bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of MALT1 Protease Activity Is Selectively Toxic for Activated B CellÃ,Â–Like Diffuse Large B Cell Lymphoma Cells.
Authors: Ferch Uta , Kloo Bernhard , Gewies Andreas , Pfaender Vera , Düwel Michael , Peschel Christian , Krappmann Daniel , Ruland Jürgen 
Published: October 2019

Abstract
Abstract 1271
Poster Board I-293
Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell-like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10 and the paracaspase MALT1 for survival. CARD11, BCL10 and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11/BCL10/MALT1 (CBM) complexes couple upstream events to IKK/NF-κB activation. MALT1 possesses in addition a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here we demonstrate pre-assembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL but not in germinal center B cell-like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.

Disclosures
No relevant conflicts of interest to declare.
Impact of Treatment Intensity and Factor VIII Products On the Development On High Titre Inhibitors in Children with Severe Hemophilia A: Results of a Non-Concurrent Cohort Study.
Authors: Kurnik Karin , Halimeh Susan , Manner Daniela , Holzhauer Susanne , Ettingshausen Carmen Escuriola , Schobess Rosemarie , Nowak-Gottl Ulrike 
Published: October 2019

Abstract
Abstract 1303
Poster Board I-325

Background
A number of environmental and genetic factors have been identified to influence inhibitor development in children with severe hemophilia A (HA): among them, individual therapeutic regimens and the use of different factor VIII products have been controversially discussed.

Methods
In the present multicenter cohort study we evaluated the impact of i) treatment intensity [median individual dose administered during the first 6 to 8 weeks] and ii) type of factor VIII product [plasma-derived (pd); recombinant-derived (r)] on the risk of high-titre inhibitor development in 150 previously untreated patients with severe hemophilia A (HA) consecutively ascertained between 1982 and 2007 from five German catchment areas. Patients were followed over a period of 200 exposure days from HA onset. Study endpoint was inhibitor-free survival time related to treatment with adjustment for treatment period. Plasma levels of factor VIII were determined by one-stage clotting assays. Inhibitor testing was performed at least monthly to 3 monthly when on therapy using the Bethesda method or its modification [Nijmegen]: The lower detection limit was set at 0.6 Bethesda units [BU]. A peak inhibitor titer of > 5 BU was defined as high responder [HR]. A positive inhibitor testing was stated when an inhibitor was measured at least in two independent follow-up visits. The cumulative inhibitor-free survival was calculated using multivariate Cox regression [hazard ratio (HR) and 95% confidence intervals [CIs]].

Results
During the follow-up period 30 of 150 children (20.0%) developed a high titre inhibitor. In univariate analysis the median dose increase per IU/kgbw significantly increased the hazard towards HR inhibitor development [HR/CI: 1.08/1.05-1.11]. In addition, 14 of 52 children treated with rFVIII concentrates (27%) versus 16 of 98 children (16.3%) treated with pdFVIII concentrates developed HR during the observation period [HR/CI: 1.9/0.9-3.9]. In multivariate analysis treatment intensity adjusted for FVIII products and treatment period were independently associated with the development of clinical meaningful inhibitors [HR/95%CI: 1.08/1.1-1.1].

Conclusion
Data presented here support the hypothesis that clinical meaningful inhibitor development is of multifactorial origin and that treatment intensity plays a major role.

Disclosures
Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.
Reduced Number of Dense Bodies and Reduced Serotonin Content in Platelets of Patients with Wiskott-Aldrich Syndrome.
Authors: Sokolic Robert A. , Markello Thomas , Krumwiede Marcy , Fischer Roxanne , Garabedian Elizabeth , Gahl William A. , White James G. , Candotti Fabio 
Published: October 2019

Abstract
Abstract 1321
Poster Board I-343
Wiskott-Aldrich syndrome is characterized by immune deficiency and thrombocytopenia. There is also a qualitative platelet defect in Wiskott-Aldrich syndrome, typically presenting on aggregometry as a failure of the second wave of aggregation. The pathophysiology of this defect has not been studied in detail. To investigate this phenomenon, we enumerated dense bodies and measured serotonin content in the platelets of 7 patients with Wiskott-Aldrich syndrome. Patients ranged in age from 14 to 45 years old. Five of 7 patients had had splenectomy. In these patients, the platelet count ranged from 120,000/mcL to 521,000/mcL. Platelet counts were 20,000/mcL and 46,000/mcL in the 2 patients who had not had splenectomy. The latter 2 patients had occasional petechiae, as did 2 of the splenectomized patients. Three patients had no clinical evidence of platelet dysfunction. One of these 3 had tolerated abdominal surgery without untoward bleeding. Blood specimens were taken in the course of routine follow-up, when patients were otherwise well. Platelets were prepaed for electron microscopy by the whole mount technique. For serotonin content, platelets were counted and lysed in distilled water. Serotonin in the lysate was chemically acetylated and then measured by ELISA. Serotonin levels were normalized to ng of serotonin per 10 9 platelets. The average ± standard deviation dense body count in our patient group was 1.1 ± 0.4 dense bodies per platelet (normal count 6-8 dense bodies/platelet). Serotonin content was measured in three patients, who showed 273 ± 103 ng serotonin per 10 9 platelets (normal value 621-1064 ng/10 9 platelets). Our results are the first quantitative analysis of platelet dense body counts and serotonin level in patients with Wiskott-Aldrich syndrome. In addition to further elucidating the pathophysiology of this disease, these data have implications for understanding the role of the Wiskott-Aldrich syndrome protein in the genesis of dense bodies.

Disclosures
No relevant conflicts of interest to declare.
Induction of Potent Anti-Tumor Effects by Original and TCR-Redirected CD4 + Cytotoxic T Cells.
Authors: Spaapen Robbert M , van den Oudenalder Kelly , van Elk Maureen , Aarts Tineke , Guichelaar Teun , Groen Richard WJ , Bloem Andries C , Storm Gert , Martens Anton C , Lokhorst Henk M , Mutis Tuna 
Published: October 2019

Abstract
Abstract 1333
Poster Board I-355
The curative Graft versus Tumor (GvT) effect of allogeneic stem cell transplantation and donor lymphocyte infusions is mainly mediated by donor derived T cells recognizing minor Histocompatibility antigens (mHag) presented by malignant cells. Traditionally, CD8+ cytotoxic T cells (CTLs) are considered as “the” effector cells of these anti-tumor responses, whereas a sole helper role is attributed to CD4+ T cells. CD4+ T cells often possess killer capacities in vitro, raising the possibility that they may also mediate anti-tumor effects without the need for CD8+ T cells. Hence, we here explored the feasibility of adoptive immunotherapy with sole CD4+ CTLs by testing the therapeutic capacity of a mHag-specific, CD4+ CTL (3AB11) in a human GvT model. Rag2−/−γc−/− mice were inoculated with BLI detectable, mHag+ Multiple myeloma cells. Treatment of established tumors with 3AB11 but not with control CD4+ T cells by triple consecutive injections of 30-40×106 cells/day rapidly reduced the medullary growing tumors, illustrating for the first time the feasibility to establish a significant GvT effect by targeting a sole mHag recognized by CD4+ CTLs. The therapy was less effective at a higher tumor load and unsuccessful by a single injection of 20×106 cells, underscoring the critical importance of T cell dose-to-tumor load ratio to establish an efficient anti-tumor effect. In further exploration, tumors were also significantly reduced by treatment with “dual antigen-specific” T cells, which were generated by transduction of the T cell receptor (TCR) of clone 3AB11 into recall antigen (Tetanus Toxoid; TT)-specific T cells. Finally, the in vivo persisting dual-specific T cells could be boosted by administration of TT loaded mHag negative B cells, demonstrating for the first time the feasibility and potential advantages of immunotherapy with TCR-transduced “dual antigen-specific” CD4+ T cells. We conclude that potent GvT effects may be achieved in clinical trials by targeting a sole mHag antigen with original or TCR-redirected CD4+ CTLs.

Disclosures
No relevant conflicts of interest to declare.
Avascular Necrosis in Untreated Patients with Type 1 Gaucher Disease.
Authors: Mistry Pramod K , Deegan Patrick , Vellodi Ashok , Cole J. Alexander , Yeh Michael , Weinreb Neal J. 
Published: October 2019

Abstract
Abstract 1353
Poster Board I-375

Objective
To determine the incidence of avascular necrosis (AVN) in untreated patients with type 1 Gaucher disease (GD1).

Methods
All patients with GD1 enrolled in the ICGG Gaucher Registry as of July 2007 were included in this analysis. All GD1 patients who either never received treatment or eventually went on to receive treatment were identified. Follow-up began on each patient's date of earliest reported assessment in the Registry. Among patients who never received treatment, follow-up continued until the last recorded assessment date in the Registry. For patients who eventually went on to receive treatment, follow-up continued until the date of initiation of therapy. Incidence rates (and Poisson exact 95% confidence intervals) of AVN were determined for both groups of patients. AVN was typically ascertained from X-Ray or MRI results.

Results
As of July 2007, the inclusion criteria were met by 3,497 patients. The incidence rate of AVN among untreated patients was 22.8 per 1,000 person years (95% CI 20.2 to 25.7). Patients with antecedent splenectomy (total or partial) had a higher incidence rate of AVN (46.6 per 1,000 person-years, 95% CI 38.4 to 56.1) compared to patients without a splenectomy (incidence rate 17.0 per 1,000 person-years, 95% CI 14.5 to 19.8). The primary sites where AVN was identified in both groups were the hip and femur.

Conclusion
This is the first epidemiologic analysis to estimate incidence rates of AVN among untreated patients with GD1. Splenectomy appears to be a risk factor for GD1-associated AVN. Based on the incidence results above and presupposing equal risk distribution, without therapeutic intervention, most patients should theoretically experience at least one episode of AVN at some point in their life. However, because the GD1 population is genotypically and phenotypically heterogeneous, further analyses will attempt to identify characteristics that distinguish untreated patients at high risk of developing AVN from those who are less likely to develop this serious complication.

Disclosures
Mistry: Genzyme Corporation: Honoraria, Research Funding. Deegan:Genzyme Corporation: Honoraria. Vellodi:Genzyme Corporation: Honoraria, Speakers Bureau. Cole:Genzyme Corporation: Employment. Yeh:Genzyme Corporation: Employment. Weinreb:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Characterization of Nur77+ Cells in Murine Peripheral Blood.
Authors: Hubbeling Harper , Beck Thomas , Moran Amy , Hogquist Kristin , Maltzman Jonathan , Cunningham Nicole , Punt Jenni 
Published: October 2019

Abstract
Abstract 1361
Poster Board I-385
The expression of Nur77/NR4A1, one member of the Nur Orphan Nuclear Receptor family, is tightly regulated in many cell types, including myeloid and lymphoid lineages, and can change rapidly in response to a variety of external stimuli. Best known for its role in regulating apoptosis by either transcribing lethal genes or by initiating mitochondrial production of cytochrome c, Nur77 may also play other non-apoptotic roles. In an effort to understand the fate and function of cells that upregulate Nur77, we developed a transgenic Nur77-eGFP reporter mouse. Our analysis of cells in the peripheral blood of these mice reveals two populations of circulating cells that express GFP (Nur77) ‘constitutively’: T lymphocytes and a subset of monocytes. Our preliminary data suggest that the GFP+ T cells, which, interestingly are enriched for regulatory T cells, are recent thymic emigrants that have upregulated Nur77 as a consequence of TCR stimulation during maturation. Our observations also indicate that the GFP+ monocytes define a subpopulation of ‘patrolling’ cells that may ultimately differentiate into splenic dendritic cells. Understanding the identity of these circulating GFP+ cells should provide us with insights into the regulation and function of Nur77 itself. The analysis may also clarify the significance of phenotypic differences among blood cell subtypes by providing additional information about cell origin and activity.
We thank the Arnold and Mabel Beckman Foundation (HH), HHMI (TB), and NSF (#MCB-0744570 (JP and NC)) for their support for this work.

Disclosures
No relevant conflicts of interest to declare.
Meprin αβ Deficiency Results in Accumulation of Peritoneal Macrophages and Hyperactive Pro-Inflammatory Cytokine Response in Mice.
Authors: Jin Hong-Jian , Banerjee Sanjita , Yura Renee , Bao Lei , Bond Judith , Sun Qi 
Published: October 2019

Abstract
Abstract 1364
Poster Board I-386
Meprin metalloproteases are abundantly expressed in kidney and intestinal epithelial cells, and have been implicated in inflammatory bowel disease. Recently, we demonstrated that meprin deficiency compromises homeostasis of monocytes and natural killer cells. However, the role(s) of meprins in the hematological system and the pathological consequences of meprin deficiency have not been fully characterized. We report here that mouse and human monocytes expressed meprins, and the expression of meprin α was down-regulated in monocyte-derived mature macrophages (Mφ). In a mouse model of septic shock induced by peritoneally injected bacterial lipopolysaccharide (LPS), mice carrying germline null mutation of both meprin α and βgenes (meprin double knockout, dKO) developed a more severe form of septic shock, characterized by deeper hypothermia, higher levels of blood nitrate/nitrites and suppressed monocytosis, in comparison to the wild-type mice. In addition, LPS-challenged meprin dKO mice exhibited a greater elevation of plasma IL-12, MCP-1, IL-6 and TNF-α, even though these pro-inflammatory cytokines were at lower levels in the dKO mice than the wild-type mice in the steady state. Furthermore, meprin dKO mice harbored a higher number of peritoneal Mφ than the wild-type mice, and thereby produced more soluble cytokines in response to ex vivo LPS stimulation. These results indicate that meprin deficiency is associated with accumulation of peritoneal Mφ, which may lead to hyperactive cytokine responses to inflammatory stimuli and result in increased susceptibility to LPS-induced septic shock.

Disclosures
No relevant conflicts of interest to declare.
Temporal Trends in the Proportion Cured Among Patients Diagnosed with Acute Myeloid Leukemia in Sweden 1973-2001, a Population-Based Study.
Authors: Derolf Åsa Rangert , Andersson Therese M-L , Lambert Paul C , Kristinsson Sigurdur Y , Eloranta Sandra , Landgren Ola , Dickman Paul W , Bjorkholm Magnus 
Published: October 2019

Abstract
Abstract 1378
Poster Board I-400

Background:
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is rapidly fatal without specific therapy. In a recently published population-based study we showed large differences in 1- and 5-year relative survival in AML patients in Sweden depending on age at diagnosis and year of diagnosis[1]. Here we use an alternative approach to study patient survival that simultaneously estimates the proportion of patients cured from AML and the survival time of those patients that are not cured. The cure proportion provides a better estimate of long-term survival than 5-year survival and is therefore of direct interest to patients and health care professions.

Methods:
We conducted a population-based cohort study including 6,439 patients aged 19-79 diagnosed with AML in Sweden 1973 to 2001. Patients are considered statistically cured when, as a group, their mortality returns the level of a comparable general population. We estimated mixture cure fraction models that provide estimates of both the cure proportion and the distribution of survival times of the “uncured”. Age at diagnosis was classified into four categories 19-40, 41-60, 61-70 and 71-80 and year of diagnosis was modeled using restricted cubic splines.

Results:
During the first years of the study period the cure fraction was less than 5% for all age groups and the median survival time for “uncured” approximately 0.5 years or less. In 2000 the estimated cure proportion was 68% (95% CI 56%-77%) for the youngest age group, 32% (25-39%) for those aged 41-60, 8.4% (3.1-21%) for those aged 61-70 at diagnosis and 4.3% (2.3-8.1%) for the oldest age group. The estimated median survival times for “uncured” were 0.74 (0.43-1.26), 0.71 (0.53-0.97), 0.69 (0.51-0.95) and 0.37 (0.31-0.44) years respectively (Table 1). The improvement in survival manifested as longer survival among the uncured during the early calendar years but increases in the cure proportion were observed during later years.

Conclusion:
There are large differences in the proportion cured between the age groups. In younger patients the cure proportion has increased dramatically, while survival of the “uncured” actually decreased in the last time period. In the older age groups improvement is merely seen within the survival of the “uncured”.
[1] Derolf AR, Kristinsson SY, Andersson TM-L, Landgren O, Dickman PW, Björkholm M. Improved patient survival for acute myeloid leukemia: A population-based study of 9,729 patients diagnosed in Sweden 1973-2005. Blood. 2009 Apr 16;113(16):3666-72.

Disclosures:
No relevant conflicts of interest to declare.
VTE Prophylaxis Across the Continuum of Care in US Medical Patients at Risk of Venous Thromboembolism.
Authors: Amin Alpesh , Lin Jay , Ryan Amy 
Published: October 2019

Abstract
Abstract 1386
Poster Board I-408

Background:
Medical patients with chronic medical illnesses are often at risk of VTE both in-hospital and post-discharge. However, although injectable prophylaxis options are available and suitable for providing in-hospital and post-discharge prophylaxis, there is often a lack of continuity in VTE post-discharge prophylaxis. This analysis evaluated in-hospital and post-discharge VTE prophylaxis patterns for US medical patients.

Methods:
Premier's Perspective™ inpatient data were cross-matched at the individual patient level with Ingenix LabRx® outpatient data from the I3 database (January 2005-December 2007) to assess VTE prophylaxis patterns in medical patients (cancer without surgery, heart failure, severe lung disease, infectious disease) at risk of VTE (according to the American College of Chest Physicians 2004 guidelines) and with no contraindications for anticoagulation. Inpatients were assessed for any anticoagulation received in-hospital and were followed post-discharge to assess their outpatient prophylaxis use. Drug utilization and clinical practice patterns during and within 30 days after hospitalization were collected and compared descriptively between groups.

Results:
Of the 9,675 medical discharges at risk of VTE and included in this analysis, 6,185 (63.9%) did not receive any anticoagulation at all. Of the remaining 3,490 (36.1%) discharges that did receive anticoagulation, 2,045 (58.6%) received enoxaparin and 1,044 (29.9%) received unfractionated heparin (UFH) (Table). After discharge, 98.2% of all patients did not receive any prophylaxis within the following 30 days. Only 174 (1.8%) discharges received outpatient prophylaxis, with 67.8% receiving warfarin alone and 18.4% receiving enoxaparin and warfarin (Table).

Conclusion:
This analysis presents both inpatient and outpatient VTE prophylaxis patterns in real-world medical patients that are at risk of VTE. Nearly 64% of patients received no inpatient VTE prophylaxis, and less than 2% received outpatient prophylaxis. Further efforts to improve VTE prevention in hospitalized patients are required, with particular emphasis needed on the transition to outpatient prophylaxis.

Disclosures:
Amin: sanofi-aventis: Research Funding, Speakers Bureau, The authors received editorial/writing support in the preparation of this abstract funded by sanofi-aventis U.S., Inc.. Lin: sanofi-aventis: Employment. Ryan: sanofi-aventis: Research Funding.