bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymidine Phosphorylase Exerts Complex Effects on Bone Resorption and Formation in Myeloma
Authors: Liu Huan , Liu Zhiqiang , Du Juan , He Jin , Lin Pei , Behrang Amini , Starbuck Michael W , Novane Nora M , Shah Jatin J. , Davis Richard Eric , Hou Jian , Gagel Robert , Yang Jing 
Published: October 2019

Abstract
Thymidine phosphorylase (TP), an enzyme that can reversibly catalyze the conversion of thymidine to thymine and 2-deoxy-D-ribose (2DDR), has been shown to participate in tumor angiogenesis and proliferation. Yet little is known regarding its function in bone. The goal of this study is to elucidate the role and mechanism of myeloma-expressed TP in the activation of osteoclast-mediated bone resorption and the suppression of osteoblast-mediated bone formation. We hypothesized that myeloma-expressed TP plays an important role in the pathogenesis of myeloma bone disease. We observed that TP is highly expressed in myeloma cells but not in normal plasma cells. To examine the role of myeloma-expressed TP in lytic bone lesions, we categorized all tested patient-derived myeloma cells and human myeloma cell lines into two groups: TP-high and TP-low expressing cells. These myeloma cells, as well as human myeloma cells with overexpressed or knocked downed levels of TP, were injected into the implanted human bone chips of SCID-hu mice or the femurs of SCID mice. Analysis of radiography and histomorphometry were used for assessing lytic lesions. Our results showed that injection of TP-high expressing myeloma cells into mice caused more lytic lesions than injection of TP-low cells. To examine its role in osteoclast and osteoblast differentiation, the progenitors were co-cultured with the myeloma cells, and analyzed with staining of TRAP and Alizarin red S. We observed that co-culture with TP-high expressing myeloma cells induced more osteoclast differentiation and less osteoblast formation than those co-cultured with TP-low cells. Mechanistic studies further showed that TP-high expressing myeloma cells secreted more 2DDR than TP-low cells. The secreted 2DDR bound to the integrin aVb3 in osteoclast progenitors, activated the PI3K/Akt signaling, and enhanced DNMT3A expression and methylation of IRF8, leading to increased NFATc1 expression and osteoclast differentiation. The secreted 2DDR could also bind to the integrins aVb3 and a5b1 in osteoblast progenitors, activated the PI3K/Akt signaling, and enhanced DNMT3A expression and methylation of RUNX2 and osterix, leading to decreased osteoblast differentiation. We further examined the patient bone marrow samples, and demonstrated a positive correlation between TP expression in myeloma cells and osteolytic bone lesions in myeloma patients. Thus, our study not only elucidates a novel mechanism of myeloma-induced increased osteoclast-mediated bone resorption and suppressed osteoblast-mediated bone formation, but also implicates a potential therapeutic approach for myeloma bone disease.

Disclosures
No relevant conflicts of interest to declare.
Comparison of Clinical Diagnosis for Hereditary Spherocytosis with Molecular Diagnosis By Multi-Gene Target Sequencing in Korea
Authors: Choi Hyoung Soo , Choi Qute , Kim Jung Ah , Im Kyong Ok , Park Si Nae , Park Yoomi , Kim Ju Han , Shin Hee Young , Kim Seon Young , Kang Hyoung Jin , Kook Hoon , Kim Soo-Jeong , Kim Inho , Kim Ji Yoon , Kim Hawk , Park Kyung Duk , Park Kyung Bae , Park Meerim , Park Sang Kyu , Park Eun Sil , Park Jeong-A , Park Ji Kyoung , Baek Hee Jo , Seo Jeong Ho , Shim Ye Jee , Ahn Hyo Seop , Yoo Keon Hee , Yoon Hoi Soo , Lee Kun Soo , Lee Kwang Chul , Lee Jae Min , Lee Mee Jeong , Lee Sun Ah , Lee Jun Ah , Lee Jae Hee , Lee Ji Won , Won Young-Woong , Lim Young Tak , Jung Hyun Joo , Cheuh Hee Won , Choi Eun Jin , Jung Hye Lim , Lee Dong Soon , the Korean Society of Hematology The Hereditary Hemolytic Anemia Working Party of 
Published: October 2019

Abstract
Background: Hereditary spherocytosis (HS) is the most common cause of hereditary hemolytic anemia. Current tests used to diagnose HS focus on the detection of hemolysis or indirectly assess protein defects. Direct methods to detect protein defects are complicated and difficult to implement. Recent next-generation sequencing (NGS) methods enable large-scale gene mutation analyses to be used for such diagnoses. In this study, we investigated the patterns of genetic variation associated with HS among the patients diagnosed with HS clinically. Specifically, we analyzed mutations in red blood cell membrane protein-encoding genes (17 genes) in context with 5 genes for the differential diagnosis (thalassemia, congenital dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria) in Korean HS.
Methods: In total, 60 patients diagnosed with HS were enrolled in this study. Targeted sequencing of 43 genes (17 membrane protein-encoding genes, 20 enzyme-encoding genes, and 6 additional candidate genes) was performed using the Illumina HiSeq platform and variants were called according to a data-processing pipeline.
Results: Of the 60 patients, 50 (83%) had one or more significant variants in a membrane protein encoding genes. A total of 54 significant variants (8 previously reported and 46 novel) were detected in 6 membrane protein-encoding genes; SPTB, ANK1, SPTA1, SLC4A1, EPB41, and EPB42. The most variants (28/60 patients) were detected in SPTB. Interestingly, concurrent mutations of genes encoding enzymes (ALDOB, GAPDH, and GSR) were detected along with mutations of membrane encoding genes. One patient diagnosed with HS harbored mutation of G6PD without mutation of HS related genes. Additionally, UGT1A1 mutations were present in 5 patients. Positive rate of osmotic fragility test was 86% among patients with HS related gene mutations.
Conclusion: These results clarify the molecular genetic analysis is required for the accurate diagnosis of HS. About 17% of patients who were clinically diagnosed as HS revealed discrepancy with molecular diagnosis.
Figure Figure.

Disclosures
No relevant conflicts of interest to declare.
Outcome of Frontline Treatment with Generic Imatinib in Adult Patients with Chronic Myeloid Leukemia in Algerian Population: A First Multicenter Study
Authors: Entasoltan Badra , Bekadja Mohamed Amine , Bouhass Rachid Amar , Taibi Karima , Touhami Hadj , Mehalhal Nemra , Benlazar Mohamed , Zouaoui Zahia , Benzineb Brahim , Mesli Naima , Talbi Mustapha , Yachekour Toufik , Bachiri Aissa , Nachi Mourad 
Published: October 2019

Abstract

Introduction:
In a developing country like Algeria, such expensive therapy is not available. Alternative approaches are needed to help these adult. In Algeria 'imatib' (CIPLA-India) was introduced in 2006; but no study has been published yet in the North Africa region regarding response and outcome of this copy in CML patients. The goal of this multicenter study is to characterize newly adult CML in the western region of Algeria and to assess the effectiveness and safety of imatib (IM, copy) as frontline therapy for patients with CML.
Patients and Methods:
The study was carried out in 7 hematology centers in the western Algeria. Patients, who were diagnosed to be suffering from CML between 1st January, 2007 and 31st December, 2014 were selected for data analysis. All patients received a copy preparation, consisting of the alpha crystal form of imatinib, (IM, copy) at a oral dose of 400 mg daily and monitored for tolerance and side effects while on therapy.
Results:
Between January 2007 and December 2014, 355 patients with CML were treated with imatib (copy). The median follow- up of the study was 46 months (range: 13-107 months). Complete hematological response (CHR) was seen in 83% of patients within 3 months. According to the Sokal score, 72% patients with low, 78% with intermediate and 69% with high risk disease achieved a CHR in 3 months (p=0.26) and according to the EUTOS score, 81% of patients with low and 70% with high risk disease achieved a CHR in 3 months (p=0.08). The major molecular response (MMR) at six months (M6), M9, M12, M18 and M24 was 21%, 38%, 35%, 51% and 67% respectively and 34% of patients achieved a complete molecular response (CMR). The projected 5-year overall survival (OS) rate was 83%. Side effects of imatib (copy) in this study were similar to those reported previously for the entire imatinib mesylate treatment study and only 8% of patients were intolerant to imatib (copy) and treated with a second generation of BCR-ABL inhibitor.
Conclusion:
In conclusion, imatib (copy) is effective and safe in treating patients with CML in chronic phase and proves to have a durable outcome. To our knowledge this is the first study reporting the response to imatib (copy) in a Algerian population.

Disclosures
No relevant conflicts of interest to declare.
Long-Term Survival and Quality of Life Analysis after Autologous Stem Cell Transplantation for Lymphoma
Authors: Faict Sylvia , De Beule Nathan , De Becker Ann , Fostier Karel , Trullemans Fabienne , Schots Henri (Rik) 
Published: October 2019

Abstract
Background
Autologous stem cell transplantation (ASCT) is a frequent treatment option for various types of lymphoma. Few studies have addressed the occurrence of long-term morbidity and the quality of life (QoL) after ASCT. We analysed the overall survival (OS), the QoL and the impact of comorbidities before and after transplant in a consecutive cohort of lymphoma patients.
Methods
Patients transplanted in our center between 2003 and 2013 and with a minimum follow-up of 1 year were included. Survival was analysed by Kaplan-Meier methodology and the impact of prognostic factors was examined by standard multivariate analysis. Patients were inquired to complete the Self-reported Comorbidity Questionnaire (SCQ) as well as the EORTC QLQ-C30. Results of questionnaires were compared to a healthy reference population.
Results
A total of 85 lymphoma patients were identified with a median follow-up period of 76 months. The estimated OS probability was 62,7% (S.E. 5,5%) at 5 years and 60,8% (S.E. 5,6%) at 10,9 years. Indicators of a poor prognosis at time of transplantation were: age ≥ 60 years, high-intermediate to high-risk IPI for NHL and HCT-comorbidity index ≥ 3. Of long-term (> 1 year) survivors 40 completed the EORTC QLQ-C30. They experienced lower cognitive and social functioning and reported more fatigue, dyspnea and financial difficulties, when compared to the reference population. A small proportion of patients reported significant complaints related to pain (22,5%) and fatigue (10%). Very long-term survivors (over 5 years post ASCT) had a better physical and role functioning, with less fatigue, dyspnea, insomnia and loss of appetite as compared to patients who were transplanted more recently. Patients with more self-reported comorbidities post-ASCT did significantly worse in terms of QoL after transplantation. They experienced worse physical, role, cognitive and social functioning, and had more complaints about fatigue, pain, dyspnea, diarrhea and insomnia.
Conclusion
The presence of comorbidities pre-ASCT, as determined by HCT-CI >3, was associated with a worse OS. Surprisingly, the overall long-term impact of ASCT on the QOL was limited with adverse effects only related to cognitive and social functions. These negative consequences also decreased over time. Finally, the occurrence of comorbidities after transplantation was associated with worse QoL.

Disclosures
No relevant conflicts of interest to declare.
Population Level Survival for Patients with Rare Hematologic Malignancies in the United States in the Early 21st Century
Authors: Pulte Dianne , Weberpals Janick , Jansen Lina , Katalinic Alexander , Nennecke Alice , Holleczek Bernd , Ressing Meike , Luttmann Sabine , Brenner Hermann 
Published: October 2019

Abstract
Introduction: Population level survival has increased for most of the more common hematologic malignancies in the early 21st century. However, less information is available on population level changes in survival for patients with rare hematologic malignancies. Here, we examine survival for rare hematologic malignancies in Germany and the United States (US).
Methods: Cases of rare hematologic malignancies were extracted from the Surveillance, Epidemiology, and End Results (SEER13) database in the US, with an underlying population of 44.1 million people, and 12 regional cancer databases in Germany, with an underlying population of 28.3 million. For the purpose of this study, rare hematologic malignancies were defined as those having an incidence of less than 1 per 10,000 population in both the relevant databases. Modeled period analysis was used to examine changes in 5-year survival between 2003-07 and 2008-12 and to derive p-values for the comparison between the two periods.
Results: Ten malignancies that met the inclusion criteria and had adequate case numbers to allow a meaningful analysis were identified (see table.) A total of 13,895 cases were identified in Germany and 19,894 in the US with case numbers for individual morphologies ranging from 302 for acute erythroblastic leukemia in Germany to 4,514 for mantle cell lymphoma in the US. Overall 5-year relative survival for patients with all morphologies was estimated as 60.4% in Germany and 57.2% in the US in 2008-12. Survival for patients varied widely depending on the individual tumor type, from less than 30% for acute monoblastic leukemia and acute erythroblastic leukemia to around 90% for hairy cell leukemia and mycosis fungoides without Sezary. A statistically significant increase in survival was observed for mantle cell lymphoma, Burkitt's lymphoma, and hairy cell leukemia in Germany and for mantle cell lymphoma, anaplastic lymphoma kinase (ALK) positive anaplastic lymphoma, and acute erythroblastic leukemia in the US.
Conclusions: Five year survival varied widely for rare hematologic malignancies in Germany and the US. Significant increases in survival were observed in only a minority of rare hematologic malignancies, in contrast to the consistent increases in survival seen in almost all of the more common hematologic malignancies. Survival was lower in the US for most malignancies. Research specifically focusing on rare hematologic cancer types is needed to increase survival for these conditions.
Table Five year relative survival for rare hematologic malignancies, 2003-07 to 2008-12. Table. Five year relative survival for rare hematologic malignancies, 2003-07 to 2008-12.

Disclosures
Pulte: ApoPharma: Research Funding; Selexys Pharmaceuticals: Research Funding; EBSCO: Other: Review of content for Dynamed medical reference product.
RAB14 Regulates Human Erythropoiesis and Megakaryopoiesis
Authors: Kim Minjung , Kingsbury Tami J. , Civin Curt I. 
Published: October 2019

We recently reported that RAB GTPase 14 (RAB14) knockdown (KD) increased the frequency and total numbers of erythroid cells generated in vitro in response to erythropoietin (EPO) from either the TF1 human leukemia erythropoietic model cell line or from primary human CD34+ hematopoietic stem-progenitor cells (HSPCs). RAB14 overexpression (OE) had the opposite effect. Thus, RAB14 functions as an endogenous inhibitor of human erythropoiesis (Kim et al., Br. J. Haematol., 2015). In contrast to the greater cell numbers generated in the presence of EPO, RAB14 KD TF1 cells grown in standard culture media containing granulocyte-macrophage colony-stimulating factor (GM-CSF; as the only cytokine) generated fewer total cells, compared to empty vector-transduced control TF1 cells. Furthermore, RAB14 KD TF1 cells cultured in GM-CSF media generated greater numbers of erythroid (CD34-/CD71+/CD235a+) cells, as compared to control TF1 cells, suggesting that RAB14 KD stimulated erythropoiesis even in the absence of EPO. Cells generated from RAB14 KD TF1 cells had higher GATA1 and lower GATA2 transcription factor expression, as compared to controls, demonstrating the cells had undergone the "GATA1/2 switch," a hallmark of erythropoiesis. Consistent with higher GATA1 levels, RAB14 KD TF1 cells generated cells with higher levels of b- and g-hemoglobins. Similarly, RAB14 KD in primary human CD34+ HSPCs generated greater numbers of erythroid cells, with or without exogenous EPO. RAB14 KD CD34+ HSPCs cultured in GM-CSF media generated fewer monocytic/granulocytic (CD13+/CD33+) cells, as compared to control CD34+ HSPCs. Interestingly, RAB14 OE CD34+ HSPCs cultured in thrombopoietin (TPO)-containing media generated higher numbers of megakaryocytic (CD34-/CD41a+/CD42b+) cells, as compared to control CD34+ HSPCs. In summary, (1) RAB14 KD in TF1 cells or primary human CD34+ HSPCs increased erythropoiesis in the presence or absence of EPO, but reduced myeloid cell differentiation, probably via the GATA1/2 switch; and (2) RAB14 OE in CD34+ HSPCs increased megakaryopoiesis in the presence of TPO. Thus, RAB14 normally serves as an endogenous hematopoietic decision-maker, physiologically inhibiting erythropoiesis and stimulating megakaryopoiesis (and possibly, to a lesser extent, mono-granulopoiesis).

Disclosures
No relevant conflicts of interest to declare.
Suppression of Anti-Tumor Immunity in Chronic Lymphocytic Leukemia Via Interleukin-10 Production
Authors: Alhakeem Sara S , McKenna Mary K , Nooti Sunil K , Oben Karine Z , Rangnekar Vivek M , Byrd John C. , Muthusamy Natarajan , Bondada Subbarao 
Published: October 2019

Abstract
The most common human leukemia is B-cell chronic lymphocytic leukemia (B-CLL), which is characterized by a progressive accumulation of abnormal B-lymphocytes in blood, bone marrow and secondary lymphoid organs. Typically disease progression is slow, but as the number of leukemic cells increases, they interfere with the production of other important blood cells, causing the patients to be in an immunosuppressive state. To study the basis of this immunoregulation, we used cells from the transgenic Eμ-Tcl1 mouse, which spontaneously develop B-CLL due to a B-cell specific expression of the oncogene, Tcl1. Previously we showed that Eμ-Tcl1 CLL cells constitutively produce an anti-inflammatory cytokine, IL-10. Here we studied the role of IL-10 in CLL cell survival in vitro and the development of CLL in vivo. We found that neutralization of IL-I0 using anti-IL-10 antibodies or blocking the IL-10 receptor (IL-10R) using anti-IL-10R antibodies did not affect the survival of CLL cells in vitro. On the other hand, adoptively transferred Eμ-Tcl1 cells grew at a slower rate in IL-10R KO mice vs. wild type (WT) mice. There was a significant reduction in CLL cell engraftment in the spleen, bone marrow, peritoneal cavity and liver of the IL-10R KO compared to WT mice. Further studies revealed that IL-10 could be playing a role in the tumor microenvironment possibly by affecting anti-tumor immunity. This was seen by a reduction in the activation of CD8+ T cells as well as a significantly lower production of IFN-γ by CD4+ T cells purified from CLL-injected WT mice compared to those purified from CLL-injected IL-10R KO mice. These studies demonstrate that CLL cells suppress host anti-tumor immunity via IL-10 production. This led us to investigate possible mechanisms by which IL-10 is produced. We found a novel role of B-cell receptor (BCR) signaling pathway in constitutive IL-10 secretion. Inhibition of Src or Syk family kinases reduces the constitutive IL-10 production by Eμ-Tcl1 cells in a dose dependent manner. In addition, we found that Eμ-Tcl1 CLL cells exhibit clonal variation in their IL-10 production in response to BCR cross-linking. Further studies are being performed to understand the mechanisms by which BCR signaling affects IL-10 production.

Disclosures
No relevant conflicts of interest to declare.
Collection of Peripheral Blood Stem Cells in 118 Small Children Weighing 20 Kg or less: Experience of a Single Centre
Authors: Wen Jianyun , He Yuelin , Chen Libai , Du Jing , Peng Zhiyong , Liao Jianyun , Liu Huaying , Zhou Xiaohui , Li Chunfu , Wu Xuedong 
Published: October 2019

Abstract
Background: Peripheral blood stem cells (PBSC) are increasingly used as a source of stem cells for either autologous or allogeneic hematopoietic transplantation in children.Although technically similar to adult procedures, PBSC harvest may be difficult in young children, especially in the very small children.
Aim: In this study, we aimed to evaluatethe safety and efficacy of harvesting peripheral blood hematopoietic stem cells in very small children,and to provide a guideline.
Methods: Between Jan 2013 to Mar 2016, we evaluated 118 children weighing 20 kg or less, with the smallest patient weighing 11 kg. The patients had a median age of 59 months and included 72 children with thalassemia major and 46 young donors. The granulocyte-colony stimulating factor (G-CSF) analogs were used at a dose of 10 mg/kg/day administered subcutaneously once a day and receiving oral calcium for five days before harvesting. Blood was withdrawn at a mean rate of 30-40 ml/min through a temporaryfemoral vein catheter (12 or 14 guage) to ensure adequate blood flow and returned through a larger catheter in a peripheral vein.Total nucleated cells(TNC) and CD34+ cells were estimated in the peripheral blood before collection of the apheresis product.
Results: We collected sufficient products from all the children with one to three apheresis procedures. No serious complication was detected in all children and all aphereses were completed within 4 hours.The volume of blood per kilogram processed for each apheresis ranged from 55 to 160ml (median, 85ml). The median number of TNC and CD34+ cells collected were 12×108/kg and 15×106/kg per apheresis, respectively.
Conclusions:We conclude that collection of PBSC is a safe and practical procedure in children, even in very small children.

Disclosures
No relevant conflicts of interest to declare.