bluuebunny/crossref_metadata_2025_split huggingface dataset:
S1P Receptor 1-Mediatd Elevated IL-6 Signaling Underlies Chronic Inflammation and Multiple Tissue Damage in Sickle Cell Disease
Authors: Zhang Yujin , Zhao Shushan , Couturier Jacob , Kellems Rodney E. , Lewis Dorothy L. , Xia Yang 
Published: October 2019

Abstract
Objective-Sphingosine 1 phosphate (S1P) is a biolipid involved in chronic inflammation in multiple inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic genetic disorder associated with severe chronic inflammation. Here we evaluated the impact of S1P in chronic inflammation and underlying mechanisms in SCD.
Approach and Results-First, we demonstrated that interfering with S1P receptor signaling by FTY720, a FDA approved drug, significantly reduced systemic and local inflammation without anti-sickling effects. These findings led us to discover that IL-6 was highly elevated in the circulation and that increased S1P signaling via S1P receptors contributed to the induction of IL-6 in SCD mice. Genetic deletion of IL-6 in SCD significantly reduced local and systemic inflammation and multiple tissue damage and kidney dysfunction. Moreover, we determined that elevated IL-6 led to increased macrophage infiltration and elevated S1P1 gene expression in the macrophages of multiple tissues in SCD mice. Mechanistically, we reveled that S1P-S1P1 signaling reciprocally upregulated IL-6 gene expression in primary mouse macrophages in a JAK2-dependent manner.
Conclusion-Altogether, we revealed that elevated S1P signaling via S1P1-induced IL-6 is a key signaling network functioning as a malicious positive feed forward loop sustaining inflammation and promoting tissue damage in SCD. Our findings immediately highlight novel therapeutic possibilities.

Disclosures
No relevant conflicts of interest to declare.
Erythrocytes Retain "Hypoxic Purinergic Memory" for Faster Acclimatization upon Re-Ascent
Authors: Song Anren , Zhang Yujin , Liu Hong , Sun Kaiqi , Peng Zhangzhe , Wu Hongyu , Kellems Rodney E. , Roach Robert , Xia Yang 
Published: October 2019

Abstract
Improved and faster acclimatization to high altitude upon re-ascent is seen in humans. However, molecular basis for initial acclimatization and retention upon re-ascent to high altitude remains largely unknown. Here we report that plasma adenosine levels are induced by high altitude and retained at higher levels upon re-ascent in health lowlanders and that its elevation is positively associated with quicker acclimatization upon re-ascent. Unexpectedly, we found that, 1) erythrocyte equilibrative nucleoside transporter 1 (eENT1) is the major adenosine transporter in erythrocyte. 2) eENT1 protein level is downregulated in both humans at high altitude and mice under hypoxia. 3) Deletion of eENT1 allows rapid accumulation of plasma adenosine to offset hypoxic tissue damage in mice. Mechanistically, 4) we revealed that ADORA2B-mediated PKA-dependent phosphorylation, ubiquitinization and proteasomal degradation underlies hypoxia-mediated reduced eENT1 protein. Thus, the reduced eENT1 resulting from the initial hypoxia establishes erythrocyte "hypoxic purinergic memory" to promote quicker and higher accumulation of plasma adenosine and faster acclimatization upon re-ascent.

Disclosures
No relevant conflicts of interest to declare.
Effects of Environmental Changes on Emergency Rooms Visits for Adult Sickle Cell Disease
Authors: Master Samip , Patel Abhishek , Mansour Richard Preston 
Published: October 2019

Background:
Acute pain crises from vaso occlusive episodes are major cause of morbidity, hospitalization and emergency room visits for patients with sickle cell disease. Major causes of acute painful crises have been attributed to dehydration, infections and fever. Weather change has also been attributed as one of the major cause of acute pain crises by physicians and patients. Data on effects of environmental changes on acute pain crises in patients with sickle cell disease is mixed. Here we report our investigation to see if number of emergency room visits for adult patients with SCD were associated with environmental changes.
Method:
At our hematology clinic we take care of around 300 adult patients with SCD and we have on average around 11,000 emergency room visit per years from these patients. Electronically from EHR (Electronic health Record), we pulled out data on number of emergency room visit every day for adult patient with SCD in year 2015.We also gathered data on daily environmental changes from a national weather website for the year 2015 and collected data on daily temperature changes, humidity and precipitation/rain in our area. We did analysis to see if there was any correlation between the weather changes and emergency room visit.
Results:
As shown in graphs below, there was no correlation between the number of ER visits and weather changes in adult patient with SCD.
Conclusion:
Our analysis showed that there was no correlation between number of ER visit for adult patient with SCD and weather changes like -temperature, humidity and precipitation/rain.
ER Visits and Precipitation
ER visits, temperature and humidity
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of Disease Related Complications from in Adult Patients with Sickle Cell Disease
Authors: Master Samip , Patan Shajadi , Cingam Shashank , Mansour Richard Preston 
Published: October 2019

Abstract
Introduction: Sickle cell disease can lead to variety of complications like strokes, acute chest syndrome (ACS), sickle cell hepatopathy, priapism, renal dysfunction, avascular necrosis (AVN) ofjoints , pulmonary hypertension and leg ulcers. Average life expectancy of patient with SCD has improved with better treatments available. Most of literature on SCD in form pediatric literature and data on adults is considerably lacking. We did a retrospective analysis to investigate the prevalence of complications in adult patients with SCD.
Methods: We take care of around 300 adult active patients with SCD at our hematology clinic. We did a retrospective analysis from 458 adult patients seen at our clinic between 2001 and 2016. We collected data on gender, race, type of SCD, complications like stroke, acute chest syndrome, iron overload, leg ulcers, AVN, hepatopathy and renal dysfunction.
Results: A total of 458 adult patients with SCD were analyzed. 231 were female and 227 were males. The total number of patients with SC disease was 114, SS was 263, sickle beta thal was 75 and 4 had SS with hereditary persistence of Hemoglobin F (SS HPF). The number patient with complication has been listed in table below.
Conclusion: Adult Centers for the treatment of Sickle Cell Disease need to optimize care directed at these high frequency, life changing and life shortening complications. Multidisciplinary care teams have to focus on these chronic complications that include transfusion program, iron overload treatment and prevention, orthopedic care and Hepatitis C and B directed carealong with acute complication care. This retrospective study serves as the basis for our adult Sickle Cell Disease program at Louisiana State University Health Science Center in Shreveport, Louisiana.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
Learning Not to Judge a Book By Its Cover: A Case Series of Malignancy Masquerading As Common Presentations of Sickle Cell Disease
Authors: Zaidi Ahmar Urooj , Martin Lo'Rell , Callaghan Michael U , Sarnaik Sharada A. , Taub Jeffrey W 
Published: October 2019

Abstract
Background: Sickle cell disease affects 100,000 people in the United States. Cancer does not appear to be more common in individuals with sickle cell disease however many presenting signs and symptoms of cancer overlap with signs and symptoms of sickle cell disease, complicating diagnosis. Furthermore, sickle cell disease can complicate surgical, chemo- and radio- therapies for malignancy.
Methods: We reviewed the past 46 years experience of cancers in children with sickle cell at a large urban pediatric referral center. We identified 5 cases and reviewed the presentations, treatments, response to therapy, sickle cell complication and laboratory values, including transfusion needs and effect of chemotherapy on fetal hemoglobin levels.
Results: We identified five cases of malignancies in children with sickle cell disease including cases of acute lymphoblastic leukemia (ALL), Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), Wilms tumor and renal cell carcinoma. An additional patient with sickle cell trait was diagnosed with metastatic renal medullary carcinoma. The patients were ages 6-18 years old at diagnosis and 4 were female. All had delays in diagnosis as their initial signs and symptoms overlapped with sickle cell disease (abdominal mass mimicking splenomegaly, low blood counts, fever and posterior reversible encephalopathy syndrome, hematuria). All five achieved complete remission with multi-modality therapy (excluding stem cell transplants) and are currently doing well 1- 20 years after treatment. Admissions for pain were reduced during and for some period after cancer therapy and 2 patients had marked, and in one case, prolonged elevation of fetal hemoglobin after therapy.
Discussion: Children with sickle cell develop cancers that can be confused for sickle cell related complications. Cancer therapy can be well tolerated and successful in children with sickle cell. Sickle cell complications are decreased during cancer therapy likely secondary to frequent therapy related transfusion and therapy induced increases in fetal hemoglobin.

Disclosures
Callaghan: Biogen: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Baxalta: Honoraria, Research Funding; Grifols: Honoraria; Roche: Honoraria, Research Funding.
Comparison of the Diagnostic Power Between Cytokine Pattern and Procalcitonin for Predicting Infection in Pediatric Hematology/Oncology Patients
Authors: Tang Yongmin , Xia Tian , Xu Xiaojun , Zhao Ning , Luo Zebin 
Published: October 2019

Abstract

Objectives: Neutropenic fever is very common in chilidren with chemotherapy. Due to the fact that an infection is usually suggested, broad antibiotic therapy is usually administered. However, early diagnosis of the infection is usually difficult and the antibiotic therapy may not be alway appropriate. Furthermore, blood culture is usually negative for those heavily treated patients by antibiotics. So a sensitive biomarker for early recognition of inction is desired. Previous studies have shown that procalcitonin (PCT) is a good marker for predicting infection. However, in our experience, the sensitivity of infection recognition by PCT is low. Our previous studies have shown that cytokine profiles presented very high sensitivity and sepecificity for predicting infection in hematology-oncology children at the time of neutropenic fever. However, the diagnositic power between cytokine profiles and PCT in those patients has not been systemically compared. The aim of this study was to evaluate the diagnostic power of the cytokine pattern and serum PCT level for predicting infection in pediatric hematology/oncology patients.
Methods: In this retrospective study, a total of 3023 samples (2819 febrile episodes and 204 control samples) derived from 992 (including 164 afebrile patients as control) hospitalized hematology-oncology children. Th1/Th2 cytokines including Interleukin (IL)-2, Il-4, IL-6, IL-10, Tumor necrosis factor (TNF) α and interferon (IFN) γ were measured by a FACScalibur flow cytometer using cytometric bead array (CBA) techniques. According to the etiology, imaging and clinical symptoms, 2819 febrile episodes were divided into 5 groups including blood culture positive sepsis, clinical diagnosed sepsis, non-sepsis infection, viral infection and systemic fungal infection.
Results: IL-6 and IL-10 levels as well as positive rates in bacterial infection group were significantly higher than those in viral infection group and control group. In positive blood culture sepsis group, 92.8% (297/320) and 82.2% (263/320) patients had increased IL-6 and IL-10 levels that exceeded the upper limit of the normal range. However, the positive rates of PCT and C-reactive protein (CRP) in bacterial infection group were only 33.8% (108/320) and 73.1%(234/320), respectively, which were significantly lower than those of IL-6 and IL-10 (P<0.01). Based on the receiver operating characteristic (ROC) curves, PCT presented a poorer sensitivity in the diagnosis of severe infection, as compared with IL-6 and IL-10 (p<0.01). As for specificity, IL-6 and IL-10 was also significantly higher than PCT in the diagnosis of Gram-negative bacterial infection.
Conclusion: The specific cytokine pattern of highly elevated IL-6 and IL-10 shows higher diagnostic accuracy than PCT for bacterial and severe infection among febrile hematology-oncology children.

Disclosures
No relevant conflicts of interest to declare.
Synergistic Effects of a Procoagulant Bispecific Antibody and Rescue Therapies on Thrombin Generation- a Potential Safety Risk
Authors: Knappe Sabine , Hartmann Rudolf , Goldstein Brahm , Ewenstein Bruce M. , Valentino Leonard , Scheiflinger Friedrich 
Published: October 2019

Abstract
Background: Investigational non-factor products, such as ACE 910 (Emicizumab), offer potential new treatment options for hemophilia patients with inhibitors. However, their uncertain and unregulated mechanisms of action raise multiple concerns around safety and efficacy in specific clinical contexts. As an antibody to FIXa and FX, ACE 910 lacks the inherent regulatory characteristics that are present in replacement factor and bypassing agents in the context of hemostasis.
FEIBA is a plasma-derived, activated prothrombin complex concentrate developed to prevent and treat bleeding episodes in hemophilia A and B patients with inhibitors. There are more than 40 years of clinical experience with FEIBA. Extensive prospective clinical study data, as well as post-approval pharmacovigilance data demonstrated the product to be safe and highly effective. In an ongoing phase III study (NCT02622321), hemophilia A patients with inhibitors are treated with Emicizumab. To evaluate the treatment options for ACE910-treated patients experiencing breakthrough bleeding, we studied, in-vitro, the thrombin generation profile of various combinations of FEIBA with a biosimilar version of ACE910.
Methods: A biosimilar antibody to Emicizumab (BS-Em) was expressed in mammalian cells, purified and extensively biochemically characterized. Therapeutic doses of BS-Em (200-600nM) in combination with several concentrations of FEIBA (0.1-1IU/ml) were analyzed in standard in-vitro thrombin generation (TG) experiments (1pM TF trigger) using 3 inhibitor patient plasma. A normal range of TG for the experimental conditions used was established using plasma from 34 healthy individuals.
Results: The combination of FEIBA and BS-Em resulted in peak thrombin values of >500nM (600nM BS-Em/1IU/ml FEIBA) while the normal range was established to span peak thrombin levels of ~50-120nM thrombin. Titration experiments established that at 600nM BS-Em, FEIBA concentrations of >0.2IU/ml led to peak thrombin values 4- 10-fold higher than the normal range.
Conclusions: Our in-vitro experiments demonstrate an excessive thrombin generation potential for the combination of BS-Em and FEIBA at concentrations expected to be generated in patients participating in this study. Caution and clinical judgement will be required when considering the use of ACE910 in hemophilia A patients with inhibitors as options to treat breakthrough bleeds if they occur might be reduced or lead to potential AE.

Disclosures
Knappe: Shire: Employment. Hartmann:Shire: Employment. Goldstein:Shire: Employment. Ewenstein:Shire: Employment. Valentino:Shire: Employment. Scheiflinger:Shire: Employment.
Intermediate-Dose Tertiary Prophylaxis Show a Better Joint Protection in Adults with Severe Hemophilia Than Low-Dose Patterns
Authors: Zhou Xuan , Huang Shunhua , Qiu Shiqiu , Liu Zhuqin , Sun Jing 
Published: October 2019

Abstract
Background and Introduction:
Prophylaxis treatment is considered optimal care for patients with severe hemophilia during childhood to prevent bleeding and reduce the incidence of joint disability. However, tertiary prophylaxis may also benefit Adults with Severe Hemophilia, but the optimal dose tailoring of FVIII is still unknown. We initiated a study to compare the low-dose and intermediate-dose regimen for tertiary prophylaxis in adults with severe hemophilia A.
Methods:
Patients with severe hemophilia A (F VIII < 1%) born between January, 1978, and January, 1988, who were treated at the hemophilia treatment centre at Nanfang hospital and treatment data available were eligible for enrollment in the study. The main exclusion criteria were a history of FVIII inhibitor (titer ≥ 0.6BU [Bethesda unit]), detectable FVIII inhibitors at screening (titer ≥ 0.4 BU), chronic liver disease, immunodficiency, another hemostatic defect and the need for major surgery. A total of 40 adults with severe hemophilia were enrolled, including 25 patients with low-dose prophylaxis (5-10 IU/kg twice a week) and 15 patients with intermediate-dose prophylaxis ( FⅧ 15-20 IU/kg twice a week). Breakthrough acute bleedings were treated according to the regular practice and guidelines.
Results:
The study was conducted over a 2-year period (January 2014 to December 2015).Compared to low-dose prophylaxis group, Intermediate-dose tertiary prophylaxis group reduced the annual number of total and joint bleeds (median 13 vs 5.5 and median 10 vs 4; P= 0.001, respectively), and annual target joint bleeding rate were also significantly lower (median 8 vs. 3.5, P =0.002). The breakthrough bleeding events were largely lower in intermediate-dose group than in low-dose group (P=0.03). After prophylaxis, the FISH score in Intermediate-dose group increased from median 21 (range 15-28) to median 24 (range 17-28) (P=0.02) and in low-dose group from median 22 (range 14-28) to median 24 (range 14-28) (P=0.02) respectively. The improvement of FISH score were different between two groups (P=0.04). Meanwhile, The Health-related Qualityof life (HRQoL) in patients with severe hemophilia were measured by the SF-36. The SF-36 score showed better results in terms of overall perceived health status between patients with Intermediate-dose and with low-dose prophylaxis (P < 0.01).
Conclusion:
Compared to low-dose prophylaxis, Intermediate-dose tertiary prophylaxis may show a better joint protection in Adults with Severe Hemophilia, for Intermediate-dose regimen not only means less joint bleeding, but also helps joint function restore and Quality of life improvement. Our study established that Intermediate-dose tertiary prophylaxis may be a better choice for adults in a number of hemophilia treatment centers in China.

Disclosures
No relevant conflicts of interest to declare.
Rivaroxaban As Treatment for Thromboembolic Venous Disease in Patients with Cancer or Neoplastic Hematology
Authors: Campos-Cabrera Gregorio , Campos-Villagomez Jose-Luis , Campos-Cabrera Salvador , Campos-Cabrera Virginia 
Published: October 2019

Abstract
Introduction: Patients with cancer or neoplastic hematology (CNH) has 6 fold risk of thromboembolic venous disease (TVD) than general population and accounts the 20 % of new cases. NCCN treatment recommendation for TVD is with heparin and vitamin K antagonists, however every institution develops its own guidelines and protocols, and the FRONTLINE-2 survey designed to evaluate how clinicians perceive the risk of venous thromboembolism in cancer patients and to provide insight into current strategies for thromboprophylaxis and management has interestingly results. The phase III studies from rivaroxaban that led to its approbation by the FDA in different indications included 6 % of the patients that had some type of cancer and their evolution among the TVD was not different than those without it. There are phase II and III studies where rivaroxaban has shown promising results in this setting.
Objective: describe the evolution in patients with CNH whom developed TVD during treatment and received rivaroxaban.
Material and methods: adults with CNH with TVD during treatment and received rivaroxaban according our protocol (Hematología 2015; 16 supl 1: 115-116).
Results: there are 73 patients receiving rivaroxaban for TVD, 20 patients (27.4 %) has CNH. Gender: 10 female and 10 male, ratio 1/1. Age 23 to 90 years old, mean 54.5. Diagnosis: 1 CLL, 3 ALL, 3 HL, 3 NHL, 1 amyloidosis, 3 low grade MDS, 1 AML-M3, 1 primary myelofibrosis, 4 non neoplastic hematology (brain, kidney, breast and unknown primary). All patients has TVD treatment related, in three of them catheter related (2 HL and 1 NHL). Four died from neoplastic disease (2 male and 2 female): 1 HL, 1 NHL, 1 brain and 1 unknown primary. Eleven patients continue on rivaroxaban for acute treatment and secondary prevention due high risk factors. Five are on aspirin as secondary prevention. In lymphoid neoplasia patients receive prophylactic fluconazol and no interactions were observed. Patient with AML-M3 switches to enoxaparin while taking tretinoin as maintenance. No patient needed dose adjustment. No recurrent TVD or bleeding were observed.
Conclusions: in this small group of patients rivaroxaban was well tolerated without adverse effects or mortality due to recurrent TVD or bleeding. No patients with MM or MPD were observed due the prophylactic use of aspirin. The knowledge of rivaroxaban interactions for adjustments or change in the anticoagulation is essential for a good evolution, permitting its rational use in institutional protocols and lowering costs for anticoagulation compared to enoxaparin.

Disclosures
No relevant conflicts of interest to declare.