applications.
BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA) is an unmodified, full-length recombinant human FVIII product with a primary amino acid sequence identical to that of sucrose-formulated recombinant FVIII (rFVIII-FS; Kogenate® FS, Bayer). rFVIII-FS was shown previously to be stable in solution for up to 7 days, to be safe and effective for CI during surgery, and to be suitable for pediatric and adult patients. The present study investigated whether BAY 81-8973 has adequate potency and purity up to 24 hours after reconstitution, which may indicate suitability for CI applications.
BAY 81-8973 drug product in 250-IU and 500-IU vial sizes was tested 0, 4, 8, 12, and 24 hours after reconstitution with sterile water for injection and storage at room temperature in 30-mL polypropylene syringes (BD Plastipak™, BD, Franklin Lakes, NJ). The drug product was tested for potency (chromogenic assay), purity (high performance liquid chromatography - size exclusion chromatography [HPLC-SEC]), total protein content, pH, solution clarity, and subvisible particulates (high accuracy liquid particle counting - subvisible particles [HIAC-SVP]).
There were no changes in potency, pH, clarity, aggregation, chain dissociation, subvisible particles, or total protein with either 250- or 500-IU BAY 81-8973 for up to 24 hours. Results were also consistent with the demonstrated safety and efficacy of rFVIII-FS for CI during surgery. These data indicate that BAY 81-8973 may be suitable for CI applications for up to 24 hours.

Disclosures
Teare: Bayer: Employment. Trefethen:Bayer: Employment. Garger:Bayer: Employment. Mathew:Bayer: Employment.
Phosphatidylinositol-3,4-Bisphosphate-Akt Signaling Pathway Promotes Platelet Activation
Authors: Marjanovic Jasna , Rumancik Brad , Weber Luke , Wangmang Felix , Fickes Dane , Postnov Dmitri , Nguyen Dung , Lee Yoon , Ngo-Lam Richard , Wilson Monita 
Published: October 2019

Abstract
Phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) is a messenger that accumulates in platelets in a phosphoinositide 3-kinase and platelet aggregation-dependent manner. PtdIns(3,4)P2 is broken down by inositol polyphosphate 4-phosphatases, type I (INPP4A) and type II (INPP4B). These enzymes do not catalyze hydrolysis of phosphoinositides other than PtdIns(3,4)P2, and therefore provide unique means for studying the role of this lipid in platelet activation. We have found that the dominant isoform of 4-phosphatases expressed in platelets is INPP4A and we have generated radiation chimera mice with the deficiency in INPP4A restricted to hematopoietic cell lineage. Compared to wild type platelets, agonist-stimulated INPP4A-deficient platelets accumulated higher levels of PtdIns(3,4)P2. An increase in platelet aggregation in INPP4A-deficient platelets was observed with all tested agonists. To study platelet function in vivo, we performed carotid artery injury mouse thrombosis model experiments. Time to occlusion was dramatically reduced in mice with INPP4A deficiency. These data support the hypothesis that by regulating PtdIns(3,4)P2 levels, INPP4A downregulates platelet aggregation and thrombus formation. To investigate mechanisms mediating INPP4A-dependent signals, we compared levels of phosphorylated Akt and phosphorylated glycogen synthase kinase (GSK) in wild type and INPP4A-deficient platelets in response to agonist stimulation. An increase in phospho-Akt levels was observed in INPP4A-deficient platelets, suggesting that in addition to its well-characterized regulator, PtdIns(3,4,5)P3, PtdIns(3,4)P2 can promote Akt activation. Interestingly, this was not accompanied by a significant increase in phospho-GSK levels, suggesting a possible novel mechanism involved in platelet aggregation.

Disclosures
No relevant conflicts of interest to declare.
A Novel Recombinant Eklf-GATA1 Fusion Protein Reduces Sickling of Cultured Mouse Erythrocytes
Authors: Zhu Jianqiong , Li Hongzhen , Aerbajinai Wulin , Kumkhaek Chutima , Chin Kyung , Rodgers Griffin 
Published: October 2019

Abstract
β-hemoglobinopathies are inherited disorders caused by mutations/deletions in the β-globin chain that lead to structurally defective β-globin chains or reduced (or absent) β-globin chain production. These diseases affect multiple organs and are associated with considerable morbidity and mortality, representing a major public health challenge. Current gene therapy approaches for the treatment of hemoglobinopathies involve viral transduction of hematopoietic stem cells with antisickling globin genes. Hemoglobin A2 (HA2, α2δ2), expressed at a low level due to the lack of Eklf binding motif in its promoter region, is fully functional and could be a valid anti-sickling agent in sickle cell disease, as well as a substitute of hemoglobin A in β-thalassemia. We had previously demonstrated that two Eklf-GATA1 fusion proteins could significantly activate δ-globin expression in human CD34+ cells. Here we report the effects of Eklf-GATA1 on hemoglobin expression and phenotypic correction using erythrocytes cultured from mouse hematopoietic progenitor cells with sickle cell disease. We found that enforced expression of Eklf-GATA1 fusion protein enhanced globin gene expression in the erythrocytesas compared with vector control. The long-form Eklf-GATA1 up-regulated β-globin gene expression 1.8-fold, δ-globin gene expression 3.3-fold, and γ-globin gene expression 1.7-fold. The medium-form EKLF-GATA1 up-regulated δ-globin gene expression 2.6-fold and γ-globin 1.3-fold, but had no significant effect on β-globin gene expression. HPLC revealed a percentage of HA2 was increased from 2.1 % in vector-transduced cells to 8.9% in medium-form Eklf-GATA-transduced-cells (p<0.01) and 6.3% in long-form Eklf-GATA-transduced-cells (p<0.01). Upon deoxygenation, the percentage of sickling erythrocyte was lower to 30.6% in medium-form Eklf-GATA-transduced cells as compared with 40.7% in vector-transduced-cells (p<0.05). Flow cytometry analyses of CD71/GPA and thiazole orange staining indicated that erythroid cell differentiation and enucleation were not affected by Eklf-GATA1. ChIP-sequencing analysis has demonstrated that Eklf-GATA1 fusion proteins and GATA1 having a similar protein-DNA binding pattern at a global level. Our results have found that the long form Eklf-GATA1 fusion protein has a major effect on δ-globin induction than β-globin; the medium form Eklf-GATA1 is able to elevate δ-globin expression without having an effect on β-globin expression. The above findings indicate that these fusion constructs could be a valuable genetic therapeutic tool for hemoglobinopathies, and warrant further preclinical study and evaluation.

Disclosures
No relevant conflicts of interest to declare.
Tigit Expression Defines a Subset of Activated Treg Cells with Prognostic Relevance in Follicular Lymphoma
Authors: Yang Zhi-Zhang , Kim Hyo Jin , Jalali Shahrzad , Wu Hongyan , Price-Troska Tammy , Ansell Stephen M. 
Published: October 2019

Abstract
T cell Ig and ITIM domain (TIGIT) is an immune checkpoint molecule that is expressed on a variety of cell types including NK cells, effector and memory T cells, and Treg cells. Upon ligation with CD155, TIGIT delivers an inhibitory signal and negatively regulates anti-tumor responses. While important in normal T-cell biology, the pathological significance of TIGIT expression and function in the tumor microenvironment of the patients with follicular lymphoma (FL) is largely unknown. The present study sought to phenotypically and functionally characterize TIGIT+ T cell subsets in FL. While its expression is not detected on resting T cells in peripheral blood, we found that TIGIT is highly expressed on intratumoral T cells from FL. Treatment with cytokines such as IL-4 and TGF-β downregulated TIGIT expression on T cells. We found that TIGIT is predominantly expressed on effector memory T cells (TEM) with an activation/exhausted phenotype, and TIGIT+ T cells have higher expression levels of CD69 and PD-1 when compared to TIGIT- T cells. Functionally, TIGIT+ T cells displayed reduced capacity of cell proliferation and cytokine production (IFN-γ and IL-2). Using mass cytometry (CyTOF), we observed that TIGIT is abundantly expressed on some intratumoral Treg (CD4+CD25+Foxp3+) cells, while other Treg cells lack TIGIT expression in FL, forming two subsets of Treg cells: CD4+CD25+TIGIT+ and CD4+CD25+TIGIT-. These two subsets are phenotypically distinct in that CD25+TIGIT+ cells exhibited increased expression of activation/costimulatory markers such as CD69, CD27 and CD28 compared to CD25+TIGIT-, suggesting an activated Treg subset of CD25+TIGIT+ cells. This CD25+TIGIT+ subset had increased suppressive function and could more effectively inhibit activation and proliferation of CD8+ T cells than CD25+TIGIT- cells. Furthermore, we found that lymphoma B cells promoted the development of TIGIT-expressing T cells as TGF-β-mediated downregulation of TIGIT on T cells was inhibited when CD19+ lymphoma cells were present. Using a cohort of 31 FL patients, we found that intratumoral TIGIT-expressing T cells were associated with a favorable prognosis. Patients with TIGIT+ T cell numbers greater than 50% had better overall survival than patients with TIGIT+ T cell numbers less than 50%. Taken together, our results reveal a role of TIGIT in defining Treg cell subsets with different immune function and TIGIT expression may be useful in predicting patient outcome in FL.

Disclosures
Ansell: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding.
Effect of Metabolic Reprogramming on the Biological Activity of Acute Myeloid Leukemia Cells
Authors: Liu Tongyuan , Li Dengju , Zhou Jianfeng 
Published: October 2019

Abstract
ABSTRACT
Metabolic reprogramming of acute myeloid leukemia (AML) cell lines has been described as a compensatory adaptation to fulfill their energy requirements for its rapid proliferation. In this study,we examined the role of the glutamine (Gln) removal or inhibition of glutaminase by GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol- 2-yl) ethyl sulfide(BPTES) in AML cell lines SKM-1 to Observe whether it has an effect on the biological activity of SKM-1 cells. Our results indicated that inhibit glutamine uptake or utilization can inhibit cell growth and induce apoptosis in AML. we used Long non-coding RNAs (LncRNAs) Gene Microarray to analyze gene expression after Gln deprivation treatment. We found that the expression of MT2A, MT1X, MT3, MT1H, MT1F and MT1E in the metallothionein (MT) gene family was significantly upregulated and the expression of AGT、CSF1R、PAK7、MYCN、ARG1 was significantly downregulated . We further analysed the expression of MT isogenes by quantitative real-time PCR (RT-PCR). The results showed that the gene expression of the MT gene family was upregulated, consistent with the results of the Gene Microarray. These findings indicate that metallothionein may play an important role in the glutamine metabolic pathway of AML cells. metformin, a commonly used antidiabetic drug, play an important role in Glucose Metabolism.We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in SKM-1 cell lines and its anti-leukemic activity was enhanced when used in combination with Gln deprivation or Cytarabine. These findings show that Gln deprivation or Metformin enhance the sensitivity of SKM-1 cell line to chemotherapeutic agents. Taken together , targeting amino acid metabolism and glucose metabolism are promising new therapeutic strategies to enhance the efficacy of chemotherapeutic agents in AML.
Conflict of interest
No relevant conflicts of interest to declare.
Acknowledgments:
Tongyuan Liu analyzed the data, plotted the tables and figures and wrote the paper; Dengju Li designed projects and revised the paper. This work was supported by the National Natural Science Foundation of China (Grant no. 81770168).

Disclosures
No relevant conflicts of interest to declare.
Nonbiological Factors Affecting Outcomes in Adolescent and Young Adults with Lymphoma
Authors: Xavier Ana C. , Costa Luciano J 
Published: October 2019

Abstract
Background: Lymphoma is one of the most common cancers in adolescent and young adults (AYA). Although histology, stage, age, and gender are known to affect outcome, little is known about nonbiological factors (NBF) that may affect access to care on survival.
Objectives: To determine the impact of NBF in the survival of AYA with classical Hodgkin lymphoma (cHL) or non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), lymphoblastic lymphoma (LL), and anaplastic large cell lymphoma (ALCL).
Design/Methods: The impact of NBF (insurance status, median household income, and educational achievement in the county of residence) along with biological factors (histology, stage, gender, age, and race/ethnicity) on survival of AYA lymphoma patients was analyzed using a SEER-18 (Surveillance, Epidemiology, and End Results) cohort diagnosed between 2007 and 2014.
Results: There were 8,173 cases of cHL and 4,973 cases of NHL with a median follow-up of 44 months and 32 months, respectively. Five-year overall survival (OS) for AYA patients with localized cHL according to insurance status was 98% vs. 91% vs. 92% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). The 5-year OS for advanced stage cHL was 91.5% vs. 85% vs. 85% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). In multivariate analysis, the increase risk of death was associated with Medicaid (HR 2.23, 95% C.I. 1.76-2.81), and uninsured (HR 1.88, 95% C.I. 1.38-2.55), after adjustment for age, gender, histology and stage (P<0.001). Five-year OS for AYA patients with localized NHL according to insurance status was 90% vs. 76.5% vs. 84.5% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). The 5-year OS for advanced stage NHL was 76% vs. 57%, and 62% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). In multivariate analysis, the increased risk of death in AYA NHL was associated with Medicaid (HR 1.95, 95% CI 1.67-2.27), and uninsured (HR 1.48, 95% CI 1.18-1.84) (P<0.001) and county level of income in the second (HR 1.33, 95% C.I. 1.07-2.64), third (HR 1.54, 95% C.I. 1.25-1.90), and forth (HR 1.57, 95% C.I. 1.27-1.93) (P< 0.001) lower quartiles (P<0.001), after adjustment for age, gender, histology, and stage.
Conclusion: Lack of insurance or Medicaid insured status and lower income are associated with increased mortality in AYA lymphomas, indicating an opportunity to increase outcomes by addressing NBF.

Disclosures
Costa: Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria; BMS: Research Funding.
Prognostic Value of Serum Beta-2 Microglobulin during and after Completing Chemotherapy in Marginal Zone Lymphoma
Authors: Yoon Byung Woo , Hong Jung Yong , Yoon Dok Hyun , Lee Kyoung Min , Kim Shin , Park Jung Sun , Park Chan-Sik , Huh Jooryung , Park Chan-jeoung , Jang Seongsoo , Ryu Jin-Sook , Lee Sang Wook , Suh Cheolwon 
Published: October 2019

Abstract
Background Baseline serum beta-2 microglobulin (B2M) has been suggested as a prognostic factor for marginal zone lymphoma (MZL). However, there have been no reports on the prognostic value of sequential serum B2M during and after chemotherapy. Herein, we retrospectively reviewed sequential values of serum B2M: baseline (B2Mb), maximum during chemotherapy (B2Mm), end of chemotherapy (B2Me), and the first increased value after completing chemotherapy (B2Mfi).
Methods Between January 2000, and June 2018, a total of 94 patients with MZL treated with rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) were identified from the database of Asan Medical Center, Seoul, Korea. Respective serum B2Ms less than 2.5 mg/L were considered normal. The cutoff value for differences between serum B2Mb and sequential values of serum B2M were calculated by using the optimal point from the receiver operating characteristic curve.
Results Median age of the study population was 55 year-old (range, 10-83) and 54 (57%) patients were male. Fifteen (16%) patients had nodal MZL, 76 (81%) had extranodal MZL and 3 (3%) had splenic MZL. In univariate analysis, serum B2Mb and B2Mfi above 2.5 mg/L were associated with poor prognosis with a hazard ratio (HR) of 2.3 (95% confidence interval (CI): 1.1-4.9; p=0.024) and a HR of 3.3 (95% CI: 1.6-7.0; p=0.001), respectively. In addition, the difference between serum B2Mb and B2Mfi greater than the optimal cutoff value of 0.6 mg/L (area under curve=0.58) was also associated with poor prognosis, with a HR of 4.0 (95% CI: 1.9-8.3; p<0.001). In multivariate analysis, serum B2Mfi above 2.5 mg/L was the only independent adverse prognostic factor in terms of progression-free survival (PFS) with a HR of 4.0 (95% CI: 1.2-14.1; p=0.023). The median time of serum B2Mfi measurement was 5.6 months from the end of chemotherapy (range, 0.5-25.1 months).
Conclusion To the best of our knowledge, this is the first report of measuring sequential serum B2M, starting from baseline to its first rise after completing chemotherapy in MZL. In MZL patients treated with R-CVP, the first increased serum B2M above 2.5 mg/L after completing chemotherapy is a powerful prognostic factor for PFS.

Disclosures
No relevant conflicts of interest to declare.
Pediatric Langerhans Cell Histiocytosis (LCH) Clinical Outcome in Hospital Civil De Guadalajara, México
Authors: Rojas Rodríguez Katterine , Soto Veronica , Rodriguez-Galindo Carlos , Friedrich Paola M. , Guzmán Edwin , Sanchez Fernado , Gonzalez-Ramella Oscar 
Published: October 2019

Abstract
Pediatric Langerhans cell histiocytosis (LCH) clinical outcome in Hospital Civil de Guadalajara, México.
Introduction : LCH results from clonal proliferation of functionally and immunophenotyped inmature round Langerhans cells along with eosinophiles, machrophages, lymphocytes and ocasionally multinucleated giant cells (1). Its incidence is 2-10 cases by million of children below 15 yr in US (2). Our objective was to describe the clinical characteristics and treatment outcome of patients with LCH at Departement of Hematology-Oncology of Hospital Civil de Guadalajara México.
Methods: It was a retrospective design and 41 pediatric patients below 18 yr were included. The diagnosis was corroborated by pathology and immunohistochemistry. Variables as age, gender, localised vs systemic disease, risk organ commitment, global survival (GS) and event free survival (EFS) were analysed. We used descriptive and inferencial statistics with SPSS program.
Results: There were included 41 patients from January 1st 2012 to December 31st 2017. Relation male:female was 1.1:1. Mean presentation was localised disease (58%). Bone was the principal affected structure (34%) and it was 71% to be combined with lung, lymph node and CNS compromise. Risk organ commitment was presented in 32%, being more frecquent bone marrow and liver in 22% each one. Time induction treatment was equal or below 12 weeks in 66% of patients. The 25% of patients had reactivation of LCH, with similar lesions to the beggining in 19.5%. We found statistically significant differences between dead patients (DP) (14.6%) and not dead patients (NDP) (85.4%) in clinical presentation: localised (0% in DP vs 69% in NDP) and systemic disease (100% vs 31%) (p=0,003) and risk organ commitment (100% in DP vs 20% in NDP) (p=0,000). Median age of 13 vs 24 months was for DP and NDP respectively.
Conclusion: Dead patients were younger than 13 months old, with systemic disease, and risk organ commitment. We found a later asking of medical advice in DP (6 months) vs NDP (2 months).
Keys words: langerhans cell histiocytosis, multisystem disease, risk organ
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Can Childhood Hodgkin International Prognostic Score Mitigate Interim Positron Emission Tomography and Predict Survival of Children with Hodgkin Lymphoma in Resource Limited Countries?
Authors: Khedr Reham , Mahfouz Sally , Fathy Hoda , Shalaby Lobna 
Published: October 2019

Abstract
Background & aim: Although 'interim' positron emission tomography (PET) may inform therapeutic decisions, Risk stratification at diagnosis allow earlier and potentially better modification during the treatment of HL. In this study, we aimed to identify the prognostic role of both the IPET and the CHIPS in predicting the prognosis of HL in our center. Patients and methods: This is a retrospective, single-center study done at the National Cancer Institute (NCI) Cairo University starting January 2011 to the end of December 2015. A total of 140 patients with newly diagnosed Hodgkin lymphoma were enrolled for analysis of all clinical, pathological and Laboratory Data. Only 83 patients were eligible for analysis of both IPET and CHIPS scoring. PET scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. Childhood Hodgkin International Prognostic Score (CHIPS), was evaluated. Log-rank testing was used to compare EFS for each CHIPS (0-3). Results: Eight three scans out of 140 patients were eligible for analysis of both IPET and CHIPS scoring. Twenty-six patients were scored positive (31.3%) and 57 (68.7%) as negative. The 5- years overall survival (OS) was 94%, 83% for patients with interim positive scans and 97% for patients with interim negative scans (P 0.01). The 5-year Event-free survival (EFS) rate was 86.7% for the whole study population, 76% for patients with interim positive scans and 91% for patients with interim negative scans (P 0.04). The 5 year OS was 100% for patients with CHIPS = 0, 80.4% for patients with CHIPS = 1, 75% for patients with CHIPS = 2, and 100% for patients with CHIPS = 3 (a very limited number of patients), with a p-value of (0.055). Hemoglobin level </= 10) and initial Total Leucocytic count(</= 15,000) were independent prognostic predictors; OS P- value (0.003 and <0.001 ) respectively- and EFS P- value (0.03 and <0.001 ) respectively. Conclusion: The prognostic role and validity of using the interim PET scan response have been confirmed to be strongly related to treatment outcome by the present study; however, the use of CHIPS is a good inexpensive approach to predicting risk in patients with HL that may improve ability to tailor therapy to risk factors known at diagnosis. Other Variables including TLC as well as Hb level will need further larger studies to identify their impact.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.