bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimization of Thrombin Generation in Hemophilia a
Authors: Van De Berg Tom , Beckers Erik AM , Hackeng Tilman M. 
Published: November 2021

Abstract
Background: Hemophilia A (HA) is a bleeding disorder characterized by decreased or absent FVIII. Clinical analysis of coagulation potential in this patient population is classically based on APTT based FVIII assays. Although both the one-stage FVIII assay and the chromogenic FVIII assay can measure FVIII concentrations reliably these types of assays only give insight on the initiation of coagulation. Global coagulation assays, like thrombin generation (TG), can be used to measure the full coagulation spectrum of initiation, amplification and propagation. However the frequently used commercially available TG kits lack sensitivity for measurements of hemophilia plasma within the lower FVIII ranges which are essential in explaining differences in bleeding phenotype.
Aim: We aim to optimize the sensitivity of the TG-assay for measurements in hemophilia A patients, especially in the lower FVIII ranges.
Methods: In order to minimize patient specific sensitivity a hemophilia A pool plasma (HAPP) was created. Analysis of the influence of pre-analytical variables, like contact activation inhibitors, on the assay was performed. Initiation of coagulation by different reagents was compared for sensitivity towards factor FVIII titrations in patient plasma. Other assay variables like phospholipids and temperature were adjusted to increase sensitivity even further.
Results: Commonly used tissue factor (TF) initiated TG at varying concentrations was unable to significantly differentiate in FVIII levels below 20%. In contrast, TG activation with low concentrations of TF in presence of FXIa appeared to be highly sensitive for FVIII changes both in high and low ranges. Additionally, a representative baseline TG-curve in severe HA plasma could only be produced using this dual TF/FXIa-activation. There was a value in the addition of contact activation inhibitors in the assay. Higher phospholipid concentrations seem to benefit this assay setup compared to a TF only setup.
Conclusion: TF/FXIa dual activation thrombin generation increased assay sensitivity in severe hemophilia plasma, allows for dose-dependent measurements in low FVIII ranges and provides a solid baseline curve that can be used for further clinical evaluation of coagulation potential and possibly therapeutic monitoring in hemophilia A.
Figure 1 Figure 1.

Disclosures
Hackeng: ACS Biomarker BV: Current Employment, Current equity holder in publicly-traded company; Coagulation Profile BV: Current Employment, Current equity holder in publicly-traded company.
Pomalidomide, Bortezomib, and Dexamethasone (PVd) for Chinese Multiple Myeloma Patients at First Relapse
Authors: Qiu Lugui , An Gang 
Published: November 2021

Abstract
Background:
The phase 3 OPTIMISMM（NCT01734928） trial done at 133 hospitals and research centres in 21 countries but no Chinese site involved in this study. In the OPTIMISMM study ,pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated excellent efﬁcacy in patients at ﬁrst relapse, including immediately after upfront lenalidomide treatment failure and other common ﬁrst-line treatments, the mPFS was 20.73 months, the ORR was 90.1%, and no new safety signals were observed. Building on these promising results, we decided to explore PVd in Chinese patients at ﬁrst relapse.
Study Design/Methods:
This is a multicenter, prospective, single-arm phase 2 study designed to evaluate the efﬁcacy and safety of PVd in Chinese patients at ﬁrst relapse.
Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had only 1 prior antimyeloma regimen. Key exclusion criteria included creatinine clearance&lt;30 mL/min requiring dialysis, grade ≥3 peripheral neuropathy, or grade 2 peripheral neuropathy with pain. Patients with prior exposure to bortezomib were eligible, provided they were not refractory to a bortezomib-containing regimen dosed at 1.3 mg/m 2 twice weekly.
Patient（n=62,Figure 1）will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond. Dexamethasone was given on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and on days 1, 2, 8, and 9 of cycles 9 and beyond; patients received 20 mg of dexamethasone if aged ≤75 years and 10 mg otherwise.
The primary endpoint is ORR, the secondary endpoints are≥VGPR, MRD(-) rate, PFS, OS and safety. ORR will be assessed by the International Myeloma Working Group criteria after each cycle until PD. The Kaplan-Meier method will be used to estimate PFS and OS. Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 7 sites of China.
Disclosures: Research Sponsor: CHIATAI TIANQING PHARMACEUTICAL GROUP.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Baseline Hepcidin Does Not Predict the Response to Iron Therapy in Pregnant Women with Iron Deficiency
Authors: Hansen Rebecka , Kurtzhals Joergen , Styrishave Bjarne , Holm Charlotte 
Published: November 2021

Abstract

Introduction:
Hepcidin, the master regulator of iron economy, is decreased during pregnancy to facilitate adequate iron transfer across the placenta. Conversely, iron need increases substantially during pregnancy often leading to iron deficiency and subsequently anemia. The PREG-01 Study compared the efficacy and safety of intravenous (IV) ferric derisomaltose (FDI) vs. oral iron in treating persistent iron deficiency in pregnant women. The study found FDI to be efficacious and well-tolerated in pregnancy and the proportion of non-anaemic patients throughout the course of the study was significantly lower in the FDI group. In this analysis, we investigated the effect of baseline hepcidin on the response to IV and oral iron therapy.
Methods:
PREG-01 was a single-centre, open-label, randomized controlled trial. Women 14-21 weeks pregnant with persistent iron deficiency (ferritin&lt;30 µg/L despite oral iron treatment) received a single intravenous 1000 mg dose of FDI (n=100) or 100 mg elemental oral iron daily combined with ascorbic acid (n=101). Hemoglobin (Hb), ferritin and transferrin saturation (TSAT%) levels were captured at baseline and monitored throughout the study. The effect of baseline hepcidin on achieving non-anemic status (Hb ≥ 11 g/dL) at all study visits and the effect on change in Hb, ferritin and TSAT% were investigated by estimating odds ratios from a logistic regression model with treatment as factor and interaction between treatment and baseline hepcidin. The odds ratio estimate is for an increment in baseline hepcidin of 1 ng/mL.
Results:
Mean [standard deviation (SD)] baseline Hb was 11.97 (0.93) g/dL in the FDI group and 11.75 (0.91) g/dL in the oral iron group. Baseline hepcidin was 6.42 ng/mL in the FDI and 5.32 ng/mL in the oral iron group. Baseline hepcidin was not associated with the ability to achieve non-anaemic status either in the FDI (OR 0.98; 95% CI: 0.87-1.09) or the oral iron group (OR 0.96; 95% CI: 0.88-1.05). No statistically significant associations were found between baseline hepcidin and change in Hb, ferritin or TSAT% throughout the study (Figure 1).
Conclusions:
In a population of pregnant women with iron deficiency, but otherwise healthy, baseline hepcidin was overall low. Although there was a trend for an association between baseline hepcidin and Hb response to oral iron only, baseline hepcidin did not predict the response to iron therapy.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Ferric Derisomaltose is an IV iron preparation indicated for the treatment of iron deficiency anemia in the US.
IGF2BP3 As an N6-Methyladenosine Reader Promotes Acute Myeloid Leukemia Progression By Regulating the Stability of Target RNA
Authors: Zhang Nan , Deng Jianchuan , Zhou Fuling 
Published: November 2021

Abstract
Background: N6-methyladenosine (m6A) is the most common post-transcriptional modification of eukaryotic mRNA. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), which constitutes a subtype of this malignancy associated with poor prognosis and high genetic risk.
Methods: Bioinformatics analysis of public databases was performed to screen the differentially expressed m6A regulators in AML. Clinical samples were collected to detect the expression of IGF2BP3 in AML by RT-qPCR. The effects of IGF2BP3 on the proliferation, apoptosis and cycle of AML cells were detected by CCK-8 and flow cytometry. RNA-seq was used to identify target genes of IGF2BP3 by integrating analysis with RIP-Seq, iCLIP-Seq and MeRIP-Seq data sets.
Results:High expression of IGF2BP3 is closely associated with poor prognosis of AML and is higher in patients with high genetic risk group. IGF2BP3 was the lowest expressed in AML-M3 and the highest expressed in RUNX1 mutant type. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 suppressed dramatically induces apoptosis, reduces proliferation and impaired leukemic capacity AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-tagged RNA.
Conclusions:We provided compelling evidence to demonstrate that m6A reader IGF2BP3 contributed to tumorigenesis and poor prognosis of AML, which can serve as a target to develop therapeutics for cancer treatment.
Disclosures
No relevant conflicts of interest to declare.

Disclosures
No relevant conflicts of interest to declare.
GRK2 Regulates ADP Signaling in Platelets Via P2Y 1 and P2Y 12
Authors: Zhao Xuefei , Cooper Matthew , Yanman Yanki , Baltz Aiden , Michael James , McKenzie Steven Edward , Stalker Timothy J. , Zhu Li , Ma Peisong 
Published: November 2021

Abstract
Abstract
Venous thromboembolism (VTE), heart attack, and stroke are all diseases in which platelets play a role, through inappropriate platelet activation and subsequent thrombus formation. Most platelet agonists activate platelets via G protein-coupled receptors (GPCRs), which are targeted by many antiplatelet drugs. Along with thrombin and TxA 2, ADP has long been recognized for its important role in hemostasis and thrombosis. It activates platelets via GPCRs, P2Y 1 and P2Y 12. However, little is known about the negative feedback mechanisms governing P2Y receptor-mediated platelet activation and thrombus formation.
Here, we provide the first evidence that GPCR kinase 2 (GRK2) serves this regulatory role during platelet activation and thrombus formation by using a platelet-specific GRK2 deletion mouse model and a GRK2-specific inhibitor in human platelets. Deletion of GRK2 in mouse platelets causes increased platelet accumulation following laser-induced injury in cremaster muscle arterioles, particularly in the shell region of thrombi. In addition, this deletion increases ADP-induced pulmonary thromboembolism. GRK2 -/- platelets also have increased platelet aggregation in response to ADP, but not to PAR4 receptor agonist, TxA 2, or convulxin. Underlying these changes in GRK2 -/- platelets is an increase in Ca 2+ mobilization, Akt phosphorylation, and Rap1 activation in response to ADP, and an attenuated rise of cAMP levels in response to ADP in the presence of prostaglandin I 2. Furthermore, platelet aggregation can be restored in GRK2 -/- platelets in response to ADP re-stimulation, indicating that GRK2 contributes to ADP receptor desensitization. To further assess the role of GRK2 in the P2Y 12 signaling pathway in vivo, we examine laser-induced thrombus formation in WT and GRK2 -/- mice treated with the P2Y 12 antagonist, cangrelor. Cangrelor treatment eliminates the phenotypic difference in platelet accumulation between WT and GRK2 -/- mice in response to injury. Using a specific GRK2 inhibitor, pharmacologic inhibition of GRK2 activity in human platelets results in an increase in platelet activation in response to ADP. Finally, our biochemical studies show that GRK2 binds to endogenous Gβγ subunits during platelet activation.
Taken together, we have demonstrated for the first time that 1) GRK2 plays a negative regulatory role in platelet activation by attenuating ADP-dependent signaling, 2) it does this by limiting P2Y 1 and P2Y 12-mediated signaling, 3) GRK2 interacts with Gβγ and functions as a signaling hub in platelets for fine-tuning GPCR signaling, and 4) although the potential inhibition of GRK2 can be beneficial for treatment of heart diseases, maintaining GRK2 activity in platelets could be beneficial for prevention of thrombotic diseases.

Disclosures
No relevant conflicts of interest to declare.
CUX1 Deficiency Potentiates RAS Signaling to Drive Malignancy
Authors: An Ningfei , Imgruet Molly K , Khan Saira , Jueng Lia , Gurbuxani Sandeep , McNerney Megan E. 
Published: November 2021

Abstract
-7/del(7q) is prevalent in high-risk myeloid neoplasms and frequently co-occurs with gain-of-function mutations in the RAS pathway. Herein, we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1, that encompasses hematopoietic malignancies and solid-tumors. Mice with both oncogenic NrasG12D and Cux1 knockdown developed accelerated myeloid malignancies with leukemic transformation. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem/progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through reduction of negative regulators of RAS/PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heightened growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition. Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a viable therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.

Disclosures
No relevant conflicts of interest to declare.
Improving Residents' Knowledge of Peripheral Smears
Authors: Ashraf Sara , Shenouda Mina 
Published: November 2021

Abstract
Background: A peripheral smear is an important diagnostic tool, inexpensive, reliable and quick. It reflects the functional status of the bone marrow and can identify many blood disorders, some of which are life threatening and very time sensitive. Peripheral smears are useful to assess cytopenic states (eg, anemia, leukopenia, thrombocytopenia) or identify hematologic emergencies such as thrombocytopenic purpura/hemolytic uremic syndrome, acute myeloid leukemia, and disseminated intravascular coagulation etc. Sometimes it is sufficient to make a diagnosis solely based on them which can be life saving when time is of the essence. Based on our literature search, there are no studies to assess internal medicine residents' knowledge and understanding of peripheral smears.
Methods: We created a multiple-choice questions survey of 13 questions for residents to fill out, involving common findings on peripheral smears and those found in hematologic emergencies that every resident should be aware of. Response rate in all three program years (PGY) was 100%. 16/16 PGY-1, 10/10 PGY-2 and 9/9 PGY-3 completed the survey.
Results: Average pre-intervention score for PGY-1 was 42%, PGY-2 was 34% and PGY-3 was 30%. Questions most commonly wrong were regarding target cells, metamyelocytes, giant platelets and schistocytes. Most were correct about microcytosis and Auer rods. We then conducted the same survey weeks after our intervention, which was interactive, small group didactics sessions on peripheral smears. We compared results of the survey before and after didactics to check for improvement. Post-intervention score for PGY-1 was 98%, PGY-2 and PGY-3 were 96%.
Conclusions: Most medical residents are not aware of common interpretations of peripheral smears and this does not seem to improve with each progressive year. Improving residents' knowledge of peripheral smears is a cost effective and quick measure that can improve patient care, in addition to potentially improving internal medicine board results. In the future, we aim to make a curriculum for peripheral smear review for residents. We can compare results of the survey with hematology oncology fellows.

Disclosures
No relevant conflicts of interest to declare.
Magnetism-Induced Cell-Targeting Transplantation Improves Early Hematopoietic Reconstitution in a Murine Bone Marrow Transplantation Model
Authors: Mai Qiusui , Zhou Yongjun , Wang Zhangyuan , Chen Quanfeng , Lv Yufang , Wu Qiaolan , Huang Hao , Zhang Qiuxia , Zhang Linlin , Li Chengyao , Liu Qifa , Jiang Qianli 
Published: November 2021

Abstract
Background
Early hematopoietic reconstitution is essential for improving survival and reducing complications after hematopoietic stem/progenitor cell (HSC/HPC) transplantation (HSCT/HPCT). Increasing HSC/HPC homing to the bone marrow is a potential approach for promoting hematopoietic reconstitution.
Methods
We proposed the transplantation of HSCs/HPCs with a magnetism-induced cell-targeting transplantation (MagIC-TT) strategy. HSCs/HPCs were magnetized with CD45 microbeads. The biological characteristics (morphology, proliferation, viability, and ferroptosis) and target migration ability of these cells were studied in vitro. The hematopoietic reconstitution experiments were constructed in vivo in autologous and allogeneic bone marrow transplantation models with grouping showed as Table 1. The therapeutic effects were assessed by survival, donor chimerism, routine blood examination and histological analysis. We also performed transcriptomic sequencing for further mechanistic studies.
Results
The biological characteristics was found no significant difference between the MagIC-TT and non-MagIC-TT groups, while migration ability was greatly improved with MagIC-TT (Data not showed). The survival rate was higher in the MagIC-TT group and significantly different in the allogeneic model (P&lt;0.05). Hematopoietic reconstitution of donor chimerism, WBCs, HGB, and PLTs was faster in the MagIC-TT groups (within 22 days) (Figure 1). Confocal observation showed that more donor cells (eGFP +) were retained in the injected femur of the MagIC-TT group than in the femur of the non-MagIC-TT group 7 days after transplantation (P&lt;0.05) (Figure 2). The severity of aGVHD (Assessed by survival, body weight, back arching, fur losting, diarrhea etc.) was reduced in the MagIC-TT groups in the allogeneic model (P&lt;0.05) (Data not showed). Transcriptome sequencing revealed differentially expressed genes (DEGs) involved in localization/locomotion and pathways, cytokine-cytokine receptor interactions and chemokine signaling pathways between the two groups (Figure 3).
Conclusion
The MagIC-TT strategy improves HSC/HPC homing, resulting in faster hematopoietic reconstitution in a murine bone marrow transplantation model.
Key words
Magnetism; Hematopoietic Stem Cell Transplantation (HSCT); Cell Homing; Hematopoietic Reconstitution; Ferroptosis
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study
Authors: Suo Yuan , Liu Jiapei , Sun Yiming , Wu Qiaoyuan , Jin Hua , Liu Qifa 
Published: November 2021

Abstract
Background
Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center.
Methods
A total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD.
Results
The median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04).
Conclusions
Our study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients.
Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.