bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-Inflammatory Activities of Sulfated Non-Anticoagulant Heparin Derivative Beyond Its Anti-Sickling and Anti-Selectin for the Effective Management of Sickle Cell Disease
Authors: Darwish Noureldien , Abdulmalik Osheiza , Mousa Shaker A 
Published: November 2020

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by the inheritance of a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells (RBCs). RBC sickling increases the adhesiveness of RBCs to alter the rheological properties of the blood and trigger inflammatory responses, leading to hemolysis, vasoocclusive crisis, pulmonary complications, plethora, and other pathological sequelae. Glycosaminoglycans, such as low molecular weight heparin (LMWH), have been suggested as treatments to relieve coagulation complications in SCD because of their ability to decrease thrombin generation and sickle cell adhesion. However, they are associated with bleeding complications after repeated dosing.
An alternative, sulfated non-anticoagulant LMWH derivative (S-NACH) was previously reported to have none to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectin-dependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice (1,2). S-NACH has been further engineered to possess an aldehyde moiety, which confers anti-sickling properties primarily due to specific interactions with HbS to increase its affinity for oxygen.
Our in vitro sickling assay under hypoxic conditions using S-NACH at 0.5 - 2 mM demonstrated that S-NACH significantly reduced the sickling of SS cells and in a concentration-dependent manner, with comparable to that of 1 mM GBT440 (Figure 1 A-C). A similar concentration dependent effect on increasing HbS affinity for oxygen using oxygen equilibrium study was documented.
In an vivo animal model using Townes' SCD animals plasma levels of pro-inflammatory cytokines IL-1β, IL-6, IFN-γ, MCP-1, TNF-α, M-CSF, and VEGF were increased in SCD untreated samples in contrast to a significant decrease (*P&lt; 0.001) in S-NACH-treated animals, at both 2 and 6 h. In addition, S-NACH was able to increase the decreased levels of the endogenous anti-inflammatory IL-10 (Figure 1 D).
The above set of novel findings about S-NACH established it to be effective for the management of SCD via the modulation of thromboinflammatory pathways, involved in thromboembolism and end organ damage, beside anti-sickling, anti-selectin and without causing any bleeding risk.
Reference
1. Alshaiban A, Muralidharan-Chari V, Nepo A, Mousa SA. Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Non-anticoagulant Heparin Derivative. Clin Appl Thromb Hemost. 2016 ;22(3):230-8.
2. Mousa SA: Compositions and method for anti-sickling of red blood cells in sickle cell disease. US Patent 9,822,190, November 2017.

Disclosures
Mousa: Vascular Vision Pharma Co.: Patents & Royalties.
Role of Roxadustat in Improving Erythropoiesis-Stimulating Agent (ESA)-Resistant Anemia in Patients on Maintenance Hemodialysis
Authors: Funakoshi Satoshi 
Published: November 2020

Background: Roxadustat, an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, is shown to stimulate erythropoiesis thus improving iron metabolism. Again, while hyperglycemic states are known to be associated with a decreased tissue hypoxia response, to date, roxadustat has not been revaluated for its role in improving anemia in patients with or without diabetes in clinical settings.
Methods: A total of 64 hemodialysis patients being treated with epoetin α (9000 units weekly) participated in the study after giving informed consent. They were switched from intravenous epoetin α to oral roxadustat (100 mg 3 times weekly) therapy and were assessed 8 weeks later for improvements in anemia, as well as for changes in parameters for iron metabolism and C-reactive protein (CRP).
Results: The study included 39 patients without diabetes (mean age, 71.1 ± 12.1 years; mean dialysis vintage, 7.5 ± 7.4 years; mean GA, 16.2 ± 2.9%) and 27 patients with diabetes (mean age, 70.3 ± 10.3 years; mean dialysis vintage, 5.9 ± 5.5 years; mean GA, 24.9 ± 5.5%). As shown in Table, after 8 weeks the Hb concentration was significantly increased from 10.3 ± 0.8 g/dL at baseline to 10.7 ± 1.3 g/dL in patients without diabetes (P = 0.03) but was not increased in patients with diabetes (from 10.4 ± 0.6 at baseline to 10.5 ± 1.1 g/dL). Again, the serum iron, ferritin concentrations and the transferrin saturation ratio were decreased, irrespective of whether or not they had diabetes, with no change shown in serum CRP level.
Conclusion: Switching hemodialysis patients with ESA-resistant anemia from ESA to roxadustat led to improvements in anemia only in those without diabetes, while study results suggested the involvement of mechanisms, other than impaired iron utilization or inflammation, in the impairment of hematopoiesis in those with diabetes.
Table

Disclosures
No relevant conflicts of interest to declare.
A Zebrafish Model for Severe Congenital Neutropenia with Jagn1b-Deficiency
Authors: Doll Larissa , Aghaallaei Narges , Skokowa Julia , Welte Karl , Bajoghli Baubak 
Published: November 2020

Severe congenital neutropenia (CN) is a bone marrow failure characterized by an impaired neutrophil development. This disease can be caused by different germline mutations, which one of them is Jagunal homolog 1 (JAGN1). CN patients are prone to develop life-threatening infections from birth on and the treatment of choice is recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, patients with JAGN1 deficiency poorly respond to this treatment. Therefore, the development of new therapeutic strategies to treat this disease is essential. Thus far, lack of an animal model was the main limitation to study the function of JAGN1 in neutropenia and perform high-throughput compound screening. In this work, we studied the role of jagn1b in zebrafish granulopoiesis and hematopoiesis. Two different approaches were used. First, we injected antisense morpholino that efficiently blocked the translation of jagn1b mRNA. As a second approach, we used the CRISPR-Cas9 technique to introduce mutations in the zebrafish jagn1b gene and analyzed the crispants. Both of these approaches were tested in wild-type embryos as well as the transgenic mpo:GFP reporter line, in which neutrophils are labeled with GFP. Our results showed that interference with Jagn1b reduced the number of neutrophils, without affecting the early myelopoiesis and monocytes/macrophages. Further analysis revealed that apoptosis was enhanced in embryos injected with the jagn1b morpholino, however, this effect was not restricted to the hematopoietic tissues. Our results also suggested that unfolded protein response (UPR) was activated because the expression levels of genes involved in this pathway such as chop, atf4a and atf4b were significantly upregulated in the jagn1b morphants, when compared with the wild-type counterparts. Overall, we have successfully established a novel in vivo model for studying the role of JAGN1 in granulopoiesis, and the possible role of Jagn1b in UPR response might be useful to find new targets for the development of therapeutic strategies for CN.

Disclosures
No relevant conflicts of interest to declare.
Excellent Clinical and Pharmacokinetic Real-World Experience after Switching to Rurioctocog ALFA Pegol
Authors: Benitez Hidalgo Olga , Lopez Jaime Francisco Jose , Martínez García María Fernanda , Juarez Gimenez Juan Carlos , Alvarez Martinez Eva , Suito Milagros , Bosch Francesc , Gironella Mesa Mercedes 
Published: November 2020

Background:Prophylactic treatment with standard half-life coagulation factors (SHL) requires 3-4 weekly periodic infusions. Extended half-life (EHL) factor VIII (FVIII) provides improvements in half-life (t1/2) and area under the curve (AUC) of 1.3 and 1.25 times compared to standard half-life (SHL) products. Rurioctocog alfa pegol is an extended half-life (EHL) rFVIII (rFVIII-EHL) treatment that could be a more convenient and cost-effective therapeutic alternative than SHL, since it would reduce the number of weekly infusions (NWI).
Aims:The aim of this study is to analyze pharmacokinetic (PK) parameters and compare NWI and bleeding rates after switching from SHL to this EHL in hemophilia A (HA) patients.
Methods:In a prospective study, the number of weekly infusions (NWI), annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and PK parameters were compared between previous treatment with FVIII-SHL vs rFVIII-EHL (Rurioctocog alfa pegol).
The assessment of the PK parameters: volume of distribution (Vd (dL/kg)), clearance (Cl (dL/h/kg)) and half-life time (t½ (h)) was performed by using the pharmacokinetic poblacional software online myPKFiT®.
Results:Nineteen patients from 2 Spanish hospitals (n=12 Vall d'Hebron Hospital, n=7 Hospital Regional Universitario de Málaga) were recruited. Median age was 30 years (range, 12-54), with five pediatric patients, and 18 had severe HA (one moderate HA).
Sixteen patients were under prophylactic treatment with Advate® and 1 with Kovaltry®. Two patients were switched from on-demand treatment to prophylaxis.
The median use of rFVIII-EHL was 15.63 month.
The PK parameters after the switch to the rFVIII-EHL in entire cohort and pediatric cohort are shown in Table 1.
The t ½ of rFVIII-EHL was positively correlated to preinfusion plasma levels of von Willebrand factor antigen (vWF:Ag) (Figure 1).
ABR and AJBR were reduced, as well as weekly infusion frequency (33.3%, IQR:0-50%) (Table 2). Of note, 57.9% of patients presented zero joint bleeding events after switchingtorFVIII-EHL.
Conclusions:In this prospective analysis rFVIII- EHL presents as a therapeutic alternative that allows reducing ABR and AJBR as well as weekly infusion frequency according to PK patient parameters.

Disclosures
Bosch: Roche:Honoraria;Celgene:Honoraria;Jansen:Honoraria;Abbvie:Honoraria;Novartis:Honoraria;Astra Zeneca:Honoraria;Takeda:Honoraria.Gironella Mesa:Bristol Myers Squibb:Honoraria, Speakers Bureau;Janssen:Consultancy, Honoraria.
Antithrombin Supplementation in Adults with Acute Lymphoblastic Leukemia (ALL) Following Asparaginase Therapy: A Meta-Analysis
Authors: Mosalem Osama , Mujer Mark , Abu Rous Fawzi , Cole Craig E. 
Published: November 2020

Background:
Aspagarinase is a fundamental component for the treatment of patients with acute lymphoblastic leukemia (ALL). Venous thromboembolism (VTE) is a known complication of asparaginase therapy during treatment for ALL. This is attributed to the depletion of anticoagulants, particularly acquired antithrombin deficiency following asparaginase administration. The incidence of thrombosis following asparaginase is more prevalent in adults versus children and is estimated to be around 5-35 % and 2.4-8% respectively. Multiple studies have investigated the efficacy and safety of antithrombin supplementation. The recent THROMBOTECT study showed that prophylactic use of antithrombin (AT) or low molecular weight heparin (LMWH) is associated with significant risk reduction of thromboembolism in children and adolescents during induction chemotherapy of ALL. Our study sought to review the cohort studies comparing VTE in adults with and without AT supplementation in ALL receiving asparaginase and specifically evaluate the efficacy of this strategy.
Methods:
We performed a systematic search using PubMed, Google Scholar, EMBASE, SCOPUS and ClinicalTrials.gov without language restriction up until July 20th 2020. A random effects model was utilized to calculate risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI).
Results:
Eight studies fulfilled our inclusion criteria (table 1) and were retrospective cohort studies. In adult patients, with ALL treated with asparaginase, the incidence of VTE was significantly lower in those who received AT [RR=0.46 (95 % CI= 0.31-0.70; p= 0.0002) (figure 1.1). The threshold for AT supplementation was 60-70% in most of the studies, with the exception of two studies where the threshold was 50%.
Conclusion:
In our meta-analysis of the current available data,Antithrombin supplementation in adults with ALL receiving asparaginase was associated with a significant decrease in the risk of venous thromboembolism compared to those who didn't receive thromboprophylaxis. Our data suggest the benefit of antithrombin supplementation in adults with ALL treated with asparaginase. We suggest that this strategy be implemented in a large prospective clinical trial to further confirm the benefit of this intervention.

Disclosures
No relevant conflicts of interest to declare.
Assay Interference By Emicizumab in Aptt and Chromogenic Based FVIII:C and Inhibitor Assays
Authors: Poirier Brian F , Robinson Mary , Tiefenbacher Stefan , McEwan Erin , Cogswell Caroline , Gode Roxy , Burger Emily , Allison Tyler , Littlefield Jennifer , Pikas Amanda , Schmoker Andrea 
Published: November 2020

Background:Emicizumab, a humanized bispecific antibody, has been approved for the prophylactic treatment of hemophilia A in patients with and without inhibitors. Both activated partial thromboplastin time (APTT) based FVIII:C and inhibitor assays, as well as select chromogenic FVIII:C assays have been reported to be affected in the presence of emicizumab.
Aims:To assess the effect of emicizumab spiked at 0, 25, 50, and 100 ug/mL into congenital FVIII deficient plasma, containing FVIII inhibitor at 0, 1 and 5 BU, in seven commonly used APTT and chromogenic based FVIII:C assays. Samples were also tested in an APTT and chromogenic based FVIII Nijmegen inhibitor assay.
Methods:Four IVD approved, APTT based FVIII:C assays and three chromogenic FVIII:C assays were evaluated (Table 1). In addition, FVIII inhibitor levels were measured by Nijmegen Bethesda assay using either APTT (Actin®FSL, Siemens Healthcare) or chromogenic based (FVIII Chromogenic Assay, Siemens Healthcare) FVIII:C assays.
Results:Reagent and dose-dependent increases in FVIII:C were observed for all APTT reagents tested as well as for the BIOPHEN FVIII:C chromogenic assay. The presence of low or high titer inhibitors did not impact APTT based FVIII:C measured. Neither of the two chromogenic FVIII:C assays, using bovine based FX and FIXa (i.e. FVIII Chromogenic Assay and Coatest®SP4) demonstrated measurable FVIII levels at any of the emicizumab concentrations tested. FVIII Nijmegen Bethesda inhibitor results using APTT based FVIII:C, when tested in the presence of emicizumab, consistently produced false negative results (Table 1) whereas results determined using the FVIII Chromogenic Assay measured inhibitor titers at expected concentrations.
Conclusion:Confirming previously published results, emicizumab interferes in the APTT based FVIII:C and Nijmegen Bethesda inhibitor assays. Even at low emicizumab concentrations, false negative inhibitor titers are measured in APTT based inhibitor assays. Using a bovine based chromogenic FVIII:C assay is imperative when measuring both FVIII:C and FVIII inhibitors in samples containing emicizumab.

Disclosures
Tiefenbacher: Laboratory Corporation of America Holdings:Current Employment, Current equity holder in private company;Novo Nordisk:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Shire:Honoraria;Octapharma:Honoraria;Siemens Healthcare:Membership on an entity's Board of Directors or advisory committees;BioMarin:Membership on an entity's Board of Directors or advisory committees.
Platelet Decrease and Efficacy of Platelet-Rich Plasma Return for Peripheral Blood Stem Cell Apheresis
Authors: Shima Takahiro , Sakoda Teppei , Henzan Tomoko , Kunisaki Yuya , Maeda Takahiro , Akashi Koichi , Miyamoto Toshihiro 
Published: November 2020

Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and widely performed in clinical practice. Platelet loss is the major complication of PBSC apheresis, and platelet-rich plasma (PRP) return is recommended in case of severe platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss nor the efficacy of PRP return post-apheresis. To address these questions, we assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated efficacy of PRP transfusion on platelet recovery post-apheresis.
Platelet counts reduced up to 70% post-apheresis in both allo- and auto-PBSC settings, while severe platelet count decrease (&lt; 50 x 109/L) was only observed in auto-PBSC patients (Figure 1).
We next analyzed the relationship between severe platelet (&lt; 50 x 109/L) after apheresis and several clinical factors by using univariate and multivariate analysis for auto-PBSC patients. As shown in Table 1, in univariate analysis, severe platelet counts following auto-PBSC apheresis was found more frequently in patients with lower platelet count, lower percentage of CD34+ cells in PB at pre-apheresis, repeated round of apheresis, and smaller number of collected CD34+ cells. On the other hand, in multivariate analysis, the white blood cell (WBC) counts pre-apheresis was the only significant risk factor of severe platelet count following apheresis (p = 0.038).
We finally analyzed the transitions of platelet counts in the setting of apheresis. The median platelet counts at pre-apheresis, post-apheresis, and post-PRP return were 187.0 x 109/L, 132.0 x 109/L, and 154.0 x 109/L for allo-PBSC apheresis, and 147.0 x 109/L, 111.0 x 109/L, and 127.0 x 109/L for auto-PBSC apheresis (p &lt; 0.0001 for all, allo-PBSC donors and auto-PBSC patients, respectively) (Figure 2), indicating that PRP return post-apheresis facilitated a rapid platelet recovery in both allo- and auto-settings.
Collectively, our data suggest that WBC counts pre-apheresis is a useful predictor for severe platelet decrease following auto-PBSC apheresis and that PRP return is an effective mean to facilitate platelet recovery post-apheresis.

Disclosures
No relevant conflicts of interest to declare.
Ctdna Monitoring in Predicting Relapse of Primary Mediastinal B-Cell Lymphoma
Authors: Pang Diwen , Jiang Xinmiao , Huang Ling , Teng Yan , Liu Sichu , Chen Feili , Wei Xiaojuan , Guo Hanguo , Li Wenyu 
Published: November 2020

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of aggressive B-cell lymphoma. The majority of relapses occur within the first few months resulting in a dismal prognosis, thus we need to identify the risk of early relapse. Circulating tumor DNA (ctDNA)-based response assessment may enable response adapted therapy and early prognostication. In this study, we aim to clarify the role of ctDNA-monitoring in early prediction of relapse.
Methods: We retrospectively analyzed the characteristics of 38 patients with PMBCL. The genetic sequencing and ctDNA monitoring were conducted by target next-generation sequencing (NGS).
Results: The median age was 32 years old and 26 (68.4%) were female. Most cases (31/38, 81.6%) were diagnosed with stage I or II disease and fourteen (36.8%) cases present with extranodal involvement. The 5-year PFS and OS for PMBCL patients were 65.7 and 72.1%, respectively. High IPI score were associated with poor survival by univariate analysis. The complete response (CR) rate and overall response rate of R-CHOP was similar to R-EPOCH (69.2% vs. 70.0%, P =1.000 and 84.6% vs. 95.0%, P =0.547, respectively), however the 5-year PFS and OS rate for R-EPOCH seems longer than those for the R-CHOP (PFS 82.9% vs. 53.8%, P=0.0569; OS 92.9% vs. 60.6%, P=0.0567). Radiotherapy was less delivered in the patients who received R-EPOCH than R-CHOP (5.0% vs.53.8%, P=0.003) and had no impact on prognosis. We performed genetic sequencing on twenty-three cases. STAT6(15/23, 65.2%), SOCS1(13/23, 56.5%), TNFAIP3(13/23, 56.5%) were the most common affected genes in both response and refractory/relapsed patients. Cell cycle, FoxO signaling pathway and TNF signaling pathway were more frequently involved in refractory patients. ctDNA monitoring was conducted in 16 cases and fifteen cases show undetectable ctDNA after a median of 2 (range from 1 to 5) cycles and one refractory case presented with durable positive ctDNA. Among 4 relapse cases, 3 had prior detectable ctDNA half a month earlier before imaging manifestations of relapse. Regarding prediction of relapse, positive predictive value of ctDNA is 100%.
Conclusions: Intensive induction chemotherapy can improve prognosis of PMBCL and ctDNA precisely predicted relapse. As most cases relapse within a few months, ctDNA-monitoring is crucial to improve prognosis.

Disclosures
No relevant conflicts of interest to declare.
Re-Evaluating the Prognosis and Transformation Risk of Chronic Eosinophilic Leukemia
Authors: O'Leary Daniel , Goyal Amrita 
Published: November 2020

Chronic eosinophilic leukemia, not otherwise specified, (CEL-NOS) is a rare myeloproliferative neoplasm defined by an autonomous clonal expansion of eosinophil precursors. CEL-NOS has long been considered an aggressive disease with a poor prognosis and high risk of transformation to blast phase. This impression was reinforced by a case series of 10 patients with CEL-NOS in which median overall survival was 22 months and in which one half of patients transformed to acute leukemia at a median of 20 months from time of diagnosis (Helbig et al, American Journal of Hematology, 2012). However, this has not been confirmed in any population-based or large cohort studies.
We sought to evaluate whether this poor prognosis is consistent across a larger patient database. We identified 487 patients with CEL-NOS in the Surveillance Epidemiology and End Result-18 database. Patients were predominantly male (60.5%) with a median age of 57 at time of diagnosis. Overall survival at 2 years from diagnosis for the cohort was 92.7% with a disease-specific survival of 97.2%. At 5 years overall survival remained relatively high (88.7%) as did disease-specific survival (95.6%). Median follow-up was 56.5 months (range 0-191 months). Median survival for patients who died of CEL was 5 months (range 0-46 months). This raises the possibility of a dichotomous patient population wherein there is one group of patients with a good prognosis, and a second group with aggressive disease and significantly poorer prognosis. Of note, the majority of the patients who died from CEL-NOS (21/23) died within two years of diagnosis.
Only three of the patients studied developed acute leukemia, two with acute myeloid leukemia and one acute lymphoblastic leukemia; all three died of their second malignancy within 28-60 months. An additional 11 patients developed lymphoma, 2 Hodgkin lymphoma and 9 non-Hodgkin lymphoma (NHL), including peripheral T-cell lymphoma (3/9), diffuse large B-cell lymphoma (3/9), angioimmunoblastic T-cell lymphoma (2/9), and Burkitt's lymphoma (1/9).
This data suggests that the current impression of CEL-NOS as a rare and aggressive disease with a poor prognosis may be more nuanced than previously appreciated. The limitations of SEER data are significant and include concerns regarding both accuracy of diagnosis and collection bias. However, the incongruence between current disease perception and the large-scale data available suggest that further study is both warranted and necessary. Next steps would include the creation of a prospective national registry of patients with CEL-NOS. This would assist both in giving appropriate disease-counseling for patients and in better assessing which patients might benefit from treatment with chemotherapy.

Disclosures
No relevant conflicts of interest to declare.