bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Postoperative Bleeding Following Dental Extractions in Patients on Antithrombotic Treatment
Authors: Alsheef Mohammed Abdullah , Gray Jenny , Zaidi Abdul Rehman Z. , AlJabab AbdulSalam S 
Published: November 2019

Background:
Risk of bleeding post dental extractions in patients on the anticoagulant medication is not well-established. The aim of the study is to investigate the incidence of postoperative bleeding following dental extractions in adult patients on antithrombotic medication in Saudi Arabia.
Methods:
A retrospective study of 539 patients aged 18 to 93 years of age, attended 840 visits for dental extractions from January 2012 to June 2016 at a tertiary care hospital in Saudi Arabia. All returning patients were treated as outpatients with local hemostatic measures.
Results:
Only 1.7% of the visits were associated with post-operative bleeding following dental extractions. The highest risk of bleeding occurred in patients on Warfarin (3.88%), while those on Clopidogrel had no risk associated with bleeding. Women were found to have the highest rate of bleeding associated with dental extractions especially those on new oral anticoagulant medications.
Conclusion:
Dental extractions can be safely performed on adults receiving antithrombotic treatment provided established guidelines are followed. Health care professionals must exercise caution when planning invasive dental treatment for patients on continued antithrombotic therapy.

Disclosures
No relevant conflicts of interest to declare.
Purification Platelets from Mouse Blood with Sickle Cell Disease Using Iohexol Gradient Medium
Authors: Nasimuzzaman Md 
Published: November 2019

Platelets are purified from whole blood to study their functional properties, which should be free from red blood cells (RBC), white blood cells (WBC), and plasma proteins. Since RBC and WBC contain significantly more RNA and proteins than platelets, the presence of even a small number of these cells can interfere with transcriptomic and proteomic analyses of RNA and proteins derived from platelets. Several protocols have described the isolation of platelets from human, dog, rat, and non-human primate by various methods. Some of the methods require multiple steps such as collection of platelet-rich plasma by centrifugation, filtration by separation column, negative selection of platelets with RBC- and WBC-specific antibody conjugated to magnetic beads, and so on, which are time-consuming and may degrade platelets and their contents. Moreover, mouse blood with sickle cell disease contains a significant level of fragments of RBC which should be removed from the platelet preparation.
However, the mouse yields a relatively smaller volume of blood, which makes it difficult to purify platelets. If the same small volume of gradient medium and blood samples are used, the platelet layer cannot be clearly separated from RBC-WBC layer after centrifugation. We describe a simple method for purification of platelets from mouse blood with sickle cell disease using three-fold more iohexol gradient medium relative to blood sample volume and centrifugation in a swinging bucket rotor at 400 x g for 20 min at 20 °C. The platelet layer is collected and centrifuged again at 200 x g for 20 min at 20 °C to remove the residual fragments of RBC. The recovery/yield of the purified platelets were 10-17%, and the purified platelets were in a resting state, which did not contain any significant number of RBC and WBC. The purified platelets were activated with thrombin indicating their viability. We confirmed that the purified platelets were sufficiently pure using flow cytometric and microscopic evaluation. Although flow cytometric analysis of purified platelet from sickle cell disease mice showed a few RBC events after staining with anti-TER119 antibody, the microscopic study did not show any intact RBC or larger fragments indicating that these are smaller fragments of RBC which do not interfere with the biochemical and functional studies. This method can be used for purification of platelets from the blood of other species and disease models as well.

Disclosures
No relevant conflicts of interest to declare.
Type I Interferon Signaling before Hematopoietic Stem Cell Transplantation Lowers Donor T Cell Activation Via Reduced Allogenicity of Recipient Cells
Authors: Thiele Orberg Erik , Fischer Julius Clemens , Göttert Sascha , Bassermann Florian , Poeck Hendrik 
Published: November 2019

Background: Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterised.
Methods: We applied selective RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD.
Results: Using IFNAR1-deficient donor T and hematopoietic donor cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these respective cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted T-cells after allo-HSCT. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signalling. Notably, this immunosuppressive function of DCs was restricted to a scenario of genotoxic tissue damage as neither RIG-I activation and IFN-I induction in naive (non-irradiated) mice altered allogeneic T cell activation.
Conclusion: Our findings uncover a hitherto unknown IFN-I- and context dependent immunosuppressive function of dendritic cells. This needs to be considered in the development of IFN-I based therapeutic approaches to modulate donor T cell activation after allo-HSCT.

Disclosures
No relevant conflicts of interest to declare.
Effect and Safety of Ixazomib Plus Dexamethasone (ID) in Patients with Waldenstrom's Macroglobulinemia (WM): Real-World Evidences from a Single Center in China
Authors: Xu Jiadai , Wei Zheng , Li Jing , Zhuang Jingli , Ji Lili , Liu Peng 
Published: November 2019

Introdution: As a second-generation proteasome inhibitors (PIs), ixazomib has come to China for 1 years. PIs has been proved efficacy in patients with Waldenstrom macroglobulinemia (WM), a rare form of B-cell lymphoma.
Aims: To evaluated the clinical activity and safety profile of combining ixazomib and dexamethasone (ID) in patients with WM, both in those who previous had not received systematic treatment and in those with refractory or relapsed disease (RRWM).
Patients and Methods: The protocol therapy consisted of oral ixazomib, 4 mg, on days 1, 8, and 15, with oral dexamethasone, 10 mg, on days 1, 8, 15, and 22, every 4 weeks. Progression-free survival (PFS) was set as the primary end point. Response rates, sustained hematologic improvement from baseline, and safety were set as the key secondary end points. Responses were determined according to the 6th International Workshop WM response criteria. Adverse events (AEs) were reported by CTCAE v4.03. The data cut-off is 26 July 2019.
Results: Under the premise of respecting the patient preferences, 9 symptomatic patients with WM have been enrolled, in whom 5 patients were newly diagnosed (NDWM) receiving ID as primary therapy (PT) and the other 4 patients were with RRWM having been received previous systematic therapies. All patients were included in this analysis. The baseline clinical characteristics and major therapy situations are summarized in Table 1. The median reaction time was 4.14 weeks, which was 4.00 weeks in WM patients receiving ID as PT and 7.00 weeks in RR WM patients. After a median follow-up of 6.03 months, in NDWM patients, the overall response rate was 80.0%, and the major response rate (CR+VGPR+PR) was 40.0% (2/5). Patients with RRWM were equally responsive. The overall response rate was 75.0%, and the major response rate (CR+VGPR+PR) was even relatively higher, which was 50.0% (2/4). The median PFS was not reached. The ID regimen was well tolerated with 66.7% patients reporting no drug related AE. Grade 1 adverse events reported in 3 patients included diarrhea (1/9, 11.1%), thrombocytopenia (1/9, 11.1%), digestive disturbance(1/9, 11.1%). Shingles (grade 2) was reported in 1 patient. Serum IgM decreased from 42.66 g/l (median) at baseline to 21.02 g/l (median) in NDWM patients (Fig. 1A), from 43.87 g/l (median) at baseline to 25.59g/l (median) in RRWM patients (Fig. 1B). The median level of hemoglobin in patients with a hemoglobin of less than 115.0 g/l before using ID increased from 71.6 g/dl (median) at baseline to 87.3 g/l in NDWM patients (Fig. 1C), from 73.7 g/dl (median) at baseline to 89.3 g/l in RRWM patients (Fig. 1D). There have been 2 cases suffered disease progression after receiving ID regimen.
Conclusions: ID regimen offers a relatively effective and well tolerated choice for patients with WM.

Disclosures
No relevant conflicts of interest to declare.
Pegylated Interferon in Myelodysplastic/Myeloproliferative Syndrome with Ringsideroblasts and Thrombocytosis
Authors: Benz Rudolf A. , Zimmermann Kathrin , Widmer Corinne C 
Published: November 2019

Background:In 2016 WHO recognized the provisional entity refractory anemia with ring sideroblasts and thrombocytosisas a distinct entity and renamed it myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). The disease presents hallmarks of both myelodysplastic and myeloproliferative features. Although the diagnostic criteria are well defined and there are several studies of the molecular landscape of the disease, the treatment regimen of these patients remains inconsistent. Due to lack of clinical trials, treatment options are chosen either on MDS- or MPN-based regimens and individual preferences such as patients characteristics and clinical presentation. Prevention of thromboembolic events is a reasonable goal. However, the use of platelet-lowering drugs is still not well studied and treatment related anemia leading to transfusions with accelerated iron overload limits a general use of cytoreductive treatment. To avoid worsening of the anemia while efficiently reducing thrombocytosis we treated 3 patients with pegylated interferon (pIFN) and provide insight in JAK2-allele burden measurement and additional mutations obtained with next generation sequencing (NGS).
Results:Three patients with diagnosis of MDS/MPN-RS-T were treated with 135µg pIFN during an observation period between 8 and 34 months. All 3 patients had a JAK2V617F mutation, >15% ringsideroblasts and a thrombocyte count above 600G/l. In the additional NGS analysis, two patients showed a mutation in the SF3B1 gene, one with an additional DNMT3A mutation. In the third case, NGS results revealed a mutation in the splicing factor U2AFI, which is a rare finding in patients with MDS/MPN-RS-T. JAK2-allelel burden was obtained at the beginning and showed a decrease of a mean value of 38% as measured by digital droplet PCR. Anemia was present at initial diagnosis in two patients. During observation period, none of the patient became transfusion dependent, in one case even an improvement in hemoglobin levels was achieved. Side effects of the treatment were only minimal and no thromboembolic as well as major bleeding event occurred under additional acetylsalicylic acid medication.
Conclusion: In summary we show that in patients with MDS/MPN-RS-T a therapy with pIFN achieved rapid decrease of thrombocyte values without lowering hemoglobin levels at a maximal dose of 135µg per week. JAK2-allele burden reduction and a low side effect profile further demonstrate the value of this treatment option for these often elderly patients. However, larger studies are needed to confirm our data.

Disclosures
No relevant conflicts of interest to declare.
ZFP91 Regulates Multiple Myeloma Cell Proliferation through IL-1β Mediated IL-6 Secretion in the Tumor Microenvironment
Authors: Jeyaraju Danny V , Kumari Ekta , Amatangelo Michael , Bjorklund Chad C. , Hsu Chih-Chao , Thakurta Anjan 
Published: November 2019

Multiple myeloma is a malignancy of terminally differentiated plasma cells that are primarily resident in the bone marrow. Despite novel therapies, myeloma remains a fatal disease. Through interactions with immune cells in the bone marrow microenvironment, myeloma cells have been shown to facilitate their own proliferation and drug resistance. Therefore, targeting the immune support cells in the myeloma bone marrow microenvironment could add further value to existing treatment regimens.
ZFP91, a C2H2-type zinc-finger protein, is a substrate of IMID drugs (An et al, Nat. Commun. 2017). The downstream target of ZFP91 in myeloma has been elusive so far. Our myeloma-specific ZFP91 interactome data and recent publications indicate an immune related function for ZFP91. A recent study also indicated that treatment of healthy volunteers with iberdomide, impaired the ability of monocytes to secrete IL-1β in response to LPS (Schafer PH, et al. Ann Rheum Dis 2018). To further investigate this, we generated CRISPR knockouts of IKZF1, IKZF3 and ZFP91, three major substrates of lenalidomide and iberdomide, in THP-1 monocytic cells. Upon LPS induction, loss of ZFP91 impaired the ability of THP-1 monocytic cells to secrete IL-1β (WT 70 pg/ml of IL-1β vs ZFP91-/- 4.5 pg/ml of IL-1β). Loss of IKZF1/3, the other two substrates of lenalidomide and iberdomide did not impair IL-1β secretion.
IL-1β is a known activator of IL-6, a critical cytokine for myeloma cell proliferation. As a next step, we created a co-culture model to mimic a minimal myeloma tumor microenvironment with ANBL-6 (IL-6 dependent) myeloma cell line and primary bone marrow stromal cells in the presence of pre-conditioned media from LPS stimulated THP-1 monocytes. Preconditioned media from ZFP91-/- monocytes impaired proliferation of myeloma cells in the co-culture model due to lack of IL-1β, the inducer of IL-6 from the stromal cells. Mechanistically, loss of ZFP91 impairs the TLR4 signaling pathway. Thus, targeting ZFP91 impairs proliferation of myeloma cells within the bone marrow microenvironment by acting in trans from monocytes.
Our findings for the first time identify a tumor cell proliferative role for ZFP91 in the myeloma tumor microenvironment. In addition, it establishes ZFP91 as an immune substrate of lenalidomide and iberdomide and could be a key player that mediates the immune functions observed.

Disclosures
Jeyaraju: Celgene Corporation: Employment, Equity Ownership. Kumari:Celgene Corporation: Employment. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Hsu:Celgene Corporation: Employment. Thakurta:Celgene: Employment, Equity Ownership.
Combination of Chidamide with the CHOEP Regimen in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Prospective, Multicenter, Single-Arm, Phase 1b/2 Trial
Authors: Zhang Wei , Su Liping , Liu Lihong , Gao Yuhuan , Wang Quanshun , Su Hang , Song Yuqin , Zhang Huilai , Shen Jing , Jing Hongmei , Wang Shuye , Cen Xinan , Liu Hui , Liu Aichun , Li Zengjun , Luo Jianmin , He Jianxia , Wang Jingwen , O'Connor Owen A. , Zhou Daobin 
Published: November 2019

Background: Chidamide is a novel benzamide class of histone deacetylase (HDAC) inhibitor. In a pivotal phase 2 trial with refractory or relapsed peripheral T-cell lymphoma (PTCL), chidamide produced ORR 28% with CR 14% leading to its approval by the China Food and Drug Administration in 2014 for refractory or relapsed PTCL. We sought to assess the safety, tolerability and efficacy of the novel histone deacetylase inhibitor chidamide in combination with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) (Chi-CHOEP) for previously untreated PTCL.
Patients and methods: This was a prospective, multicenter, single-arm Phase 1b - 2 clinical trial conducted exclusively in China. In the phase 1b study, three dose levels of chidamide were explored. In the phase 2 portion, patients were treated at the RP2D. The primary endpoint of the Phase 1b was determination of the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and RP2D. The primary endpoint of the phase 2 study was determination of the overall response rate (ORR).
Results: A total of 82 patients were enrolled between March 2016 and Dec 2017 at 17 sites across China. The cutoff date for the analysis was July 2018. In phase 1b dose-escalation study, 15 patients were treated and the second dose cohort (20 mg biw) was declared the MTD and thus the RP2D. Subsequently, 67 patients were enrolled and treated at the RP2D in the phase 2 part of the study. Overall, among 82 enrolled patients in the entire phase 1b/2 study, the median number of cycles per person was five (range 1-8) and the relative dose intensity was 75.4%. The most common toxicities in the Phase 1b/2 study included leucopenia, anemia, and neutropenia. No reactivation of Epstein-Barr virus or Hepatitis B virus was observed. For entire phase 1b/2 study of 82 patients, the ORR was 68.3% with a CR rate of 43.9%. In the phase 2 part of the study, the ORR was 73.2% with 47.8% CR. with a median follow-up of 12.7 months (range 0.3-30.8 months), the median PFS for entire phase 1b/2 study was 17.4 months and the 1-year PFS was 52.9%. The median OS had not yet been reached, and the 1-year OS was 74.5%. In the phase 2 study, the median PFS was 17.4 months and the 1-year PFS was 53.6%. The median OS had not yet been reached, and the 1-year OS was 76.3%.
Conclusion: Chi-CHOEP is an effective and feasible novel regimen for untreated PTCL. These data warrant further investigation in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT02987244.

Disclosures
No relevant conflicts of interest to declare.
Successful Treatment of Mucosal Bleeding with Tranexamic Acid in Pediatric Patients with Hemostatic Disorders
Authors: Nakadate Hisaya , Ishiguro Akira , Sakamoto Atsushi 
Published: November 2019

Objects
Hemostatic disorders, including thrombocytopenia and/or coagulation disorders, sometimes cause mucosal bleeding and/or bleeding risks. In some cases, severe mucosal bleeds cannot be adequately controlled by standard therapy. Tranexamic acid (TA) is used in preventing and reducing bleeding in such medical settings. But there is little information on useful TA management of mucosal bleeding in hemostatic disorders.
Materials and Methods
4 patients with ITP, 2 hemophilia A patients and one VWD patient were treated with TA (1.5 - 3.0 g/day ) due to recognizable mucosal bleeding. 2 patients were under regular treatment for ITP. The remaining 2 patients with ITP did not require additional therapy. 2 hemophilia A patients were mild case and require on demand therapy of FVIII concentrates. VWD patient did not require any therapy with no mucosal bleeds.
Results
One of the ITP patients were suffering from frequent nasal bleeding and kept her away from school for 1.5 years. She had been going back to school without limitation of physical activity in spite of low PLT count. Remaining 3 patient of ITP who was suffering from frequent nasal bleeds had been managed with TA ( 1.5 g/day ). 2 hemophilia patients who were experienced oral mucosal bleed after tooth extraction were successfully managed with TA ( 1.5 g/day ). VWD patient who were suffering from frequent nasal bleed were ceased after initiation of TA.
Conclusions
Cessation or, at least significant improvement of bleeding was achieved shortly after initiation of TA in all cases. TA was well tolerated and discontinued after cessation of bleeding. We recommend the use of TA in hemostatic disorder patients with bleeding and/or an increased bleeding risk. Ultimately, cessation of bleeding plays a key role in the QOL improvement of such affected patients. However, future studies are required to optimize dose and administration routes (intravenous or oral).

Disclosures
No relevant conflicts of interest to declare.
R4 Rgs Subfamily Proteins Suppress Engraftment and Regulate SDF-1/CXCR4 Signaling in Human CD34+ Hematopoietic Stem/Progenitor Cells
Authors: Chan Kathy , Wong Tsin Sik , Li Karen , Zhang Xiao-Bing , Wang Ronald , Lee King Yiu , Cheng Frankie Wai Tsoi , Li Chi Kong , Leung Kam Tong 
Published: November 2019

Members of the Regulators of G-protein Signaling (RGS) are GTPase-accelerating proteins and have been implicated in SDF-1-directed trafficking of mature hematopoietic cells. However, their roles in hematopoietic stem and progenitor cells (HSPC) remain largely unknown. In this study, we investigated the expression, functions and mechanism of R4 RGS subfamily members on migration and engraftment of human HSPC. Our results demonstrated that cord blood (CB), bone marrow (BM) and mobilized peripheral blood (MPB) CD34+ cells expressed specific RGS mRNAs, of which RGS1, RGS2, RGS13 and RGS16 were significantly upregulated by SDF-1 (1.6-1.9 fold, n=5, P&lt;0.05). In the presence of AMD3100, a CXCR4 inhibitor, the stimulating effects of SDF-1 on RGS expression were completely abolished (n=6). SDF-1-directed functions (chemotaxis, trans-matrigel migration and calcium flux) and signaling (phosphorylation of Akt, ERK and Stat3) were significantly inhibited in RGS1, RGS13 and RGS16-overexpressing CD34+ cells (n=4-6, P&lt;0.05) but not in RGS2-overexpressing cells, whereas actin polymerization, adhesion and colony formation were unaffected by these RGS members. In the NOD/SCID mouse xenotransplantation model, overexpression of RGS1, RGS13 or RGS16 in CD34+ cells did not impact their short-term homing but substantially compromised their long-term engraftment efficiency in bone marrow and spleens of recipient mice by 91.4%, 83.7% and 71.2%, respectively (n= 8-9; P&lt;0.05). Genome-wide expression microarray and qPCR validation identified 32 common differentially expressed genes (1 upregulated and 31 downregulated) in RGS1, RGS13 or RGS16-overexpressing CD34+ cells. Network analysis revealed the potential mechanisms of RGS1, RGS13 and RGS16 downstream of SDF1/CXCR4 and Gαi protein, leading to compromised Akt, ERK and Stat3 phosphorylation and negative regulation of stem cell functions (CCNA1, SPP1, LPAR5, IL1RL1, HPSE), complement activation (C3AR1, C5AR2, C5AR1), proteolysis (TIMP3, MMP14) and cell migration (THBS1, F2RL2, PROS1, CCL1). Our results highlight the unprecedented functions of R4 RGS proteins in HSPC migration and engraftment, and provide the foundation of future design of RGS-targeting strategies to enhance the efficiency of clinical HSPC transplantation.

Disclosures
No relevant conflicts of interest to declare.