bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of High-Resolution Donor-Recipient HLA Matching and Mismatching Frequencies On Choosing Donor in Chinese Population for Unrelated Allo-HSCT.
Authors: He Jun , Chen Zi-Xing , Bao Xiaojing , Qiu Qiaocheng , Yuan Xiaoni , Li Yang 
Published: October 2019

Abstract
Abstract 4503
The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor (URDs) transplantation. Hematopoietic stem cell transplantation (HCT) from volunteer URDs may give a chance of cure for patients with malignant hematological diseases. Although donor-recipient HLA matching is associated with better outcomes, many are not able to identify an HLA-A, -B, -C, -DRB1, DQB1 matched URD and are faced with choosing the closest matching among the available donors. The Chinese Marrow Donor Program (CMDP) has completed a retrospective high-resolution HLA typing on sufficient patient-donor pairs to analyze high resolution matching and mismatches probability at specific loci. These data are critical for selecting the best available partially HLA-matched donor for patients undergoing HLA-mismatched URD HCT. We have performed high-resolution typing for HLA-A,-B,-C,-DRB1,-DQB1 by using SBT, SSOP and SSP techniques on 1092 donors and 931 patients from the data base of CMDP. Among 1092 donors, the allele with highest frequency were HLA-A*1101, A*0201, A*2402, A*0207, A*3303, A*0206 and A*3001; HLA-B*4001, B*4601, B*5801, B*1302, B*1501, B*5101and B*1301; HLA-Cw*0102, Cw*0702, Cw*0304, Cw*0801, Cw*0602, Cw*0303, Cw*0302 and Cw*0401; HLA-DRB1*0901, DRB1*1501, DRB1*1202, DRB1*0701, DRB1*0803, DRB1*0405, DRB1*0301 and DRB1*1101; HLA-DQB1*0301, DQB1*0303, DQB1*0601, DQB1*0202, DQB1*0602, DQB1*0302, DQB1*0401, DQB1*0201 and DQB1*0502. The probability of HLA high-resolution DNA matching between 1092 donors and 931 patients(10/10 match) was 16.7%. Mismatching at a single HLA-A, -B, -C, -DRB1 or DQB1 locus (9/10) was 17.7%. A single mismatch at each locus of HLA-A, -Cw,- DRB1,- DQB1,- B was 6.8%, 6.3%, 2.0%, 1.7%, and 0.8%, respectively. Double mismatch (8/10) was 18.4%, such as loci A+ Cw(5.0%), DRB1+DQB1(4.6%) and B+ Cw(3.8%). The donor/patient pairs mismatched between allele of A*0201 and A*0206, A*0201 and A*0207, A*1101 and A*1102, B*4006 and B*4002, B*1501 and B*1527, Cw*0304 and Cw*0302, Cw*0304 and Cw*0303, DRB1*1501 and DRB1*1502, DRB1*1202 and DRB1*1201, DRB1*0406 and DRB1*0403, DRB1*1401 and DRB1*1454, DQB1*0303 and DQB1*0302, respectively, were statistically associated with lower-risk Allo-HSCT. These results suggested that high-resolution DNA matching or mismatching for HLA-A, -B, -C, -DRB1 and DQB1 alleles could be associated with better clinical outcome and higher survival. Furthermore, the identification of high risk mismatch and permissive mismatch would be beneficial for the selection of a suitable donor.

Disclosures:
No relevant conflicts of interest to declare.
Severe Chronic Neutropenia in Korean Children.
Authors: Lee Mee Jeong , Park Hyeon Jin , Shin Hee Young , Kang Hyoung Jin , Koo Hong Hoe , Kook Hoon , Kwon Young Joo , Kim Sun Young , Kim Soon Ki , Kim Heung Sik , Moon Hyung Nam , Park Kyung Duk , Park Byung-Kiu , Park Seong Shik , Park Eun Sil , Baek Hee Jo , Seo Jong Jin , Sung Ki Woong , Song Joon Sup , Ahn Hyo Seop , Won Sung Chul , Yoo Keon Hee , Lyu Chuhl Joo , Lee Kun Soo , Lee Soo Hyun , Lee Young Ho , Lim Yeon Jung , Lim Young Tak , Lim Jae-Young , Im Ho Joon , Han Dong kyun , Hwang Tai Ju 
Published: October 2019

Abstract
Abstract 4513

Introduction
Severe chronic neutropenia (SCN) is a rare hematologic disorder defined by an absolute neutrophil count less than 0.5×109/L for several months or years. They usually suffer from recurrent infections. Principal subtypes of SCN are congenital, cyclic, idiopathic and primary autoimmune neutropenia (AIN).

Patients and Methods
Medical records collected from a national survey were retrospectively analyzed on newly diagnosed SCN patients in Korea between January, 1999 and December, 2008 in respect to the diagnosis, clinical manifestations, treatments and prognosis of the patients.

Results
There were 64 patients (Male, 20; Female 44) reported from 16 hospitals: congenital, 19; cyclic, 16; idiopathic, 25; and immune in origin, 4. The main clinical manifestation was various types of bacterial infections. Two cases (1 congenital, 1 cyclic) were diagnosed by family histories. The median age at diagnosis was 12 months (11 days-158 months). A bone marrow examination was done in 45 patients (70.3 %) at the median age of 26 months (1 day-158 months), with the interval between the initial CBC and BM study being 7.3 months (9 days-138 months). The ELA2 mutation, done in 6 patients, was not detected. Only one patient with congenital SCN evolved to AML at 54 months after diagnosis, who is under chemotherapy. Most patients were treated with G-CSF (5-10 μg/kg/day) during infection episodes. The median follow up duration was 23 months (11 days – 176 months). Two patients of congenital SCN died of infection (pneumonia, meningitis) and 8 patients were lost to follow up, and the remaining are alive.

Conclusions
SCN is a rare hematologic disease with inherent vulnerability to infections, thus early detection with proper management should be important for survival of SCN patients. We propose a nation-wide, prospective study to delineate the prevalence, molecular diagnosis, natural history, the optimal use of G-CSF, and prognostic factors in Korean patients with SCN.

Disclosures:
No relevant conflicts of interest to declare.
Expected Long-Term Survival of Older Patients Diagnosed with Non-Hodgkin Lymphoma in 2007-2011.
Authors: Pulte Dianne , Gondos Adam , Brenner Hermann 
Published: October 2019

Abstract
Abstract 4525

Background
New therapeutic options have led to substantial increases in survival expectations of patients with non-Hodgkin lymphoma (NHL) in recent years. In contrast to many malignancies, survival in older patients has improved in NHL at a rate similar to that in younger patients. In the past, the impact of these innovations on long-term survival of NHL patients on the population level has only been disclosed with substantial delay. In order to reduce this delay, we employed a newly developed projection method to estimate survival of patients age 60 and older with NHL in 2007-11.

Methods
In order to demonstrate the validity of model based projection, we calculated survival for 4 prior periods for which observed 5-year survival data is available by three methods: cohort analysis, period analysis, and model based projection and compared the results to the actual observed survivals from the same time periods. We next calculated survival estimates for the most recent patient cohort for which 5- and 10-year survival data is available, period analysis for 2002-06, and projection estimates for 2007-11.

Results
A preliminary empirical evaluation of the method using historical data indicated good performance in projection of age specific and overall 5- and 10-year relative survival in older patients with model based projection giving a result closer to the observed survival than either cohort analysis or period analysis for all age groups in each time period. Five and 10-year survival estimates for 2007-11 for patients aged 60+ were 65.1% and 53.5%, respectively, 8.9 percentage units (% units) and 14.8% units, respectively, higher than survival estimated from the most recent cohort analysis available (see table). Age specific 5- and 10-year relative survival estimates using model based projection ranged from 76.9% and 66.6%, respectively, for age 60-64 to 50.7% and 37.5%, respectively, for patients age 80+. Survival estimates by model based projection were higher for all age groups including 80+, both high and low grade disease, nodal and extranodal disease, and both genders.

Conclusions
Patients over 60 diagnosed with NHL in 2007-2011 have much higher long-term survival expectations than suggested by previously available survival statistics. The use of model based projection is reliable in this patient population and demonstrates steady improvement in survival over time for older patients with NHL. This reinforces the findings from clinical trials which show that treatment of NHL is tolerable and effective in older patients.

Disclosures:
No relevant conflicts of interest to declare.
Bone Marrow Derived Mesenchymal Stem Cells and Radiation Response: a Kinetic Study of Gene Response Using Microarray Analysis.
Authors: Garrigou Philippe , Mayol Jean-Francois , Mouret Catherine , Delaunay Christophe , Drouet Michel , Herodin Francis , Peinnequin Andre , Pugnière Pascal 
Published: October 2019

Abstract
Abstract 4575
Mesenchymal Stem cells (MSC) are an important radiosensitive component of the so called hematopoietic stem cell niche. Importantly this supportive microenvironment influences the stem cell repopulation capacity as well as the quiescent/non proliferative state of hematopoietic cells. Senescence is considered as a major process in MSC response following irradiation. However, other studies have reported in mice the reduction of the pool of bone marrow mesenchymal stem/progenitor cells following TBI independently of senescence. An altered osteoblastic differentiation was pointed out in these studies. Furthermore, MSC have been shown to be involved in the repair of ionizing radiation damage of distant epithelial sites which requires adherence genes mitigation. The aim of this study was to clarify some of these points using an in vitro model of irradiation and short term culture.
Briefly, confluent human BM-MSC were irradiated at the dose of 2.5 Gy (dose rate: 95 cGy.min-1) and immediately put into culture (Minimum essential medium supplemented with 10% FCS and 10 μg/ml of ciprofloxacin, penicillin and streptomycin). Six, 12, 24, 48 and 72 hours after irradiation, cells were harvested and lysed. Total RNAs were purified using the automatic Qiacube system (Qiagen,Courtaboeuf, France) and processed on DNA microarray scanner (Agilent technologies Inc.) according to supplier's recommendations. Data were analyzed with GeneSpring GX Expresion Analysis software version 10.0 (Agilent) in order to identify the transduction pathways involved.
No apoptosis was observed during this short term incubation. Among other genes we identified plasminogen activator inhibitor 1 (PAI-1) as a factor highly upregulated after irradiation, in addition to CD151. This is in accordance with MSC response to nutrient-poor, hypoxic stress environment (Copland et al, Stem cells 2009). As MSC are radiosensitive cells, this may indicate that PAI impacts MSC survival through the mitigation of their adhesiveness to surrounding matrices. As PAI-1 is an important factor involved in the balance of blood coagulation and fibrinolysis as well as in the regulation of angiogenesis, one may speculate the consequences of PAI-1 release from MSC on blood homeostasis. Work is going on to describe the main response target genes. This could allow us to identify therapeutic strategies based on ex-vivo or in vivo manipulation of MSC in a purpose of tissue remodelling.

Disclosures:
No relevant conflicts of interest to declare.
Expression of the Transcription Factor Lymphoid Enhancer Binding Factor-1 (LEF-1) Is Correlated to Aberrantly Increased Fibromodulin Transcripts in Chronic Lymphocytic Leukemia (CLL).
Authors: Erdfelder Felix , Gehrke Iris , Gandhirajan Rajesh Kumar , Hertweck Magdalena , Razavi Regina , Paesler Julian , Filipovich Alexandra , Uhrmacher Sabrina , Poll-Wolbeck Simon Jonas , Hallek Michael , Kreuzer Karl Anton 
Published: October 2019

Abstract
Abstract 4589
Chronic lymphocytic leukemia (CLL) is characterized by accumulation of monoclonal CD5+ B lymphocytes. Fibromodulin is a secreted extracellular matrix protein usually found in articular cartilage, bones, connective tissue and collagen rich tissues but has been shown to be excessively expressed in CLL. Moreover, we and others could show that WNT signaling is highly activated in CLL. The aim of our study was to investigate a possible connection between fibromodulin overexpression and the WNT pathway. Moreover, we wanted to explore possible relations between these parameters and the prognosis of CLL. Fibromodulin mRNA transcripts were correlated with the mRNA expression of the WNT pathway transcription factors lymphoid enhancer binding factor-1 (LEF-1) and T cell factor-4 (TCF-4) in primary CLL cells. Furthermore, we assessed correlations between the mRNA expression levels with ZAP-70 and CD38 protein expression. These parameters have been shown to be associated with a poor prognosis. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used and calculated PCR-efficiency corrected relative expression values of Fibromodulin, LEF-1 and TCF-4 mRNA in primary CLL-cells determined. ZAP-70 and CD38 expression was determined by flow cytometry analysis. Based on 20 primary CLL samples we found a significant positive correlation between Fibromodulin and LEF-1 mRNA levels (Spearman's rho = 0.65, p = 0.009). Also, LEF-1 and TCF-4 were found to be strongly correlated (Spearman's rho = 0.61, p = 0.027). In contrast, fibromodulin and TCF-4 mRNA levels were only weakly correlated (Spearman's rho = 0.33, p = 0.271). CD38 and ZAP-70 did not correlate significantly to any of the other values. Both parameters did also not exhibit significant correlations with fibromodulin, LEF-1, and TCF-4 mRNA. The positive correlation of TCF-4 and LEF-1 was expected as LEF-1 has been shown to be a target gene of TCF transcription factors. The strong positive correlation of fibromodulin and LEF-1 indicates that fibromodulin might be a target gene of LEF-1 or part of the same (TCF-4 independent) transcription regulation pathway. Studies investigating theses functional relationships are underway.

Disclosures:
Hallek: BayerScheringAG: Honoraria, Research Funding.
Human Embryonic Stem Cell-Derived and Fetal Macrophages Exhibit Mainly Features of Alternative (M2) Polarization.
Authors: Klimchenko Olena , Di Stephano Antonio , Solary Eric , Routier Melanie , Vainchenker William , Norol Françoise 
Published: October 2019

Abstract
Abstract 4598
Monocyte heterogeneity has long been recognized and 2 functional subsets of human monocytes that exert specific roles in homeostasis and inflammation in vivo, M1 and M2 monocytes, has been described. The different monocyte subsets seem to reflect developmental stages with distinct physiological roles but few is known whether the macrophage diversity arises in early ontogeny.
Human embryonic stem cells (hESC) provide an unique model for in vitro studies of the early ontogeny of the hematopoietic system. Human embryonic monocytes were obtained from embryoid bodies cultured for 3 weeks in the presence of BMP4, VEGF and a mixture of hematopoietic cytokines. The sorted CD14+CD45+ cells were further cultured for 7 -10 days in the presence of GM- and M-CSF. Embryonic stem cells derived monocytes and macrophages were identified by several criteria including morphology, cytochemical staining, ultrastructural and functional features. In contrast to early mouse hematopoiesis that bypass the series of monoblaste/monocyte precursors human embryonic monocyte lineage developped by process similar to definitive monopoiesis. Two distinct subpopulations of monocytes, first CD14+CD16- then CD14+CD16+ could be successively identified. Transcriptional and functional assays suggest that CD14+CD16- population is not an embryonic counterpart of CD14+CD16- “inflammatory” adult monocytes but a precursor for CD14+CD16+ macrophages and dendritic cells. Moreover, both tested populations possess phenotypical markers of M2 polarization and were positive for a expression of scavenger receptors CD163+ and CD36+ of CCR5 and negative for CD62L. Additional transcriptional studies and chemokine pattern confirmed their IL10 high IL12low phenotype, clearly indicating their M2 polarization state. M2 polarization was confirmed in fetal macrophages derived from CD34+ cells issued from livers of first-trimester fetuses. Involvment of embryonic and foetal monocytes in homeostasis are under investigation.
Collectively, our data provide insight into alternative macrophage polarization during early embryogenesis and adds further data to the growing body of evidence that establishment of macrophage heterogeneity is related to early ontogeny.

Disclosures:
No relevant conflicts of interest to declare.
Effect of Sickle Cell Disease Type, Age and Gender On the Prevalence of Chronic Organ Damage in Adults with Sickle Cell Disease.
Authors: Osarogiagbon Raymond U. , Haider Syed N , Tang Jun 
Published: October 2019

Abstract
Abstract 4607

Introduction
The high mortality risk that sickle cell disease (SCD) patients experience from infancy is cumulative through adulthood, largely because of the effect of cumulative end organ damage, which is a more powerful predictor of early mortality than frequency of painful episodes. The latter, though, gets more attention from patients and caregivers. Any vascular territory is susceptible to damage. The most common target organs are the brain, lungs, kidneys, retina and joints. We examined the prevalence of the full spectrum of end organ damage in a cohort upon entry into our adult SCD program and compared the clinical and laboratory characteristics of patients based on age, gender and SCD type.

Patients and Methods
Retrospective review of prospectively collected data on 118 adults upon entry into our program between February 2005 and October 2008. All patients underwent a standardized battery of tests to evaluate hematological and biochemical parameters at entry. Historical presence of episodes of acute chest syndrome, pneumonia, stroke, avascular necrosis, osteomyelitis, leg ulcers, priapism, and cholecystectomy and hydroxurea therapy was quantified. Pulmonary hypertension (PHT) was defined as a tricuspid regurgitant jet velocity (TRJV) ≥2.5 m/s on Doppler echocardiography; sickle cell nephropathy (SCN) as glomerular filtration rate, (GFR) < 90ml/min. and/or 24-hour protein>300mg and/or urine protein/creatinine ratio>0.3); cerebrovascular disease (CVD) as evidence of previous ischemic and/or hemorrhagic infarct and/or aneurysm formation on brain MRI/MR angiography; and sickle cell retinopathy (SCR) as background to proliferative retinopathy) on fluorescent retinal angiography. Characteristics of patients were evaluated with t-test for continuous variables and chi-square test for the categorical variables.

Results
The relevant statistically significant correlative variables in these 3 comparisons are shown in the following tables.

Conclusions
Our study highlights the various differences in the prevalence of sickle cell disease-related end organ damage and morbidity among different age, gender and two major sickle cell disease categories. It shows the significant progression of organ damage with advancing age and the more severe nature of SS/Sβ0 phenotype. Further expansion of this assessment may help identify specific high risk groups that can be targeted as candidates for more intensive preventive interventions.

Disclosures:
No relevant conflicts of interest to declare.
TDC Imaging and Atoxic Contrast and Cerebrovascular Lesions in SCD Adults Patients.
Authors: Leite Ana Claudia C , Veloso Orlando CG , Lobo Clarisse Lopes de Castro , Oliveira Raquel VC , Bahia Paulo RV 
Published: October 2019

Abstract
Abstract 4612
Silent infarcts have been reported in approximately 20% of children with SCD. The prevalence in SCD adult patients has not been studied previously.

METHODS
We studied 187 patients (mean age 29 years) Each of these patients underwent a neurological examination, duplex scan of carotids and TCD image with atoxic contrast (micro bubbles). Eighty of these patients were sorted to perform MRI and MRA to study lacunar infarction, encephalomalacia, leukoencephalopathy, Moya Moya syndrome and aneurysm (measured by number and size).

RESULTS
The overall prevalence of silent infarcts was 52%. Comparing the two methods regarding sensitivity and specificity, obtained respectively 88 and 85%. The positive predictive value of the TCD image with contrast was 80%. There was only one case of intracranial aneurysm, observed by both imaging methods. The other asymptomatic patients with abnormal TCD (low definition of image contrast or absence of flow to TCD image) presented diagnostic criteria of vascular occlusion with secondary collateral (Moya Moya Syndrome).

CONCLUSIONS
Use of atoxic contrast (micro bubbles) increases the sensitivity of TCD image for diagnosis of intracranial lesions in SCD adults patients, even in asymptomatic individuals, enabling the diagnosis of silent infarcts.

Disclosures:
No relevant conflicts of interest to declare.
Changes in Serum Protein Profiles During Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT): Clinical Significance of Serum C-Reactive Protein and Haptoglobin Levels.
Authors: Lee Se Ryeon , Ryu Joohyun , Ahn Jae-Sook , Kim Yeo-Kyeoung , Yang Deok Hwan , Lee Je-Jung , Sung Hwa Jung , Choi Chul Won , Kim Byung Soo , Park Byoung Chul , Kim Hyeoung-Joon 
Published: October 2019

Abstract
Abstract 4658

Background
Successful hematopoietic stem cell transplantation involves the restoration of hematopoietic function after engraftment, arising from the differentiation and proliferation of hematopoietic stem cells. Several factors influence the course of allo-HSCT. In particular, knowledge of serum proteome changes during the allo-HSCT period might increase the efficacy of diagnosis and disease prevention efforts.

Method
The sera from five representative patients who underwent allo-HSCT were analyzed by 2-DE and LC-MS/MS. To verify the clinical significance of identified serum proteome, we assessed the representative APPs, C-reactive protein (CRP) and haptoglobin in 78 patients who underwent allo-HSCT at Chonnam National University Hospital (CNUH) who were included between June 2002 and April 2008. Serum level of CRP and haptoglobin were measured weekly from D-7 or D-0 to D+21 of allo-HSCT.

Result
Fourteen proteins showing significant changes in expression were further examined, and most were identified as APPs. Studies of 78 additional patients confirmed that CRP and haptoglobin undergo expression changes during allo-HSCT and thus have the potential to serve as representative markers of various hematologic diseases. Maximal CRP level affected the development of MTCs and other problems, FUO. In particular, an increase in CRP level 21 days after allo-HSCT was found to be an independent risk factor for MTC. Maximal haptoglobin and haptoglobin level 14 days after allo-HSCT were predictive of relapses in underlying hematologic disease.

Conclusion
Our results reveal the usefulness of a proteomic approach in the clinical follow-up of patients after allo-HSCT, and suggest that CRP and haptoglobin can be monitored after allo-HSCT to assess risks of early transplant-related complications and relapse.

Disclosures:
No relevant conflicts of interest to declare.