bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mirnas and Gene Expression Profiles in CD34+ Cells Are Dependent On the Source of Progenitor Cells Employed in Transplantation.
Authors: Báez Alicia , Martin-Antonio Beatriz , Prats-Martín Concepción , Álvarez-Laderas Isabel , Barbado María Victoria , Caballero-Velázquez Teresa , Piruat Jose Ignacio , Carmona Magdalena , Pérez-Simón Jose Antonio , Urbano-Ispizua Alvaro 
Published: October 2019

Abstract
Abstract 3020

Introduction:
Hematopoietic progenitors cells (HPCs) used in allogenic transplantation (allo-HSCT) may have different biological properties depending on their source of origin: mobilized peripheral blood (PB), bone marrow (BM) or umbilical cord (UC), which may be reflected in miRNAs or gene expression. The identification of different patterns of expression could have clinical implications. The aim of this study was to determine differences in miRNAs and gene expression patterns in the different sources of HPCs used in allo-HSCT.

Materials and Method:
CD34 + cells were isolated by immunomagnetic separation and sorting from 5 healthy donors per type of source: UC, BM and PB mobilized with G-CSF. A pool of samples from PB not mobilized was used as reference group. We analyzed the expression of 375 miRNAs using TaqMan MicroRNA Arrays Human v2.0 (Applied Biosystems), and gene expression using Whole Human Genome Oligo microarray kit 4×44K (Agilent). The expression levels of genes and miRNAs were obtained by the 2-ΔΔCTmethod. From expression data hierarchical clustering was performed using the Euclidean distance. To identify genes and miRNAs differentially expressed between the different sources of HPCs statistical Kruskal Wallis test was applied. All analysis were performed using the Multiexperiment Viewer 4.7.1. The function of the miRNAs and genes of interest was determined from the various databases available online (TAM database, Gene Ontology and TargetScan Human).

Results:
Forty-two miRNAs differentially expressed between the different sources were identified. As compared to BM or UC, in mobilized PB most miRNAs were overexpressed, including the miRNA family of miR515, which is characteristic of embryonic stem cells. On the other hand, 47 genes differentially expressed between the different sources were identified. Interestingly, a similar pattern of expression was observed between movilized PB and UC as compared to BM. Interestingly, 13 of these genes are targets of the miRNAs also identified in this study, which suggests that their expression might be regulated by these miRNAs.

Conclusion:
There are significant differences in miRNAs and gene expression levels between the different sources of HPCs

Disclosures:
No relevant conflicts of interest to declare.
Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.
Authors: Bacigalupo Andrea P , Raiola Anna Maria , Dominietto Alida , Van Lint Maria Teresa , Gualandi Francesca , Lamparelli Teresa , Bregante Stefania , Ghiso Anna , Grazia Carmen Di , Varaldo Riccardo 
Published: October 2019

Abstract
Abstract 3034
Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1).
The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7).
In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival.

Disclosures:
No relevant conflicts of interest to declare.
Autologous Re-Transplantation for Patients with Relapsed Multiple Myeloma: A Single Center Experience with 200 Patients.
Authors: Neben Kai , Sellner Leopold , Heiss Christiane , Benner Axel , Raab Marc S , Hillengass Jens , Hose Dirk , Lehners Nicola , Egerer Gerlinde , Ho Anthony D , Goldschmidt Hartmut 
Published: October 2019

Abstract
Abstract 3086

Background:
Therapeutic options for patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (ASCT) include novel agents, conventional chemotherapy or salvage ASCT, with no standard of care.

Design and Methods:
We retrospectively reviewed all myeloma patients who relapsed after upfront ASCT and received an autologous re-transplantation as salvage therapy at our center over a period of 15 years (n=200). The aim of our study was to evaluate the role of salvage ASCT in terms of efficacy and to define patients who may benefit most from this treatment approach.

Results:
The median follow up after salvage ASCT was 57.1 months. Median progression-free survival (PFS) and overall survival (OS) after salvage ASCT were 15.2 and 42.3 months, respectively. Overall response rate (≥partial response) was 80.4% at day 100, excluding 6 patients who died before assessment. Factors associated with improved PFS and OS after salvage ASCT included remission duration of >18 months after upfront ASCT, bortezomib- or lenalidomide containing therapies for reinduction, response to reinduction, ISS stage I prior to salvage ASCT and year of salvage ASCT 2005 or thereafter. The remission duration after upfront ASCT and the ISS prior to salvage ASCT were combined to create a risk-stratification model with three distinct prognostic groups.

Conclusions:
Salvage ASCT causes low morbidity and is capable of achieving sustained disease control in patients with myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Stratification by duration of remission after upfront ASCT and ISS allows prediction of survival after salvage ASCT. To circumvent the problem of stem cell harvest in intensively pretreated patients, we recommend collecting and cryopreserving sufficient stem cells for both upfront and salvage ASCT early in the course of myeloma treatment.

Disclosures:
No relevant conflicts of interest to declare.
Haploidentical Mismatched Allogeneic Versus Autologous Hematopoietic STEM CELL Transplantation in Adult Patients with ACUTE Myeloid Leukemia (AML) in First Complete Remission (CR1): A Pair-Matched Analysis From the Acute Leukemia Working Party of EBMT.
Authors: Gorin Norbert C. , Labopin Myriam , Ciceri Fabio , Velardi Andrea , Santarone Stella , Arcese William , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 3093
In the absence of a matched family donor, adult patients with AML in CR1 are nowadays usually offered, as a first choice, an allogeneic transplant from an alternative donor (haplomismatched donor or cord blood cells), but there has been thus far no demonstration that outcome when using an alternative donor would be superior to outcome following an autologous stem cell transplantation (ASCT).
Between January 2000 and December 2010, 113 AML patients transplanted in CR1 with an haplo-mismatched family donor and 4444 patients autografted were reported to the EBMT registry. For the purpose of this analysis, we performed a matched pair analysis (113 haplo/226 autos) using age and interval from diagnosis to transplant as matching factors. The median follow up was 18 months (range, 1–128). Patients allografted were transplanted more recently (median year of transplant: 2008 vs 2004, p<10e-4), and they received more frequently total body irradiation in the pretransplant regimen (58% vs 17%). Engraftment following an haplo- mismatched transplant occurred in 93% of cases vs 99% after ASCT and recovery of ANC>500/mm3 was slightly delayed (15 days vs 13 days, p<10e-4). The outcome at two years, following an haplo mismatched transplant versus an ASCT was: LFS 44±5% vs 54±4% (p=0.008); OS 44±6 % vs 68±4% (p<10e-4); Non Relapse Mortality (NRM) 37±5% vs 2±2 ( p<10e-4) and Relapse Incidence (RI) 19±4% vs 43±4% (p<10e-4). Following an haplo mismatched transplantation the incidence of chronic extensive GVHD was 24+/− 6%. By multivariate analysis adjusted on year of transplantation, source of stem cells and TBI, the RI was no longer statistically different between the 2 groups, NRM was higher following haplo (HR=11.8; p<0.0001) and LFS was better following ASCT (HR=0.52; p=0.004).
Though this study did not account for cytogenetics and molecular markers (data collection is ongoing), these results suggest that outcome following ASCT in CR1 may be better compared to outcome following a haplo-mismatched transplantation. Recent developments in both transplant approaches may change the results in the near future and may justify a randomized prospective study.

Disclosures:
No relevant conflicts of interest to declare.
The Benefit of Allogeneic Hematopoietic Cell Transplantation in Older Patients with Acute Myeloid Leukemia Is Restricted to Those in First Complete Remission At the Time of Transplantation.
Authors: Michelis Fotios V. , Messner Hans A. , Atenafu Eshetu G , Kim Dennis Dong Hwan , Kuruvilla John , Lipton Jeffrey H. , Uhm Jieun , Loach David , Gupta Vikas 
Published: October 2019

Abstract
Abstract 3097
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for some patients with acute myeloid leukemia (AML). Whether older patients with AML benefit from curative potential of HCT similar to younger patients is not well understood. To understand this issue, we evaluated the impact of age and remission status on 242 consecutive patients that underwent HCT between 1999 and 2011 in our program. Based on age and remission status, patients were divided into 4 groups: Gp 1, CR1 age <60 (n=116); Gp 2, CR1 age ≥60 (n=32); Gp 3, CR2 age <60 (n=78); and Gp 4, CR2 age ≥60 (n=16).
Median age of all patients was 48 years (range 18–71), 123 patients (51%) were male. Peripheral blood stem cells were used in 178 patients (74%), bone marrow in 64 patients (26%). Donors were matched related (n=155, 64%) or matched unrelated (n=87, 36%). Median follow up of survivors was 65 months (range 12–145). No significant difference was found in terms of cytogenetic risk distribution between the 4 groups (p=0.14). Of the 48 patients ≥60 years of age, 46 (96%) received reduced-intensity conditioning regimens.
Survival at 2-years in Gp 1, Gp 2, Gp 3, Gp 4 was 59%, 43%, 43% and 23%, respectively (Fig 1). Corresponding relapse free survival (RFS) was 59%, 34%, 40%, and 19%, respectively. Cumulative incidence (CI) of relapse in the four groups was 14%, 34%, 21% and 25% respectively. The corresponding CI of non-relapse mortality (NRM) was 27%, 31%, 38% and 56% respectively. In a univariate analysis, the hazard ratios for survival for Gp 2, Gp 3 and Gp 4 were 1.488, 1.533 and 2.718 in reference to Gp 1, respectively.
Our data demonstrate that patients ≥60 years with AML in CR1 benefit from curative potential of HCT. Due to high NRM, patients ≥60 years in CR2 do not appear to benefit from curative potential of HCT. Therefore, if in an older patient HCT is indicated, attempts should be made to deliver the HCT in CR1.

Disclosures:
No relevant conflicts of interest to declare.
Association of Functional Single Nucleotide Variation in the NLRP3 Gene with Survival Outcomes After Unrelated Bone Marrow Transplantation.
Authors: Takami Akiyoshi , Espinoza J. Luis , Matsuo Keitaro , Morishima Yasuo , Onizuka Makoto , Kashiwase Koichi , Fukuda Takahiro , Kodera Yoshihisa , Nakao Shinji 
Published: October 2019

Abstract
Abstract 3140
NLRP3 is an intracellular trigger of IL-1β production that plays important roles in the regulation of inflammation and apoptosis. A single nucleotide variation in the 3'-untranslated region of the NLRP3 gene, rs10754558 (+29940G>C), is linked to several immunological diseases. When we examined the impact of the NLRP3 genotype in a cohort consisting of 392 pairs of patients with hematologic malignancies and their unrelated HLA 12/12 matched bone marrow donors transplanted through the Japan Donor Marrow Program, the recipient NLRP3 GG genotype was found to be associated with a significantly worse 5-year overall survival (OS) rate (34% vs. 50%, P=0.006) (Fig. 1) and a trend toward a higher transplant-related mortality (TRM) rate (39% vs. 27%, P=0.09) than the recipient CC or CG genotype. The recipient GG genotype remained statistically significant in the multivariate analysis for OS (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.22 to 2.22; P=0.004) and TRM (HR, 2.28; 95% CI, 1.20 to 4.35; P=0.01). The donor NLRP3 genotype did not significantly influence the transplant outcomes. Next, we investigated the functional relevance of the NLRP3 +29940G>C variant. When leukocytes from healthy individuals were stimulated in vitro with NLRP3 ligand, the leukocytes with the NLRP3 GG genotype produced significantly more IL-1β than those with the NLRP3 CC or CG genotype (Fig. 2). These findings substantiate the functional relevance of the NLRP3 variant, and suggest that the higher IL-1β secretion in the peri-transplant period by recipients with the NLRP3 GG genotype likely accounts for their poor transplant outcomes. NLRP3 genotyping could therefore be useful in predicting prognoses and creating therapeutic strategies for improving the final outcomes of patients who undergo allogeneic hematopoietic stem cell transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Regions on Chromosomes 1 and 14 Are Associated with VWF:Ag Levels in African Americans Using Mapping By Admixture Linkage Disequilibrium
Authors: Paterson Andrew D , Roslin Nicole M , Christopherson Pamela A. , Bellissimo Daniel B , Flood Veronica H , Haberichter Sandra L. , Montgomery Robert R , Investigators Zimmerman Program 
Published: October 2019

Abstract
Background: VWF:Ag is highly heritable, however, despite genome-wide linkage and association analysis, mostly in European derived populations, the genetic basis for VWF levels is only partially understood. African Americans (AfAm) have significantly higher VWF:Ag than European Americans: although variants in VWF and ABO can account for some of this, it is not clear whether they explain all of this ethnic difference. A powerful method to identify chromosomal regions that account for ethnic differences is mapping by admixture linkage disequilibrium (MALD). MALD uses markers that differ markedly in allele frequency between ancestral populations, estimates the global ancestry for each individual, and compares local ancestry between subjects with different trait values to global estimates to identify regions of the genome that account for the ethnic differences of a trait.
Hypothesis: Loci that are associated with VWF:Ag levels in AfAm can be mapped using MALD.
Methods: From 188 AfAm healthy volunteers from the Zimmerman Program for the Molecular and Clinical Biology of VWD, 96 were selected to have 98≤VWF:Ag≥ 164 IU which represent the <25% and >75% of VWF:Ag distribution. They were genotyped using Illumina HumanCoreExome genome-wide SNP chip. SNPs were selected for MALD if they had allele frequency difference between ancestral population (YRI and CEU from HapMap) of >0.4. Related and non-admixed individuals were excluded. Extreme trait analysis was performed using ADMIXMAP.
Results: 16 males and 68 females (mean age 41 years, SD=13) of whom 41 had with Ag≤98and 43 with Ag ≥164 IU were subjected to analysis with 2254 ancestry informative markers across the genome with a mean spacing of 1.8 cM (1.3 Mb). Estimated African ancestry was 79% (SD=13%, range 24-96%), while European ancestry was 20% (SD=12%, range 4-72%). Comparing the subjects at extremes of VWF, regions on chrs 1 (110-147 Mb) and 14 (22-40 Mb) had |Z| scores >3 (p<0.0025) which is the conventional cut-off in MALD studies. At chrs 1 and 14, greater African admixture was associated with higher VWF:Ag, consistent with the expected direction. No significant admixture signal was observed at the VWF (p=0.39) or ABO (p=0.48) loci, which may represent low power due to small sample size.
Discussion: These pilot results require replication in a larger number of independent subjects, as well as fine-mapping to identify the underlying variants responsible for differences in VWF between individuals.

Disclosures
No relevant conflicts of interest to declare.
Risk of Stroke in Patients with Multiple Myeloma: A Nationwide Population-Based Study
Authors: Liu Chia-Jen , Liu Yao-Chung , Hong Ying-Chung , Ku Fan-Chen , Gau Jyh-Pyng , Chiou Tzeon-Jye , Tzeng Cheng-Hwai 
Published: October 2019

Abstract
Background. Patients with multiple myeloma are at risk of thromboembolism. However, studies investigating the relationship between multiple myeloma and ischemic stroke are limited. Therefore, we conducted a nationwide population-based study to investigate the risk of stroke among patients with multiple myeloma and the association between myeloma-related therapy and development of stroke.
Material and methods. We recruited patients with newly diagnosed multiple myeloma aged 20 years or older without antecedent cerebrovascular events from Taiwan's National Health Insurance database between January 1, 2004 and December 31, 2011. Hazard ratios (HRs) of stroke risk for patients with multiple myeloma compared with an age-, sex-, and comorbidity-matched cohort were calculated by Cox proportional regression analysis. Additionally, therapeutic agents were put into Cox models as time-dependent covariates to avoid immortal time bias.
Results. This study consisted of 2,296 patients with multiple myeloma and 22,960 matched individuals, with a median age of 65 years (interquartile range 55-73). One hundred thirteen cerebrovascular events developed among 2,296 patients with multiple myeloma, with a follow-up of 4,119.2 person-years. The stroke incidence was 1.23 times higher in the multiple myeloma cohort than in the matched cohort (27.4 vs. 22.2 per 1,000 person-years), with an age-, sex-, and comorbidity-adjusted HR of 1.38 (95% confidence interval [CI] 1.14-1.67; P < 0.001). The multivariable Cox proportional hazard models showed bortezomib treatment as an independent risk factor determining the subsequent stroke in patients with multiple myeloma (adjusted HR 2.01; 95% CI 1.22-3.28; P = 0.006). This effect was not seen with steroids, thalidomide, or other chemotherapy agents.
Conclusion. Our study reveals an increased risk of stroke among patients with multiple myeloma compared with the matched cohort. Bortezomib treatment is associated with a higher risk of stroke in patients with multiple myeloma.
Figure. Incidence of stroke occurrence in patients with multiple myeloma and the matched cohort Figure. Incidence of stroke occurrence in patients with multiple myeloma and the matched cohort

Disclosures
No relevant conflicts of interest to declare.
A Single Nucleotide Polymorphism Affects the Binding Affinity of H2A.X and Regulates Latexin Transcription and Hematopoietic Stem Cell Function
Authors: Liang Ying 
Published: October 2019

Hematopoietic stem cells (HSCs) provide life-long production of blood cells and undergo self-renewal division in order to sustain the stem cell pool. Precisely regulated HSC pool maintenance and blood cell production is vital for organismal survival. We have identified a protein, latexin (Lxn), as a novel regulator of HSCs in mice, whose natural variation in the expression is inversely correlated with HSC population size. However, the molecular mechanisms involved in transcriptional regulation of Lxn in HSCs have not been clearly defined, and the genetic factors contributing to its natural variation are unknown. Here we report that an upstream regulatory sequence of the Lxn gene controls the promoter activity, and histone protein H2A.X interacts with the promoter and acts as a transcriptional activator. We identify a functional single nucleotide polymorphism (SNP), rs31528793, in the Lxn promoter that is associated with the differential binding of H2A.X, as identified by mass spectrometry. SNP rs31528793 attenuates the ability of H2A.X to bind and activate the Lxn promoter, as shown by chromatin immunoprecipitation and promoter luciferase assay. Moreover, overexpression of H2A.X increases the endogenous Lxn level and decreases HSC number and self-renewal. Concomitant blockage of Lxn activation significantly reverses these phenotypic changes, suggesting Lxn is one of the downstream targets and functional mediators of H2A.X. This study, for the first time, reveal the regulatory mechanism involved in Lxn transcription and uncover the functional role of naturally occurring genetic variants in determining differential gene expression and phenotypic diversity in HSC population.

Disclosures
No relevant conflicts of interest to declare.