bluuebunny/crossref_metadata_2025_split huggingface dataset:
Positive Impact of Chronic Graft-Versus Host Disease on Survival in 928 Allogeneic Hematopoietic Stem Cell Transplant Recipients
Authors: Gurman Gunhan , Ataca Pinar , Atilla Erden , Civriz Bozdag Sinem , Toprak Selami Kocak , Yuksel Meltem Kurt , Demirer Taner , Akan Hamdi , Arslan Onder , Topcuoglu Pervin , Beksac Meral , Ilhan Osman , Ozcan Muhit 
Published: October 2019

Abstract
Introduction:
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a standard curative treatment option in hematological diseases. The anti-leukemic activity relies not only the effects of conditioning regimen but also the immune mediated graft-versus leukemia (GVL) effect. Donor T cells are responsible for the GVL and causes complications namely acute and chronic graft versus host disease (GVHD). Herein, we aim to present the relation of graft versus host disease with survival and relapse.
Patients and Methods:
We retrospectively evaluated 928 Allo-HSCT between 1989 and 2015 followed in our institution. Chi-square test and student's t test were used in comparison. P <0.05 was considered statistically significant.
Results:
551 patients were male (59%) and 377 patients (41%) were female. The median age of the group was 34 (range 15 -71). Patients received stem cell from related donors more frequently (85%) with HLA full match (66%). Peripheral blood was the source of stem cells in 645 recipient (70%) followed by bone marrow (28%). 75 patients were diagnosed as benign hematological disorders. The most common malign hematological diagnosis was acute myeloid leukemia in 366 patients (39%). Patients received 80% of myeloablative conditioning regimen prior to transplantation. 43% of the patients diagnosed as acute GVHD and 45% had chronic GVHD. 798 achieved engraftment (86%) neutrophil engraftment median of 16 days, platelet engraftment median of 14 days. Relapse was detected in 6% of patients. The overall survival (OS) was 59 months and progression free survival (PFS) was 33 months. Acute GVHD had no impact on OS, PFS, relapse rate. The OS in patients with chronic GVHD was significantly higher than in GVHD negative patients (68.8 vs 56.9, P=0.009). Although chronic GVHD patients had lower risk of relapse and higher PFS, the results were not statistically significant.
Conclusion:
GVHD is a serious complication and important cause of post transplant morbidity. Chronic GVHD is associated with lower risk of relapse in previous studies. In this study, we have concluded the improved OS in patients with chronic GVHD. The immune mediated GVL effect may be the reason for anti-leukemia effect and improved survival.

Disclosures
No relevant conflicts of interest to declare.
The Light Chain of Rat Factor VIII Confers Its Superior Cofactor Activity
Authors: Wang Qizhao , Firrman Jenni , Pokiniewski Katie A , Cao Wenjing , Wei Hongying , Herzog Roland , Xiao Weidong 
Published: October 2019

Abstract
Hemophilia A is caused by genetic defect of human coagulation factor VIII (hFVIII) and patients have to take lifelong replacement therapy to prevent excessive bleedings upon hemostatic challenges. Due to the short half-life of hFVIII, replacement treatment has to be given frequently and inhibitors against infused hFVIII can be developed in about 20-30% of patients. These shortcomings have generated tremendous interest in developing HA gene therapies which is more efficient and long-lasting. However, early preclinical studies have shown FVIII activities were still limited after vector delivery. A Modified hFVIII with higher specific activity and pharmacodynamics properties is highly desirable to overcome the disadvantages of current protein replacement and gene therapy strategies.
In the current study, we successfully constructed a B-domain deleted rat FVIII(rBDDF8) that contained a PACE/furin recognition site (RHQR) within a 14 amino acid linker between A2 and A3 domains. The rBDDF8 displayed significantly higher coagulation activity(~2.5-fold) than hBDDF8 after transfection into HEK 293 cells. In order to explore the mechanism for the observed superior cofactor activity, we constructed heavy chain(rHC) and light chain(rLC) of rFVIII. The rHC and rLC are able to reconstitute 5 times more FVIII activity than their human counter parts. However, when rHC is associated with human FVIII light chain (hLC), the reconstituted FVIII activity is lower that from hHC and hLC, suggesting that high coagulation activity of rFVIII is not mediated by its HC. On the contrary, when FVIII is constituted by hHC with rLC, we found that the activity is increased by 3~5-fold as against hHC and hLC. The hHC antigen level of FVIII reconstituted from hHC and rLC was 1.5-fold higher than that of hHC and hLC, suggesting that higher activity of FVIII with hHC and rLC is not through increased secretion. The specific activity deduced from activity/antigen ratio showed that FVIII with rLC is 3 times higher more than FVIII with hLC. To investigate the potential application of rFVIII in gene therapy, rBDDF8 was delivered in hemophilia A mouse model using AAV8 vectors. The high dose rBDDF8(4*1011 vg/mouse) resulted 2.5U FVIII activity at week 17, which is much higher(about 10-fold) than that of hBDDF8. When the rFVIII was delivered by dual chains strategy, i.e, administering vectors carrying only LC or HC simultaneously, it also showed 2-4 fold increased in FVIII activity. Interestingly, the combination of hHC and rLC also generated similar FVIII activity as rHC and rLC, further proving the rLC is the major contributor to the superior coagulation activity of rFVIII. Our results showed that the rFVIII has higher cofactor activity conferred by its LC. Our results suggest that rFVIII can be further exploited to make an ideal candidate for hemophilia gene therapy using AAV vectors.

Disclosures
No relevant conflicts of interest to declare.
Small Molecule Bda-366 As a Bcl2-BH4 Antagonist for Multiple Myeloma Therapy
Authors: Deng Jiusheng , Park Dongkyoo , Wang Mengchang , Deng Qiaoya , Matulis Shannon , Boise Lawrence H. , Deng Xingming 
Published: October 2019

Abstract
Multiple myeloma (MM) is the most common hematological malignancy in USA, characterized with excessive abnormal clonal plasma cells in the bone marrow. Despite the great improvement in MM treatment by targeting the normal plasma cell biology of the cells during the last decade, the disease still remains incurable. B-cell lymphoma-2 (Bcl2) protein has four domains: BH1 (Bcl2 homology domain 1), BH2, BH3 and BH4, and plays critical roles in promoting the survival and drug-resistant of MM cells. Unlike the BH1, BH2, and BH3 domains, the BH4 region is responsible for the anti-apoptotic function of Bcl2 protein. Current BH3-mimetic and other Bcl2 inhibitors have been trailed in clinic but showed limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a Bcl2-BH4 domain antagonist with potent anti-MM effect. BDA-366 bound to the BH4 resulted in the decrease of Bcl2 phosphorylation and the exposure of the BH3 domain as detected by anti-Bcl2-BH3 antibodies. Consequently, BDA-366 treatment induced robust apoptotic death on both human MM cell lines (RPMI8226 and U266) and primary MM cells from patients. In NOD-scid/IL2Rγnull (NSG) murine xenograft model, administration of BDA-366 (20mg/kg/day, 5 doses) markedly suppressed the growth of human MM tumor cells in vivo. We propose that BDA-366 as a novel BH4-based anti-MM agent could provide a more efficient pharmacological approach to treat MM.

Disclosures
No relevant conflicts of interest to declare.
Predictive Value of Rothman Index in Patients That Develop Febrile Neutropenia
Authors: Rubio Luis Alberto , Banach David , Lee Alfred I 
Published: October 2019

Abstract
Background: Febrile Neutropenia (FN) in cancer patients is associated with a high mortality rate yet identifying patients with FN at highest risk for short term morbidity and mortality remains challenging. The Rothman Index (RI) is a real-time composite measurement of a patient's condition using 26 clinical variables sensitive to signs of patient clinical decline. RI has been shown to predict intensive care unit (ICU) admission, hospital readmission and short term mortality among inpatients. A prior study from our institution demonstrated that hospitalized patients with hematological malignancies and RI < 60 have a greater likelihood of readmission or discharge to hospice rather than those with higher RI scores. The aim of this study was to explore RI as a predictor of adverse outcomes in patients with hematological malignancies who have FN.
Methods: Chart records of all patients with hematological malignancies and FN who were hospitalized at Yale Cancer Center between February of 2013 and July of 2014 were reviewed. Clinical variables collected included demographics, malignancy type, comorbidities, admission condition and microbiological data related to the FN episode. The primary outcome measure was a composite of in-hospital mortality and discharge to hospice care. Variables associated with the primary outcome in univariate analysis were entered into a multivariate logistic regression model for analysis.
Results: Of 308 patients with hematological malignancies, 180 (58.4%) developed FN during their admission and 38 (12.3%) died during the admission or were discharged to hospice. A total of 85 (27.6%) patients had a RI < 60, 155 (50.3%) had a RI between 60-80, and 71 (23.1%) had a RI > 80. Controlling for malignancy type, major medical comorbidities and microbiologically confirmed bacterial infection, RI < 60 was independently associated with this outcome (Odds ratio 3.02, 95% Confidence Interval 1.25-7.34). Baseline renal disease, pneumonia, respiratory failure and sepsis were also associated with the primary outcome.
Conclusion: RI is an objective measure that can independently predict poor outcomes among inpatients with FN. RI can guide clinicians caring for patients with FN in both prognostication and identifying high risk patients with an RI < 60 who are at higher risk for mortality, discharge to hospice, or high risk of readmission. The utility of this scoring system should be compared to existing risk stratification systems used in Oncology to identify its optimal use in the clinical setting.
Table 1. Factors associated with inpatient mortality or hospice discharge among hematologic malignancy inpatients with febrile neutropenia Variable OR 95% CI for OR p RI < 60 3.02 1.25-7.34 .015 Respiratory Failure 3.51 1.07-11.56 .039 Renal Disease 4.97 1.38-17.9 .014 Sepsis 8.18 1.63-41.2 .011 Pneumonia 8.01 1.42-45.1 .018

Disclosures
No relevant conflicts of interest to declare.
Understanding the Patient's Experience with Acute Myeloid Leukemia: A Patient Interview Study
Authors: Tomaszewski Erin L. , Fickley Catherine , Maddux LeAnne , Krupnick Robert , Bahceci Erkut , Paty Jean , van Nooten Floortje 
Published: October 2019

Abstract
INTRODUCTION: One way to capture the patient reality of living with disease is to talk with patients and listen to them describe their experience. We sought to understand the patient perspective regarding the signs and symptoms of acute myeloid leukemia (AML) and the impact of these on patients, through direct, qualitative patient interviews.
METHODS: We conducted individual interviews with patients with AML (median age=48, 37% male) in Japan and the USA following a semi-structured interview guide, containing both open- and closed- ended questions. These questions aimed to understand the patient's experience both spontaneously and with specific probing. Patients were asked to describe their individual experience of living with AML including signs, symptoms, impacts, and the experience during treatment of the disease.
RESULTS: Forty-one patients were interviewed in the two regions: 23 in US, and 18 in Japan. The sign, symptom, and impact 'concepts' identified were very similar across regions. Forty-nine symptoms were mentioned by US patients; 32 by Japanese patients. The signs/symptoms reported most frequently and as most bothersome included: fatigue, bruising, weakness, dizziness, shortness of breath, and bleeding (Table 1). Twenty-three unique impacts of signs/symptoms were mentioned in the US and 20 in Japan. The most frequent and bothersome impacts reported included: decreased ability to maintain social/familial roles, anxiety, decreased ability to function, depression, fear, remission uncertainty, appetite loss, and low sex drive (Table 1). These concepts were corroborated by two additional sources: interviews with clinicians and published literature.
DISCUSSION: The priority concepts expressed by patients were relevant and important to all four AML patient groups in both regions. This data provides valuable insight into patients' experiences with AML and helps to select the appropriate patient-reported outcomes for clinical trials.
Table 1. AML Symptom and Impact Frequencies US Frequency (N=23), n (%) Japan Frequency (N=18), n (%) Symptom Fatigue 22 (95.6) 16 (88.8) Bruising 18 (78.2) 7 (38.8) Weakness 18 (78.2) 15 (65.2) Dizziness 15 (65.2) 12 (52.1) Shortness of Breath 13 (56.5) 15 (65.2) Bleeding 12 (52.1) 13 (72.2) Impact Decreased ability to maintain social/familial roles 21 (91.3) 13 (72.2) Anxiety 20 (86.9) 17 (94.4) Decreased ability to function 20 (86.9) 17 (94.4) Depression 16 (69.5) 7 (38.8) Fear 15 (65.2) 12 (52.1) Remission uncertainty 15 (65.2) 17 (94.4) Appetite loss 14 (60.8) 13 (72.2) Low sex drive 11 (47.8) 7 (38.8)

Disclosures
Tomaszewski: Astellas Pharma, Inc.: Consultancy. Fickley:Astellas Pharma, Inc.: Consultancy. Maddux:Astellas Pharma, Inc.: Consultancy. Krupnick:Astellas Pharma, Inc.: Consultancy. Bahceci:Astellas Pharma Global Development: Employment. Paty:Astellas Pharma, Inc.: Consultancy. van Nooten:Astellas: Employment.
Three Dimensional Speckle Tracking Echocardiography (3D-STE) for Early Detection of Subtle Myocardial Deformation Dysfunction in Thalassemic Patients
Authors: Moustafa Agha Hala Mounir Mohamed , AbdelMassih Antoine , Abd El Rahman Mohamed Youssef , Milanesi, Ornella , Castaldi Biagio , Geranio Giulia , Frizziero Ludovica , Basso Giuseppe , Putti Maria Caterina , Essam Ahmed , Esmail Reem , El-Kamah Ghada , Hamdy Mona , El Baz Heba , El Behary Noha , Hanna Carol , El Tagy Hassan , Atef Mishriky Mary , Mamdouh Mirna , Khalifa Hossam , Adam Soheir 
Published: October 2019

Abstract
Background: Among patients with beta-thalassemia early detection of transfusion-induced myocardial iron loading and its intervention with aggressive chelation therapy may delay or reverse heart failure. Three dimensional speckle tracking echocardiography (3D-STE) is a novel tool that may early detect myocardial affection in these patients.
Methods: Thirty-two thalassemic patients with a mean age of 18.1± 7.03 years and 30 aged matched healthy control subjects have been included in the study. Patients have been recruited from pediatric hematology clinics in both Cairo University, Egypt (n=18) and Padova University, Italy (n=14). 3D-STE was performed to all patients and control subjects in addition to the myocardial relaxometry T2* by cardiac MRI.
Results: The left ventricular ejection fraction (LVEF) derived from 3D echocardiography among the studied thalassemia patients was within normal range 62.5± 5.6%. Compared to the normal subjects, thalassemia patients had a statistical significant reduction of the left ventricular global longitudinal strain (-16.81± 0.93% vs -18.76 ± 1.12 %, p=0.001), the left ventricular global circumferential strain (-10.56 ± 0.61% vs -11.83 ± 0.71 %, p=0.001 ) and the left ventricular global area strain (-20.13 ±1.18% vs -22.48 ±,1.29 %, p=0.001). No statistical significant correlation was found between the severity of myocardial iron overload measured by T2* and the measured left ventricular global strain.
Conclusion: In asymptomatic thalassemia patients with preserved left ventricular global systolic function 3D-STE derived strain can detect early subtle myocardial dysfunction. The observed subtle myocardial deformation dysfunction is not related to the extent of myocardial iron deposition.

Disclosures
No relevant conflicts of interest to declare.
Platelet-Neutrophil Aggregates Promote Pulmonary Arteriole Microembolism in Sickle Cell Disease
Authors: Bennewitz Margaret F. , Vats Ravi , Tutuncuoglu Egemen , Gladwin Mark T. , Sundd Prithu 
Published: October 2019

Abstract
Introduction: Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ~100,000 Americans and millions of people worldwide. The acute chest syndrome (ACS), a form of acute lung injury, is a major cause of morbidity among SCD patients. The current treatment for ACS is primarily supportive and the molecular mechanism remains largely unknown. SCD patients hospitalized with vaso-occlusive pain crisis (VOC) often develop ACS within the ensuing days, suggesting a role for pulmonary vaso-occlusion in the onset of ACS. However, the cellular and molecular mechanism and the anatomical site of pulmonary vaso-occlusion are still elusive.
Materials and Methods: Intravenous (IV) bacterial lipopolysaccharide (LPS) was used to induce VOC in SCD mice. Intravital multiphoton excitation (MPE) fluorescence microscopy was used to study the blood cell trafficking within the pulmonary microcirculation of live SCD or control mice. Fluorochrome-conjugated anti-mouse Ly-6G, Ter-119, and CD49b antibodies were administered IV for in vivo staining of circulating neutrophils, red blood cells and platelets, respectively. Cellular trafficking was recorded at baseline and 2 hours after IV challenge with LPS. Image sequences were analyzed to identify vaso-occlusion, which was defined as cellular aggregation and stasis of blood flow within the pulmonary blood vessels.
Results and Discussion: Preliminary data using MPE imaging in transgenic SCD mice revealed that vaso-occlusion was absent at baseline in unchallenged SCD mice and the cellular trafficking within the pulmonary microcirculation was comparable in SCD and control mice. Doses of IV LPS (0.01-5 mg/kg of body weight), which were innocuous to control mice were found to be lethal to SCD mice. Remarkably, MPE imaging of the lung microcirculation revealed that IV LPS led to microembolism of the pre-capillary pulmonary arterioles by platelet-neutrophil aggregates in SCD but not control mice. The microembolism involved either entrapment of circulating platelet-neutrophil aggregates or in situ aggregation through sequential steps of neutrophil arrest on the arteriolar endothelium, followed by platelet nucleation on arrested neutrophils and microthrombus formation.
Conclusions: Initial findings demonstrate that pulmonary vaso-occlusion in SCD mice involves microembolism of the pre-capillary pulmonary arterioles by platelet-neutrophil aggregates. Future studies will determine the molecular interactions responsible for pulmonary arteriolar microembolism.
Acknowledgments: This study is supported by the 11SDG7340005 from the American Heart Association (P.S.) and the VMI startup account (P.S.). M.F.B is supported by the NIH NHLBI VMI T32 training grant T32HL110849.

Disclosures
No relevant conflicts of interest to declare.
The Heme Scavenger Hemopexin Reverts Heme-Driven Pro-Inflammatory Phenotypic Switching of Macrophages in Sickle Cell Disease
Authors: Vinchi Francesca , Costa da Silva Milene , Ingoglia Giada , Petrillo Sara , Brinkman Nathan , Zuercher Adrian , Cerwenka Adelheid , Tolosano Emanuela , Muckenthaler Martina U. 
Published: October 2019

Abstract
Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages as well as chronic inflammation. Here we demonstrate that in addition to activating the vascular endothelium, hemoglobin and heme alter the macrophage phenotype in sickle cell disease.
We show that exposure of cultured macrophages to hemolytic aged red blood cells, heme or iron causes their functional phenotypic change towards a pro-inflammatory phenotype, with increased expression levels of inflammatory markers such as IL-6 (P<0.001), TNFα (P<0.0001), IL-1β (P<0.001) MHCII (P<0.001), CD86 (P<0.05) and CD14 (P<0.0001) and decreased expression levels of anti-inflammatory markers such as IL-10 (P<0.0001), CD206 (P<0.0001), Arginase-1 and Ym1. Interestingly, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle cell disease triggers similar pro-inflammatory phenotypic alterations in hepatic macrophages, increasing the expression levels of IL-6 (P<0.0001), MHCII (P<0.05), CD86 (P<0.0001) and iNOS (P<0.01). On the mechanistic level, heme-induced pro-inflammatory phenotype switching of macrophages critically depends on ROS production and activation of the TLR4 signaling pathway.
We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice (P<0.05) and reduces production of cytokines (IL-6, TNFα: P<0.01) and reactive oxygen species (P<0.001). Importantly, in sickle mice the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages, by decreasing the expression of IL-6 (P<0.05), MHCII (P<0.01), CD86 (P<0.001) and iNOS (P<0.05).
Taken together, our data suggest that therapeutical administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation in sickle cell disease.

Disclosures
Brinkman: CSL Behring: Employment. Zuercher:CSL Behring: Employment.
Neutrophil Transmigration into the Joint of RA-Induced Mouse Is Markedly Blocked By EC-18, Via STAT3 Signaling
Authors: Shin Jae Min , Kim Young-Jun , Yoon Sun Young , Kim Myung-Hwan , Suh Cheolwon , Sohn Ki-Young , Kim Heung-Jae , Han Yong-Hae , Chong Saeho , Kim Jae Wha 
Published: October 2019

Abstract

Neutrophil trafficking during the inflammatory response is effectively regulated by the enhanced IL-6 expression which orchestrates chemokine production and leukocyte apoptosis. Inappropriate regulation of leukocyte trafficking can lead to impaired neutrophil clearance and increased tissue damage from the accumulation of neutrophil-secreted proteases and reactive oxygen species at the site of inflammation. In collagen-induced arthritis (CIA) mouse model, arthritic symptoms were recapitulated with an increase of IL-6 level in the synovium, which was recuperated by the treatment of EC-18 to the level comparable with commercial therapeutics (such as Remicade or Methotrexate). When the tissues were stained with neutrophil-specific antibodies, EC-18 significantly reduced the infiltration of neutrophils into the synovium. EC-18, a monoacetyl-diglyceride (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), has been isolated from the antlers of Sika deer (Cervus nippon Temminck), which were known to have immunosuppressive and anti-arthritic activities. In this study, we have discovered that EC-18 regulates the activity of signal transducer and activator of transcription 3 (STAT3), which is a master regulator of IL-6 expression. EC-18 caused the decrease of IL-6 production in a macrophage cell line, RAW264.7, and RA-fibroblast-like synoviocyte (RA-FLS) via the regulation of STAT3 signaling without affecting NF-κB signaling, which is also a well-known regulator of IL-6 expression. The expression of RANKL, a key factor for osteoclast differentiation and activation, was also regulated by STAT3, and decreased by EC-18 treatment. In fact, EC-18 inhibited osteoclastogenesis of hematopoietic stem cells. Therefore, blocking STAT3 activity by EC-18 treatment was able to inhibit the inflammatory cytokine loop triggering RANKL expression, thereby inhibiting joint destruction. Cardinal features of rheumatoid arthritis (RA) are chronic synovial inflammation and joint damage caused by the activity of cytokines and proteins expressed from cells in synovial fluid. Interleukin (IL)-6, a multifunctional pro-inflammatory cytokine, plays a critical role in the pathogenesis of joint and systemic inflammation in RA. Therefore, EC-18 could be utilized as a potential therapeutic agent for the treatment of sustained inflammation and joint destruction.

Disclosures
No relevant conflicts of interest to declare.