bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statins Reduce Disease Activity (SLAM-R) and Organ Damage Accrual (SLICC Damage Index, SDI) Scores in SLE Patients From A Multi-Center, Multi-Ethnic, US Cohort.
Authors: Pierangeli Silvia S , SEif Alan , Aguilar-Valenzuela Renan , Martinez-Martinez Laura Aline , Doan Ellis , Dang Neha , Papalardo Elizabeth , Reveille John D. , Alarcon Graciela S. 
Published: October 2019

Abstract
Abstract 5066

Purpose
Statins, in addition to lower cholesterol levels, have anti-thrombotic, anti-inflammatory and cardiovascular protective effects. Cardiovascular morbidity and accelerated atherosclerosis are important SLE features, but It is unclear whether statins have beneficial effects in these patients.

Objectives
To assess longitudinally the impact of statins on levels of biomarkers (cytokines/chemokines), SLAM-R and SDI.

Methods
Sera from 21 SLE patients (ACR criteria) from a multi-ethnic, multi-center cohort were assessed at baseline and at a subsequent visit after statin treatment started. Patients on >10 mg prednisone/day, or on other immunosuppressant were excluded (age range: 16-67; mean age: 44.6 yrs); 38% African American, 9% Caucasians and 4% Puerto Rican Hispanics; 86% female. Serum levels of IL1b, IL6, IL8, IFN- α,, IP-10, MCP-1. VEGF, sCD40L and TNF- α, were measured using a Millipore Millliplex™ Multiplex Assay and titers of soluble (s) E-selectin (E-sel), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), were detected by ELISA. High sensitive C reactive protein (hsCRP) was measured by nephelometry. Changes in the levels of biomarkers were tested using a signed rank test. Changes in levels of biomarkers and those in SLAM-R or SDI scores were examined with Spearman correlations.

Results
SLAM-R and SDI scores were significantly decreased by statins (p=0.0199 and 0.039, respectively). IL1b, IL6, IL8, TNF-α, VEGF, IP-10, sCD40L and sVCAM-1 levels were reduced after treatment with statins in 28%, 28%, 52%. 43%, 57%, 42%, 52% and 62% of the subjects that had detectable levels of the biomarkers at baseline, respectively, but the overall reduction was not statistically significant (see Table). hsCRP was increased in 50% of the subjects at baseline (over the cut-off point) and reduced by 37% after treatment with statins. Importantly, the changes in IL-6 after treatment with statins correlated with changes in SLICC scores (p=0.036

Conclusions
Significant number of SLE patients' samples showed a decrease in levels of some cytokines and chemokines and of hsCRP after statin treatment. Importantly, SLAM-R and SDI scores were significantly reduced by statins and the changes in IL-6 correlated with a significant decrease in organ damage accrual (SLICC).

Disclosures
No relevant conflicts of interest to declare.
The Diagnosis of the Antiphospholipid Syndrome in Our Medical University Center for the Year 2007.
Authors: Boisjoly Josie-Anne , Lepine-Martin M. D , St-Onge Carole 
Published: October 2019

Abstract
Abstract 5068

Introduction
The antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis and with obstetrical complications. According to the recommendations published in 2006, the diagnosis of SAP requires at least one clinical manifestation and, at least, one abnormal laboratory test: lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL) or anti-B2-Glycoprotein antibodies (anti-B2GP1). More, the abnormal test has to be repeated and still abnormal 3 months later. In this study, we evaluated the process leading to a diagnosis of APS in our hospital during a whole year period. The clinicians had previously received a copy of published recommendations.

Method
We registered the identification number of all patients tested for 1 or more test (LA, ACL, anti-B2-GP1) in our laboratory during the year 2007. We then, retrospectively, analyzed the medical files of the patients who had their medical evaluation in our Center. We retained the following data: sex, age, symptoms at the presentation, final diagnosis, results of the specific tests for APS with the interval between the positive tests and the control tests.

Results
During 2007, 331 patients were tested for APS in our laboratory. We analyzed the medical files of 259 patients, 184 women and 75 men, with a mean age of 43,9 years. The indications for testing were: venous thrombosis (36, 7%), arterial thrombosis (14,3%), obstetrical complications (15,7%), collagenosis (17%), prolonged TTPa (3,1%), others (13,9%). In the laboratory, we found 91 positive tests in 70 patients. For 5 patients, all the three tests were positive. Only 48 positive tests were controlled after a period of 6 to 12 weeks. In total, 24 patients had at least one positive and controlled test; from them, 10 had all the criteria for the APS and 13 had abnormal tests without the clinical criteria for the APS.

Conclusion
In this study, 3, 9% of tested patients had the diagnostic criteria for the APS. The indications for ordering the tests seemed adequate in 86% of the cases. Only 52.7% of the positive tests were controlled. We have modified our interpretation of the positive tests, suggesting a control after 3 months.

Disclosures
No relevant conflicts of interest to declare.
The Association of 14-3-3ζ and Filamin A with the Central Cytoplasmic Domain of GPIbα Involves in Regulation of the Von Willebrand Factor Binding and Signaling Functions of Platelet Glycoprotein Ib-IX.
Authors: Zhang Weilin , Yuan Yanhong , Zhao Lili , Liao Yi , Ruan Changgeng , Dai Kesheng 
Published: October 2019

Abstract
Abstract 5073

Introduction
Conformational changes in von Willebrand factor (VWF) exposed at the injured vessel wall initiate platelet tethering and simultaneously trigger signaling cascades leading to platelet adhesion, spreading, and thrombus formation. Although the intracellular signaling protein 14-3-3ζ and the membrane skeleton protein filamin A have been confirmed to interact with the cytoplasmic domain of GPIbα and involve in the regulation of VWF binding function, whereas, the mechanisms still remain unclear. We have recently identified a novel 14-3-3ζ binding site with partial phosphorylation of Ser559 in resting platelets located in the cytoplasmic filamin A binding domain of GPIbα. Disruption of the central cytoplasmic 14-3-3ζ binding site of GPIbα did not abolish the interaction between 14-3-3ζ and GPIb-IX, whereas obviously diminished VWF binding function. Here we show that disruption of 14-3-3ζ binding to GPIbα by GPIbα mutants or cell permeable peptides enhances the association of filamin A with GPIb-IX and the expression of GPIb-IX in the plasma membrane. In contrast, disruption of 14-3-3ζ binding to GPIbβ, which would enhance the opportunity for 14-3-3ζ monomer to bind to GPIbα, reduces filamin A-GPIb-IX interaction and GPIb-IX membrane expression. Compared with a GPIb-IX mutant truncating the whole cytoplasmic domain of GPIbα (Δ551), GPIb-IX mutant retaining only the central 14-3-3ζ binding site of the cytoplasmic domain of GPIbα (Δ565) showed an enhanced cell adhesion to VWF under flow and ristocetin-induced VWF binding. Furthermore, the two cell permeable peptides, MP-P and MPαC, which had been confirmed to block the central 14-3-3ζ binding site of GPIbα (MP-P) or diminished the association of 14-3-3ζ with GPIb-IX complex (MPαC), obviously inhibited ristocetin induced wild-type GPIb-IX cell aggregation. In addition, MP-P and MPαC inhibited botrocetin-induced platelet spreading and lamellipodia formation on VWF matrix, and GPIb-IX-VWF interaction induced co-immunoprecipitation of Src with GPIb-IX. Taken together, these data indicate that the binding of 14-3-3ζ and filamin A to the central cytoplasmic domain of GPIbα involves in regulation of surface expression, VWF binding and signaling functions of glycoprotein Ib-IX.

Disclosures
No relevant conflicts of interest to declare.
Remission of Paroxysmal Atrial Fibrillation with Iron Reduction in Hemophilia A.
Authors: Zacharski Leo R. , McKernan Laurel J , Metzger Michael E , Malone Maura G , Samnotra Vivek , Bhargava Archana , Steiner Paul R , Rauwerdink Cocav , Ornstein Deborah L , Cornell Cornelius J. 
Published: October 2019

Abstract
Abstract 5100
Two male first cousins with mild hemophilia A had symptomatic electrocardiographically documented paroxysmal atrial fibrillation for several years that had become resistant to pharmacologic suppression. Both had baseline factor VIII levels of 12 to 15% and experienced bleeding requiring coagulation factor infusion therapy in response to trauma and surgical procedures. Radiofrequency ablation of ectopic electrical foci was considered in both cases but deferred because anticoagulation required to prevent thromboembolic complications of radiofrequency ablation carried an unacceptably high risk of bleeding. Iron accumulation with aging has been implicated in the pathogenesis of cardiovascular disease in general and arrhythmias in particular. Uncompensated iron-catalyzed oxygen free radical formation accounts for such toxicity. Remission of arrhythmias has been reported with iron reduction therapy in patients with iron overload disorders. Effects of iron reduction on arrhythmias in settings other than iron overload syndromes are unknown. Body iron stores as assessed by serum ferritin levels were elevated in both men (389 and 305 ng/ml respectively) but neither had the C282Y or H63D genes for hemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was performed and was followed by sustained remission of PAF in both cases. These findings suggest that iron reduction with maintenance of ferritin levels below about 100 ng/ml may be effective treatment for arrhythmias apart from the classic iron overload syndromes. Effects of primary prevention of iron accumulation over time and reduction of existing elevated iron stores deserve further study in patients with bleeding disorders in whom standard treatment of diseases of aging may be costly and carry high risk. The efficacy, safety, simplicity and cost effectiveness of iron reduction therapy commends application of this investigational approach to disease prevention and treatment in the general population.

Disclosures
No relevant conflicts of interest to declare.
Serum Pro-Hepcidin Level in Helicobacter Pylori-Infected Iron Deficiency Anemia Patients.
Authors: Lee Mark , Song Eun Young , Yun Yeo Min , Yoon So Young , Cho Yo Han , Lee Sun-Young , Kim Sung-Yong 
Published: October 2019

Abstract
Abstract 5101

Background
Helicobacter pylori infection seems to subvert the human iron regulatory mechanism, and thus up-regulate hepcidin that results in unexplained iron deficiency anemia (IDA). We evaluated serum pro-hepcidin levels before and after H. pylori eradication in IDA patients to assess whether it plays a role in H. pylori-related IDA.

Materials and Methods
Subjects diagnosed as unexplained IDA underwent upper gastrointestinal endoscopy and colonoscopy to diagnose H. pylori infection and to exclude gastrointestinal bleeding. Blood sampling were done before H. pylori eradication and after a month. Serum pro-hepcidin level was measured by a commercialized enzyme-linked Immunosorbent assay kit.

Results
Initial serum pro-hepcidin levels were not different between 23 H. pylori-infected subjects (212.9 ± 88.2 ng/ml) and nine non-infected subjects (217.8 ± 56.2 ng/ml) (p=0.879). Serum pro-hepcidin level decreased after either dual oral iron replacement with H. pylori eradication (p=0.011) or H. pylori eradication without iron replacement (p=0.075). It also decreased after iron replacement in non-infected subjects (p=0.086). The reduction ratio of serum pro-hepcidin level after the treatment was not different between three groups (p=0.972).

Conclusions
Serum pro-hepcidin level decreases after either H. pylori eradication or oral iron administration with IDA improvement. Serum pro-hepcidin is related to the status of anemia rather than the presence of H. pylori itself.

Disclosures
No relevant conflicts of interest to declare.
A NOVEL Mutation of the Erythroid-Specific Aminolevulinate Synthase 2 Gene IN A Patient with Pyridoxine Responsive Sideroblastic Anemia and Deferasirox Responsive Hemochromatosis.
Authors: Caliskan Umran , Tokgoz Huseyin , Yuksekkaya Hasan 
Published: October 2019

Abstract
Abstract 5105
A-14 years-old man, admitted to our clinic with weakness and paleness since one month. He has hepatosplenomegaly. Blood tests and peripheral blood smear showed anemia that severe hypochromic, microcytic anemia. There is ringed sideroblasts without dysplastic hematopoiesis in bone marrow cytology. Liver tests were normal. A liver biopsy showed heavy parenchymal iron deposition and grade-III fibrosis. Screening for HFE gene mutations was negative. MR imaging demonstrated that severe iron accumulation in liver and heart. ALAS2 gene screening showed that novel mutation in exon 7 (Gly390Gly, c.1170, C□T). Eventually, was diagnosed as sideroblastic anemia and hemochromatosis. He was treated successfully with pyridoxine and chelating agent (deferasirox, IGL-670). The findings suggest that the Gly390Gly in ALAS2 mutation causes sideroblastic anemia and hemochromatosis, without hereditary hemochromatosis gene mutations. This mutation cause sideroblastic anemia is clinically pyridoxine-responsive. Deferasirox is effective agent for reduce hepatic iron loading in this condition.

Disclosures
Off Label Use: deferasiroks was used for hemochromatosis secondary to congenital syderoblastic anemia.
Cancer Treatment with Gemcitabine Does Not Increase Fetal Hemoglobin Levels.
Authors: Saylor Philip J , Bornhauser Chris , Read William 
Published: October 2019

Abstract
Abstract 5112

Background
Pharmacological induction of fetal hemoglobin (Hb F) can benefit patients with beta-hemoglobinopathies. Hydroxyurea (HU) is the drug most commonly used to induce Hb F. HU is converted to a free radical scavenger in vivo and inhibits the R2 subunit of ribonucleotide reductase. When used in the treatment of myeloproliferative syndromes, HU has been described to increase Hb F in people without hemoglobinopathies (Alter et al, Blood 66(2) 373-5). Gemcitabine is a nucleoside analog chemotherapeutic that inhibits the large R1 subunit of ribonucleotide reductase. We hypothesized that like HU, gemcitabine treatment would cause Hb F percentage to rise. Though oncology patients are a distinct population, gemcitabine induction of Hb F during the treatment of cancer would suggest a potential role for gemcitabine in the management of beta-hemoglobinopathies such as sickle cell disease and beta-thalassemia.

Methods
Participants for this prospective observational cohort study were recruited from the Moores UCSD Cancer Center upon documentation of a cancer diagnosis and oncologist-initiated plans for treatment with single agent gemcitabine. Enrolled subjects were gemcitabine naïve and had not received any chemotherapy for the preceding 4 weeks. Serum Hb F was quantified by electrophoresis prior to each of the first 4 gemcitabine treatments. All other laboratory evaluation was standard-of-care. The primary objective was to assess changes in Hb F among cancer patients in response to their initial 3 treatments with gemcitabine. Enrollment was halted early given the absence of a substantial treatment effect among the first 6 subjects.

Results
Six subjects were eligible. Three were men. Five were Caucasian and one was an Asian/Pacific Islander. All subjects received gemcitabine monotherapy for the treatment of adenocarcinoma of the pancreas or breast at a weekly dose of 1000 mg/m2. Baseline Hb F range was 0 – 1.0%. Four of the six subjects (three women, one man; all Caucasian) experienced no change in Hb F from baseline to the final measurement. Two subjects experienced a 0.4% increase in Hb F from baseline to the final measurement 4 weeks later. Final Hb F range was 0 – 1.4%.

Conclusions
We found that gemcitabine monotherapy for the treatment of cancer did not induce Hb F in this small study cohort. Gemcitabine may lack this ability. Alternative explanations for the absence of clinically meaningful Hb F induction include the small population studied, differences between oncology patients and the general population, short duration of treatment, and intermittent dosing of gemcitabine.

Disclosures
No relevant conflicts of interest to declare.
Immunisation against Human c-MYC Elicits a T-Cell Response and Influences Growth of High Grade B-Cell Lymphoma in Mice.
Authors: Helm Florian , Wilke Andrea , Kammertoens Thomas , Friese Christian , Mautner Josef , Loddenkemper Christoph , Bornkamm Georg , Gerbitz Armin 
Published: October 2019

Abstract
Abstract 5120
Overexpression of the proto-oncogene c-myc due to chromosomal translocation is the hallmark of Burkitt-lymphoma. The evolving high grade lymphoma is dependent on the overexpression of c-myc, which provides the necessary signal to drive uncontrolled proliferation. Therefore loss of function or recognition of c-myc overexpressing cells by c-MYC specific T-cells should result in killing of the target and a halt to lymphoma progression. C-myc is also expressed in a variety of other human malignancies. Peptide prediction reveals several potential foreign epitopes in the context of murine H2b due to 87% homology between human and mouse c-MYC. In this study we explored whether the human c-myc gene product can be a target for T-cell therapy. Wildtype C57BL/6 mice were immunized with recombinant human c-MYC protein in combination with incomplete Freund′s adjuvans and CpG, and were boosted at various time points thereafter using either c-MYC protein or 40mer peptides encompassing the non homologous regions. Control animals were vaccinated with recombinant GFP or OVA protein. C-MYC vaccinated animals displayed a higher IFNg release upon re-stimulation with c-MYC pulsed dendritic cells compared to control vaccinated animals. In ELISPOT assays we observed a higher number of IFNg positive cells (299±17 vs. 122±8.5 (GFP vaccinated) vs. 66±8.5 (OVA vaccinated)). Vaccination using single peptides revealed that peptides spanning the region from amino acid 87-123, 216-255 and 334-376 produced similar results. In addition, using a human c-MYC specific ELISA we were able to detect c-MYC specific antibodies in serum from immunized mice in a concentration up to 40mg/l. Using established cell lines from l-hu-c-myc transgenic mice, where the human c-myc gene is overexpressed due to the juxtaposition of elements of the immunoglobuline lambda locus as found in t(8;22) of Burkitt's lymphoma, we investigated whether vaccination with human c-MYC protein would influence lymphoma growth in a lymphoma transfer model. Animals were s.c. challenged with 0.1 Mio 291cells overexpressing human c-MYC and were monitored for lymphoma growth. C-MYC vaccinated animals (n=15) displayed a delay in tumor onset and a significantly better disease free survival (28 vs. 22 days, p=0.012) compared to control (OVA) vaccinated animals (n=10). This delayed growth was associated with an increased number of infiltrating CD3+/Perforin+ cells. However, all mice eventually succumbed to lymphoma growth, indicating that the T-cell response was not sufficient to control lymphoma growth in the long term. From these data we conclude that the human c-MYC is a possible target antigen for T-cells, but responses are weak and presumably low in frequency.

Disclosures
No relevant conflicts of interest to declare.
Low Absolute CD4 Central Memory Count On Day 30 Is Associated with An Increased Incidence of Chronic Graft-Versus-Host Disease.
Authors: McIver Zachariah A. , Grim Andrew , Naguib Nicolas , Barrett A. John 
Published: October 2019

Abstract
Abstract 516

Early lymphocyte recovery is an important determinant of hematopoietic stem cell transplant (SCT) outcome. We found that robust day 30 lymphocyte counts are associated with a decreased incidence of relapse, decreased rates of both acute and chronic graft-versus-host disease (a-GvHD, c-GvHD), and increased survival. Natural killer (NK) cells contribute to lymphocyte recovery and may be associated with a strong graft-versus-leukemia and anti-GvHD effect. However, the contribution of the recovery of specific T cell subsets to transplant outcome has not been fully explored. We studied 43 patients undergoing a myeloablative matched-sibling T-cell depleted or selectively depleted SCT for a variety of hematological malignancies including AML, ALL, CML, and MDS. Median age was 43 years (range, 13–68), and median CD34 cell dose was 6.1×106/kg (range, 3.1-10.1). Thirty-one patients developed a-GvHD (12 grade I, 18 grade II, 1 grade II). Twelve patients had c-GvHD (7 limited, 5 extensive). On day 30 after SCT a peripheral blood sample was collected on all patients and cryopreserved. In preparation for analysis, mononuclear cells from these samples were thawed and rested overnight. Flow cytometry was then performed on a BD FACS CantoII flow cytometer with multicolor fluorochrome antibodies to CD3, CD4, CD8, CD27, and CD45RO. Subsets were defined as follows: Naive (N) CD27+CD45RO-, Central Memory (CM) CD27+CD45RO+, Effector Memory (EM) CD27-CD45RO+, and Effectors (E) CD27-CD45RO-. Data was analyzed by BD FACSDiva software, and Kaplan-Meier survival statistical analysis was performed on the readouts. Median subset frequencies were CD3+: 254 /μL (range, 75-2085), CD4+ : 132 /μL (range, 3-501), CD8+ :101 /μL (range, 9-1361), CD4+ EM 49/μL (range, 2-252), CD4+CM 60/μL (range, 1-253), CD8+ EM: 50 cells/μL (range 2-977), CD8+ CM 28 /μL (range, 2-401), Naïve and Effector cells were minimally or non-detected in both CD4+ and CD8+ compartments. When T cell subset recovery was correlated with transplant outcomes (a-GVHD, c-GVHD, relapse and survival) one significant association was identified: low CD4+ CM counts correlated with a higher incidence of c-GvHD. Patients that had less than the median value of 60 CD4+ CM cells/μL had a significantly higher likelihood of developing c-GvHD (HR 4.28, p=0.039, see figure). Additionally, when considering degree of disease, low CD4+ CM counts were associated with the severest manifestations of c-GvHD (p=0.021). As a result, we conclude that low absolute concentrations of CD4+ CM cells on day 30 after SCT reflects a deficiency in regulatory mechanisms important in the control of alloreactivity, and may be used as a surrogate marker for individuals at risk of developing c-GvHD.

Disclosures:
No relevant conflicts of interest to declare.