bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutralizing IL-2 Early after HCT Specifically Prevents Expansion of Donor GM-CSF-Producing CD4+ T Cells That Initiate Acute Gut Gvhd
Authors: Song Qingxiao , Wang Xiaoning , Martin Paul J , Chen Yuanzhong , Zeng Defu 
Published: October 2019

Abstract
Acute graft versus host disease (GVHD) in gut has a critical impact on the outcome after allogenic hematopoietic cell transplantation (allo-HCT). It was recently reported that BATF-dependent GM-CSF-producing donor CD4+ T cells play a critical role in initiating acute gut GVHD (Ullrich et al: JCI 2018; Zeng: JCI; 2018). We recently reported that IL-2 from donor CD4+ T cells made infiltrating T cells resistant to host-tissue PD-L1-mediated tolerance (Ni & Song et al: JCI 2017). In the current studies, we tested whether in vivo neutralization of IL-2 early after allo-HCT regulates the expansion of GM-CSF-producing CD4+ T cells and the development of acute gut GVHD, and if so, whether host-tissue PD-L1 is required for this effect. We transplanted spleen (5x106) and BM cells (2.5x106) from C57BL/6 (H-2b) donors into irradiated wild-type (WT) or PD-L1-/- BALB/c (H-2d) recipients bearing BCL1 leukemia/lymphoma cells and into recipients without BCL1 cells. Recipients were treated with anti-IL-2 mAb IP (500 µg/mouse) on days 0, 2, 4 and 6, and controls were treated with isotype-matched IgG. We observed the following results. 1) Administration of anti-IL-2 fully prevented acute gut GVHD while preserving GVL activity in WT recipients. 2) Administration of anti-IL-2 did not prevent acute gut GVHD in PD-L1-/- recipients, indicating that GVHD prevention depends on expression of PD-L1 in recipient tissues. 3) Prevention of GVHD in WT recipients was associated with a marked reduction in the number of donor-derived GM-CSF-producing CD4+ T cells infiltrating gut tissue, together with decreased Paneth cell damage and bacterial translocation to the liver. These results indicate that neutralizing IL-2 early after allo-HCT specifically prevents expansion of acute gut GVHD-initiating GM-CSF-producing CD4+ T cells and prevents acute gut GVHD in a host-tissue PD-L1-dependent manner. These results also indicate that a short-term administration of anti-IL-2 following allo-HCT prevents induction of acute gut GVHD while preserving GVL effects. Current experiments are testing the molecular mechanisms whereby neutralizing IL-2 decreases the numbers of GM-CSF-producing CD4+ T cells in gut tissues via tissue expression of PD-L1. (Grant support: NIH 1R01CA228465-01 to Zeng).

Disclosures
No relevant conflicts of interest to declare.
Regulatory Reprogramming of Erythropoiesis By DNMT3A Mutation
Authors: Woo Janghee , Stehling-Sun Sandra , Deeg H. Joachim , Papayannopoulou Thalia , Urnov Fyodor D , Stamatoyannopoulos John A 
Published: October 2019

Abstract
DNA methyltransferase 3A (DNMT3A) regulates diverse epigenetic processes, and DNMT3A mutations occur frequently in myelodysplastic syndromes (MDS), including in founding clones of MDS samples. Most DNMT3A mutations affect Arg882 (R882) in the catalytic domain of DNMT3A, and are found almost exclusively in a heterozygous state. To resolve the relationship between the genetic and epigenetic architectures of R882H+ MDS, we engineered primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) to carry heterozygous DNMT3A R882H and performed temporally resolved, genome-wide regulatory mapping via DNase-seq combined with RNA-seq during erythroid differentiation in vitro, and in an in vivo transplantation model.
Compared with isogenic controls, heterozygous R882H HSPCs cells exhibited markedly impaired erythroid differentiation, accumulation of early myeloid progenitors, and diverse maturation defects. Transplantation of R882H HSPCs into W41 NSG mice revealed both impaired erythroid differentiation and preferential survival of mutant alleles in multiple hematopoietic lineages compatible with an early progenitor defect.
Regulatory profiling of DNMT3A R882H heterozygous cells during differentiation via combined DNase- and RNA-seq revealed global and sequential alterations in the regulatory landscapes in mutant cells, most prominently decommissioning of thousands of regulatory regions normally found in primitive cells that mark gene loci destined for expression during later differentiation stages. Decommissioned regulatory elements in R882H heterozygotes were concentrated around genes involved in both regulation of erythropoiesis and cell-cycle control, biasing HSPC differentiation away from erythropoiesis. Similar findings were observed in CD34+-selected bone marrows from 33 patients with MDS, comparing heterozygous DNMT3A R882H and wild type.
Collectively, our results indicate that DNMT3A R882H mutation reprograms early myeloid regulatory landscapes by preferentially targeting elements that control genes destined to be expressed at later stages of differentiation, resulting in a combined phenotype of impaired myeloid differentiation, impaired erythroid maturation, and preferential survival of R882H+ cells. The results provide novel mechanistic insights into the chromatin programming of erythroid differentiation and its connection with MDS.

Disclosures
No relevant conflicts of interest to declare.
A Rare Case of Delirium: Acquired Thrombotic Thrombocytopenic Purpura in an HIV Patient
Authors: Solanki Kinjal , Pir Syed Haris A , Khoury Constantine , Cervantes Jose F. 
Published: October 2019

Abstract
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder with incidence of one in a million. Manifestations of TTP include fever, thrombocytopenia, thrombotic microangiopathy affecting the brain, heart and kidney causing neurological symptoms, and hemolytic anemia. Not all patients with TTP will have each and every manifestation, and therefore a high index of suspicion is necessary when managing a patient with microangiopathic hemolytic anemia and thrombocytopenia. In recent years, increased incidence of TTP has been reported in patients with coexisting Human immunodeficiency virus (HIV)infection .
Clinical Case
A 55 year old female with unknown past medical history presented with confusion and altered sensorium after she was found in the airport wandering. When questioned, she was oriented to self only, and gave single phrase answers.
Vitals on admission were significant only for tachycardia with HR of 125 beats per minute. Rest of physical exam was normal. Lab work revealed severe anemia (Hemoglobin 5.1), thrombocytopenia ( Platelet count 6), borderline renal function( BUN 30, serum Creatinine 1.1) and Schistocytes on peripheral smear. TTP was the presumptive diagnosis. Without evidence of sepsis, she was treated with intravenous fluids, systemic steroids, blood products (pure red cell concentrate and fresh frozen plasma) and plasmapheresis. Patient was found to be HIV positive, and had acquired immunodeficiency syndrome with CD4 count of 193. ADAMTS13 inhibitor was 1.3 (nl <0.4) and ADAMTS13 activity level was <3 (normal range 68-163%).
Patient's mental status improved to baseline over next 3 days and, renal failure and encephalopathy resolved. Upon further investigation, she recalled having a needle stick injury around 10 years ago. She was started on elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) and prophylactic antibiotics prior to discharge.
Discussion
Despite its rare nature, TTP can be fatal if one fails to make a proper timely diagnosis. If left untreated, the mortality can reach up to 90% but with empiric treatment and therapeutic plasma exchange up to 85% survival rate can be achieved.
Through this case report, we hope to raise the awareness of this disorder with its particular association with HIV infection. The exact mechanism for HIV related TTP is unknown, but some proposed ones include the release of large amounts of von Willebrand factor and downregulation of ADAMTS13 and/or the production of antibodies against ADAMTS13. ADAMTS13 activity levels below 10% are seen in acquired and hereditary TTP, but not all patients with such exhibit low levels with this assay. Acquired TTP with low levels of ADAMTS13 has been increasingly reported in association with HIV infection, such as in this case.

Disclosures
No relevant conflicts of interest to declare.
Survival Analysis in Patients of AML with Myelodysplasia Related Changes
Authors: Ghimire Krishna , Nepal Mahesh , Rondelli Damiano 
Published: October 2019

Abstract
Introduction:
AML with myelodysplasia related changes (MRC) is a disease of elderly which has very poor outcome. There is limited data on survival disparities in AML with MRC by age and race.
Methods: We used SEER 18 registry to analyze relative survival (RS) rates among patients with AML with MRC diagnosed during 2000-2014. Patients were stratified by age (20-64 yrs, ≥65 yrs), sex and race (Caucasian, African American [ AA] and others). We used SEER Stat 8.3.4 for survival analysis.
Results: There were 2,071 patients; male 60%, median age of diagnosis 70 yrs; diagnosed with AML with MRC during 2000-2014. There were 1,742 Caucasian, 141 AA and 185 other races. The median overall survival of AML with MRC in Caucasian, AA and other races were 6.9, 6.1, 8.2 months respectively.
The RS for younger (20-64 yrs) patients was at 51.4% 1 yr , 32.8% 2 yr 27.9% and 3 yr . The RS for older patients was at 26.3% 1 yr , 12% 2 yr and 6.6% 3 yr .
When younger pts were analyzed by race, RS for Caucasian, AA, others were: 51.3%, 40.6%, 60.2% with p values 0.94, 0.104, 0.129 respectively at 1 yr ; 33.5%, 16.2%, 38.7% with p values 0.898, 0.017, 0.201 respectively at 3 years; 28.8%, 9.0%, 33.6% with p values 0.861, 0.005, 0.187 at 5 yrs respectively . There was no racial difference in RS in older patients.
When stratified by sex, RS for younger AA males vs all younger males were 33.4% vs 49.6% p: 0.05 at 1 yr; 11.6% vs 29.9% p 0.021 at 2 yrs ; and 3.9% vs 25% p 0.007 at 3 yrs respectively. There was no racial difference in RS in female sex both in younger and older patient population.
Conclusion:
Our study showed that young AA male diagnosed of AML with myelodysplasia related changes have poor outcome as compared to others. This difference is likely related to difference in disease biology and socio cultural differences and access to health care. Further studies are needed to identify potential areas of intervention.
Table. Table.

Disclosures
No relevant conflicts of interest to declare.
Relationship between Non-Prescribed Drug Use and Employment Status of Patients with Sickle Cell Disease
Authors: Idowu Modupe , Chung Tong Han , Yu Katherine 
Published: October 2019

Abstract
Introduction: Patients with sickle cell disease (SCD) suffer from recurrent episodes of acute vaso-occlusive crises that cause acute musculoskeletal pain and chronic pain due to complications such as avascular necrosis of the joints or bone infarcts. Most of these patients are on chronic opioid medications to manage their acute and chronic pain. Generally, patients with chronic pain syndrome are more prone to use illicit drugs more than the general population. In addition, patients with SCD have high rates of unemployment, which may put certain individuals at risk for negative coping behaviors such as illicit drug use. This study aim at investigating the relationship between the use of non-prescribed drug (illicit drug) and employment status of patients with SCD.
Patients and Methods: This was a pilot study of SCD patients at UT Physicians Comprehensive Sickle Cell Center from January 2012 to July 2018. We administered surveys during routine clinic visits and we reviewed clinical data in the electronic medical records. We used results of comprehensive urine drug screen (UDS) to evaluate for the use of non-prescribed drugs. UDS was done, on average every 3 to 6 months, on each patient. Descriptive analysis was performed with frequency distributions. Univariate logistic regression was conducted to investigate the association between non-prescribed drug use and employment status.
Results: A cohort of 78 SCD patients completed surveys about employment and non-prescribed drug use. In the survey, only ten patients (12.82%) reported using at least one non-prescribed drug. However, after the chart review for urine drug screens, twenty one out of seventy eight (26.92%) were using non-prescribed drugs. Most of the SCD patients using non-prescribed drug (71%) used Marijuana and three patients used multiple non-prescribed drugs. Seven out of twenty one (33.33%) of the non-prescribed drug users and 18 out of 57 (31.58%) of the non-drug users are employed. The univariate logistic regression analysis showed non-prescribed drug use is not statistically associated with employment status among SCD patients (P-value=0.8829).
Conclusions: In this sample, we concluded that there was no obvious relationship between non-prescribed drug use and employment status of patients with SCD. In our cohort, marijuana was the most commonly used non-prescribed drug, which might be partly due to its effect on chronic pain management. Non-prescribed drug use was quite common (26.92%), but was under-reported (13%) among users. It is important to note that only 3 out of 78 patients (3.85%) used multiple non-prescribed drugs; hence, polysubstance abuse was rare in our sample.

Disclosures
No relevant conflicts of interest to declare.
Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice
Authors: Spaner David , Sheng-Tanner Xiaofang , Schuh Andre C. 
Published: October 2019

AbstractAcute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation is associated with impaired deletion and anergy of host-reactive T cells. To elucidate the immunoregulatory events that may contribute to such dysregulated T-cell responses in GVHD, we studied superantigen (SAg) responses after adoptive T-cell transfer into severe combined immunodeficient (SCID) mice. SAg responses are normally regulated by mechanisms involving deletion and anergy, with SAg-reactive T cells typically being deleted rapidly in vivo. In a SCID mouse model of GVHD, however, allogeneic host SAg-reactive T cells were not deleted rapidly, but rather persisted in increased numbers for several months. Moreover, depending on the timing of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be demonstrated following the adoptive transfer of syngeneic T cells into SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of weakly reactive T cells after adoptive transfer and SAg stimulation. When transferred alone, KJ1-26.1+ T cells demonstrated impaired deletion and anergy. In the presence of more strongly staphylococcal enterotoxin B (SEB)–reactive T cells, however, KJ1-26.1+ T cells were regulated normally, in a manner that could be prevented by inhibiting the effects of more strongly SEB-reactive cells or by increasing the level of activation of the KJ1-26.1+ T cells themselves. We suggest that the control mechanisms that normally regulate strongly activated T cells in immunocompetent animals are lost following adoptive transfer into immunodeficient hosts, and that this impairment contributes to the development of GVHD.
Polymorphisms of the tumor necrosis factor-α gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma
Authors: Neben Kai , Mytilineos Joannis , Moehler Thomas M. , Preiss Astrid , Kraemer Alwin , Ho Anthony D. , Opelz Gerhard , Goldschmidt Hartmut 
Published: October 2019

Abstract
Thalidomide (Thal) is a drug with antiangiogenic, anti-inflammatory, and immunomodulatory properties that was found to inhibit the production of tumor necrosis factor-α (TNF-α) in vitro. We studied single nucleotide polymorphisms at positions −308 and −238 of the TNF-α gene promoter and measured the corresponding TNF-α cytokine levels in 81 patients (pts) with refractory and relapsed multiple myeloma (MM) who were treated with Thal. In myeloma pts carrying the TNF-238A allele (n = 8), we found a correlation with higher pretreatment TNF-α levels in peripheral blood (P = .047). After Thal administration, this TNF-238A group had a prolonged 12-month progression-free and overall survival of 86% and 100% versus 44% and 84% (P = .003 andP = .07) in pts with the TNF-238G allele, respectively. These findings suggest that regulatory polymorphisms of the TNF-α gene can affect TNF-α production and predict the outcome after Thal therapy, particularly in those MM pts who are genetically defined as “high producers” of TNF-α.
Platelets Provide Signals for CD34+ Progenitor Cells to Home to Sites of Vascular Injury.
Authors: Van Zonneveld Anton Jan , Verseyden Caroline , Loomans Cindy J.M. , Rabelink Ton J. , De Boer Hetty C. 
Published: October 2019

Abstract
Introduction Accumulating evidence indicates that vascular function is modulated by circulating progenitor cells (PCs). Circulating PCs have been shown to enhance angiogenesis, promote vascular repair, improve endothelial function, inhibit atherosclerosis and increase ventricular function after myocardial infarction. How circulating PCs home to their target sites is not known.
Hypothesis Since vascular damage, ischemia and atherosclerosis coincides with the activation of coagulation and platelets we hypothesized that fibrin, activated platelets and platelet products might trigger circulating PCs to home to sites of injury. Homing involves (1) escape of PCs from flowing blood, (2) migration towards an injury and (3) differentiation into an endothelial cell phenotype.
Methods & Results (1) Escape from flowing blood was tested in a flow model using tissue factor expressing endothelial cells (ECs) on which a fibrin network containing thrombi was formed under flow. The platelet thrombi offered flowing CD34+ cells a landing site leading to deceleration and firm attachment to the surrounding ECs. Tethering of the CD34+ was dependent on P-Selectin expressed by the platelets, since blokkage of P-Selectin or P-Selectin glycoprotein ligand-1, expressed by the CD34+, prevented deceleration of the CD34+ cells. (2) Migration of PCs was tested in a Boyden chamber in which fibrin, fibrin+platelets or platelets alone was used to attract CD34+ cells. Fibrin+platelets induced migration of CD34+ cells, while fibrin or platelets had no effect. (3) Differentiation of PCs was tested in a culture system using a fibrin clot containing platelets and a culture medium lacking serum and additional growth factors. In this way, secreted platelet products like VEGF, transforming growth factor, platelet activating factor or lysophosphatidic acid determine the culture conditions. After 10 days of culture on fibrin+platelets, CD34+ PCs showed uptake of acetylated LDL, expression of eNOS, VEGF receptor 2 and CD31, indicating that the cells exhibited endothelial-like features.
Conclusion Our results indicate that activation of the coagulation system and consequently activation of platelets, may offer circulating PCs a way to efficiently home to sites of vascular injury and thus contribute to neovascularization.
Stem Cell Factor (SCF) for Hematopoietic Stem Cell (HSC) Mobilization: Results of the Randomized IFM 99-01 Trial.
Authors: Bourin Philippe , Huynh Anne , Recher Christian , Berthou Christian , Garderet Laurent , Benbouker Lofti , Perry Anne-Marie , Facon Thierry , Hulin Cyrille , Sotto Jean-Jacques , Voillat Laurent , Michallet Mauricette , Attal Michel 
Published: October 2019

Abstract
Introduction : In multiple myeloma, the usual mobilization protocol is toxic because of the use of cyclophosphamide. Several studies showed the interest of SCF.
Objective : To compare two mobilization protocols: endoxan 4g/m2 + G-CSF 5μg/kg/j (arm A) versus G-CSF 10μg/kg/j + SCF 25μg/kg/j (arm B) in a prospective, open and, randomized trial.
Patients and methods : the studied criteria were the quality of the cell collections (objective > 5.106 CD34+ cells into 2 cytapheresis), the toxicity of the mobilization and graft phases, as well as the post-graft hematopoietic reconstitution. Multiple myeloma patients, less than 65 years old, with 0 or 1 risk factor (ß2microglobulin > 3 mg/L or chromosome 13 deletion) and who have a response ≥ 50% after 3 cures of VAD were included. After a fourth cure of VAD each patient was planed to receive a tandem transplant (IFM 99-02 trial).
Results : 150 patients (pts) were included and 138 were eligible (arm A = 67 pts, arm B = 71 pts). Pts and disease characteristics were similar in each arm. The objective of HSC collection was obtained with 92% pts in arm A and 81% pts in arm B (non significant). The total number of CD34+ cells collected were similar: 16.106 CD34+/kg (arm A) versus 15.106 CD34+/kg (arm B). Toxicity of HSC mobilization procedure was significantly different: duration of neutropenia < 500/mm3 (8 days in arm A versus 0 days in arm B, p<0.00001), duration of thrombopenia < 50 000/mm3 (5 days in arm A versus 0 days in arm B, p<0.0001), use of antibiotherapy (43% pts in arm A versus 9% pts in arm B, p<0.00001). 31% pts receiving SCF had local erythema at injection point. One pts experienced a grade 3 allergy in arm B. Hematopoietic reconstitution after first graft (high dose Melphalan 140 mg/m2, G-CSF at day 7) was not significantly different in either arm: duration of neutropenia < 500/mm3 (8 days in arm A versus 10 days in arm B), duration of thrombopenia < 50 000/mm3 (7.5 days in arm A versus 9 days in arm B), number of red blood cells units transfusions (1.5 versus 1.5). The 36 months overall survival probability was not significantly different with HDC mobilization (64%) versus SCF + G-CSF mobilization (87%).
Conclusion : In myeloma patients, HSC mobilization with SCF + G-CSF is as effective as HDC + G-CSF, and gives very significant lower toxicities.