bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency of Arterial Thromboemobolic Events in Patients with Cancer Associated Venous Thromboembolism
Authors: Attia Doaa , Jia Xuefei , Wilks Mailey L , Tripp Barbara , D'Andrea Christopher , McCrae Keith R , Khorana Alok A , Angelini Dana E 
Published: November 2020

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE.
Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated.
Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI &gt;30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban)
Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population.

Disclosures
McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.
Large Scale Ex Vivo Expansion of Γδ T Cells Using Artificial Antigen Presenting Cells for the Treatment of Acute Myeloid Leukemia
Authors: Boucher Justin C. , Yu Bin , Li Gongbo , Shrestha Bishwas , Lancet Jeffrey E. , Sallman David A. , Landin Ana Marie , Mailloux Adam William , Anasetti Claudio , Kelley Linda L. , Davila Marco L. , Bejanyan Nelli 
Published: November 2020

Patients with relapsed or refractory acute myeloid leukemia (AML) are at increased risk of mortality. Higher γδ T cell count in a bone marrow or peripheral blood of patients with leukemia is associated with better survival. However, γδ T cells are rare in the blood and functionally impaired or exhausted in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and IL-2. Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K562 CD3/CD137L/CD28/IL15RA quadruplet artificial antigen presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a GMP-compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of co-culture with aAPC, the majority of which exhibited central (47%) and effector (43%) memory phenotypes. Additionally, &gt;90% of the expanded γδ T cells expressed NKG2D, while they have low cell surface expression of PD1 and LAG2 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded, previously cryopreserved, γδ T cells were effective in killing target cells. Our results demonstrate that large scale ex vivo expansion of donor-derived γδ T cells can be achieved with the use of CD3/CD137L/CD28/IL15RA quadruplet aAPC and zol/IL-2 for clinical application as promising antineoplastic immunotherapy.
Figure 1

Disclosures
Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.
Wtapblock Cell Differentiation of Hematopoietic Stem and Progenitor Cells
Authors: Liu Yuanyuan , Xiao Feifei , Yang Bijie , Chen Zhiwei , Chen Jieping , Hou Yu 
Published: November 2020

Wilms' tumor 1-associating protein (WTAP) is a ubiquitously expressed nuclear protein has been associated with regulation of cell proliferation, apoptosis, embryonic development, cell cycle, RNA splicing and stabilization, N6-Methyladenosine RNA modification in various physiological processes. Recently,WTAPwas reported to promoter tumorigenicity in Glioblastoma and cholangiocarcinoma. Besides solid tumors,WTAPplays an important role in abnormal proliferation and arrested differentiation in acute myeloid leukemia (AML) cell, suggesting its oncogenic activity. For its promising novel therapeutic target in AML, a systematic investigation of the roles ofWTAPin normal hematopoiesis is warranted.To investigate the function ofWTAPin normal hematopoietic system, we firstly determined the mRNA level ofWTAPin different hematopoietic stem and progenitor cells (HSPCs) and several mature populations in C57/B6 mouse bone marrow (BM).WTAPwas ubiquitously expressed in different cell populations and especially elevated in HSPCs. For WTAP-null and heterozygous caused early embryonic lethality, we generated endothelial system conditional knockout (cKO) mice by crossing WTAP floxed mice with poly (I:C) induced Mx1-Cre transgenic mice. In poly (I:C) inducedWTAPfl/fl-Mx1-Cre, WTAP deficiency lead to approximately 2-fold increase in HSC and LSK pool size, and modest expansion of HPC, CLP and LMPP population. In competitive BM transplantation assay, lossWTAPshowed a significantly decreased repopulation capacity. WhileWTAPknockout did not significantly affect the proliferation, cell cycle and apoptosis of HSPCs tested by Brdu, Ki67 and Annexin-V straining assay. Mechanistically, deletion ofWTAPin HSC resulted in decreased transcription of myeloid cell and erythrocyte differentiation gene (including Jak3, Jun and Junb) and genes regulating pluripotency of stem cells (induding Akt2, Fzd1/9 and Mapk3).Collectively, we speculateWTAPplay important role in blocking cell differentiation of HSPCs. Currently, we are conducting a series of studies to reveal the underlying molecular mechanism(s) ofWTAPregulating normal hematopoiesis.

Disclosures
No relevant conflicts of interest to declare.
Fotemustine-Based in Combination with Rituximab As First-Line Induction Chemotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma:a Prospective Phaseii Trial
Authors: Wu Jingjing , Gao Fenghua , Zhang Lei , Li Xin , Li Ling , Wang Xinhua , Zhu Linan , Zhang Xudong , Fu Xiaorui , Sun Zhenchang , Dong Meng , Ding Mengjie , Yu Hui , Nan Feifei , Yan Jiaqin , Chang Yu , Wu Xiaolong , Zhou Zhiyuan , Zhang Mingzhi , Young Ken H. 
Published: November 2020

Objective:To evaluate the safety, efficacy, and feasibility of rituximab, fotemustine, pemetrexed and dexamethasone (R-FPD) regimen for primary central nervous system lymphoma (PCNSL) patients.
Methods:A prospective, single-center, single-arm, phase II clinical trial. Patients with newly diagnosed PCNSL diagnosed from the First Affiliated Hospital of Zhengzhou University from July 2018 to July 2020. R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100mg/m2 i.v. on D1) ,pemetrexed (600mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1).(NCT04083066)
Results: 30 patients were included. After two cycles, the objective response rate(ORR) was 96.4%(27/28,26 PR,1 CR,0 SD,0 PD,2 Censored),the disease control rate(DCR) was 96.4%(27/28); After four cycles, the ORR was 71.4% (15/21, 5PR,10 CR,1SD,5PD,7NR,2 Censored),DCR was 76.2%(16/21). The median progression-free survival (PFS) was 20.3 months (95%CI:5.2--35.4),The median overall survival (OS) was 22.0 months (95%CI:16.1-27.9).The grade III-IV toxicities were mainly leukopenia(17.9%), thrombocypenia(25%) and anemia(10.7%).
Conclusion: Fotemustine-based in combination with Rituximab chemotherapy can improve outcomes with the progress free survival and the overall survival benefits, as well as with better tolerability for newly diagnosed PCNSL patients.
Keywords: rituximab; primary central nervous system lymphoma; pemetrexed; fotemustine; efficacy

Disclosures
No relevant conflicts of interest to declare.
Potential Usefulness of D-Dimers Assay in Treated Patients with FVIII Deficiency to Detect a Prothrombotic State
Authors: Hermans Cedric , Lambert Catherine 
Published: November 2020

Introduction
The D-dimer (DD) assay represents a major biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, whether related to age, the presence of cardiovascular risk factors, invasive thrombogenic procedures, over-correction of FVIII or FIX, or the administration of new therapeutic agents in particular rebalancing agents such as TFPI-inhibiting molecules or Fitusiran. Arterial and venous thrombotic events have indeed recently been reported in PWH treated with these agents. It is therefore important to have simple, easily accessible biological tests available to detect and monitor the development of any prothrombotic condition in PWH with these agents and at increased risk of thrombosis. Baseline DD concentrations in PWH have not been extensively studied yet.
Patients and methods
We prospectively measured over a 18 months period the DD level in all consecutive PWH with hemophilia A (PWHA) in routine clinics outside bleeding episode, invasive procedure or acute medical or surgical problems. A total of 65 adult PWHA (17-76 yr) with severe (58) to moderate (n=7) disease without inhibitor on replacement therapy with FVIII were included. CRP, fibrinogen, FVIII and VWF levels were also measured at time of DD assay.
Results
Thirty-three patients had not measurable DD (&lt; 250 ng/ml), 15 had levels below 500 ng/ml, 10 had levels between 500-1000 ng/ml and 7 &gt; 1000 ng/ml. Age&gt;70 (3), smoking (7), arterial vascular disease (2), liver cancer (2) could explain DD &gt; 500 ng/ml in 15/17 patients.
Conclusions
Most PWHA on replacement therapy with FVIII had low or unmeasurable DD levels. The reasons for high DD level in PWHA do not differ from the general population. In most PWAH, the DD assay could be a useful tool to detect prothrombotic state, potentially related to hemophilia therapies.

Disclosures
Hermans: Bayer:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy, Research Funding, Speakers Bureau;Shire, a Takeda company:Consultancy, Research Funding, Speakers Bureau;Sobi:Consultancy, Research Funding, Speakers Bureau;Biogen:Consultancy, Speakers Bureau;CAF-DCF:Consultancy, Speakers Bureau;CSL Behring:Consultancy, Speakers Bureau;LFB:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Roche:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau;Kedrion:Speakers Bureau;EAHAD:Other;WFH:Other.
Hottip-Mediated R-Loops Regulate CTCF TAD Boundary to Control WNT/b-Catenin Pathway in AML Genome
Authors: Luo Huacheng , Zhu Ganqian , Ma Xiaoyan , Claxton David F. , Qiu Yi , Xu Mingjiang , Huang Suming 
Published: November 2020

lncRNA, transcribed from genomic DNA, can form a DNA: RNA hybridization structure to access regulatory elements. HOX loci associated long noncoding RNA (lncRNA), HOTTIP, acts as an epigenetic regulator to define oncogenic HOXA topologically associated domain (TAD) and drive HOXA associated leukemic transcription program. Activation of HOTTIP promoted AML pathogenesis by perturbing leukemic transcription program and hematopoietic/progenitor stem cells (HS/PCs) function. However, the mechanism by which HOTTIP accesses and regulates genomic DNA transcriptional output remains unknown.
Here, Combined RNA-seq, ChIP-seq, NG-Capture-C and Hi-C integrated analysis demonstrated that HOTTIP dependent stratification/formation of TADs at WNT/b-catenin loci is critical for b-catenin (CTNNB1) target gene transcription in AML cells. We further showed that HOTTIP specifically interacts with CTCF-occupied TAD boundary CTCF binding sites (CBSs) at b-catenin and its target loci (e.g. MYC and MECOM) by formation of R-loops. To test whether HOTTIP-mediated R-loops contribute to boundary maintanence and TAD stablization, we created CRISPR/dCas9-RNaseH-mediated disruption of R-loop structure In MOLM13 cells by which the Ribonuclease H (RNase H) was targeted to the HOTTIP/CTCF co-occupied CTNNB1 or MYC boundary CBSs to specifically target RNA: DNA hybridization region. Our DNA-RNA immunoprecipitation (DRIP)-qPCR data indicated that CRISPR/dCas9-RNaseH-mediated sgRNAs disrupted the R-loop structure in MYC and CTNNB1 defined TAD boundary regions. Furthermore, HOTTIP CHIRP-qPCR and CTCF CHIP-qPCR suggested that loss of R-loop structure in MYC or CTNNB1 TAD boundary CBSs decreased both CTCF and HOTTIP binding in these CBSs. Disruption of R-loops also affects the long-range interaction within CTNNB1 or MYC TADs that are important for WNT/b-catenin signaling network and AML leukemogenesis.
In conclusion, our finding demonstrated that HOTTIP forming DNA∙RNA hybridized R-loops mediate AML genome organization at specific gene loci and control leukemic transcription program. Thus, HOTTIP lncRNA mediated R-loop structure will be considered as a novel molecular mechanism in AML leukemogensis.

Disclosures
Claxton: Daiichi Sankyo Co: Research Funding; Astellas Pharma: Research Funding; Incyte Corporation: Research Funding; Cyclacel Pharmaceuticals, Inc.: Research Funding.
Bone Marrow-Derived Mesenchymal Stem Cells Inhibit CD8+ t Cell Immune Responses Via PD-1/PD-L1 Pathway in Multiple Myeloma
Authors: Liu Zhaoyun , Mi Fu , Han Mei , Tian Mengyue , Liu Hui , Fu Rong , Shao Zonghong 
Published: November 2020

High expression of the inhibitory receptor programmed death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the PD-1/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in Multiple Myeloma (MM) remain poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSCs-mediated regulation of CD8+T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased than that in normal controls (NC) (18.81±1.61% vs. 2.78±0.70 %; P&lt;0.001). Furthermore, the PD-1 expression on CD8+T cells with NDMM patients was significantly higher than that in normal controls (43.22±2.98% vs. 20.71±1.08%; P&lt;0.001). However, there was no significant difference in PD-1 expression of CD4+ T cells and NK cells between NDMM group and NC group. Additionally, the co-culture assays revealed that BMSCs significantly promoted CD8+ T cells apoptosis and suppressed CD8+ T cells function. However, PD-L1 inhibitor effectively reversed BMSCs-mediated suppression in CD8+ T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8+T cells through the PD-1/PD-L1 axis and inhibit the release of perforin and granzyme B from CD8+ T cells so as to promote the immune escape of MM.

Disclosures
No relevant conflicts of interest to declare.
Dasatinib Promotes the Maturation of Healthy Donors and Chronic Myelogenous Leukemia Patients Derived Dendritic Cells
Authors: Cao Wangjun , He Lin , Zheng Hong , Huang Xiaobing , Yang Xi , WANG Xiaodong , Dai Jingying 
Published: November 2020

Dasatinib has been discovered to obtain immunomodulatory effects in addition to the targeting effect towards BCR-ABL in chronic myelogenous leukemia (CML) patients. But the effect of dasatinib on dendritic cells (DCs) is still not fully understood. Objective To investigate the effect of dasatinib on the maturation of monocyte derived dendritic cells (moDCs) from healthy donors (HDs) and CML patients. Method Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=14) and CML patients (n=14) who had got remission of MR4.5 with imatinib treatment. The generation of moDCs was completed after 7 days of incubation in DC I medium, and another 3 days of incubation in DC II medium with or without 25nM dasatinib. On the 10th day, the moDCs were harvested and analyzed for the expression of surface markers CD83, CD80, CD86, CD40 and HLA-DR to reflect the maturation of the moDCs by flow cytometry. Results When analyzing the moDCs from all the 14 HDs together, dasatinib significantly enhanced the expression levels of the surface marker CD83 (P=0.039), CD40 (P=0.002) and HLA-DR (P=0.000) on moDCs compared with the control group, but there was no statistically significant difference in CD80 (P=0.073) and CD86 (P=0.897). Differently, when analyzing the moDCs derived from all the 14 patients together, there was no statistically significant difference in the expression levels of CD80 (P=0.086), CD86 (P=0.166), CD83 (P=0.674), CD40 (P=0.574) and HLA-DR (P=0.561) on moDCs between the dasatinib group and the control group. However, moDCs derived from 3 of the 14 patients show the enhanced expression of all the five surface makers with dasatinib administration compared to the control group. Besides, the moDCs derived from 6 of the 14 patients show the enhanced expression of at least one of the five surface markers. Notably, compared with moDCs derived from HD group (n=14), moDCs from patient group (n=14) express lower levels of CD80 (P=0.340), CD86 (P=0.007), CD40 (P=0.010), CD83 (P=0.019) and HLA-DR (P=0.036). Conclusion Dasatinib at the concentration of 25nM can efficiently promote the maturation of HD-derived moDCs in vitro, whereas this effect only occurs in part of the CML patients. And the moDCs from patients generally show much lower levels of the maturation associated surface makers compared with moDCs from HDs. Dasatinib shows potential as a DC adjuvant to be applied in DC-based therapeutic strategies, such as DC vaccine and DC cell-therapy.

Disclosures
No relevant conflicts of interest to declare.
Cidofovir, a Choice for Salvage Treatment of CMV Infection in the Patients with Haploidentical Hematopoitic Stem Cell Transplantation
Authors: Yin Zhao , Xu Na , Jiang Ling , Shi Pengcheng , Fan Zhiping , Huang Fen , Liu Qifa , Sun Jing , Yu Guopan 
Published: November 2020

Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity and has been approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. Data on the use of CDV for anti-CMV treatment in the patients with haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is rare. In this study, 31 (defined as CDV-second line treatment, ST group) out of 101 (conventional treatment, CT group) haplo-HSCT recipients with CMV infection being front-line treated with intravenous ganciclovir (GCV) or foscarnet (FSC) between the year 2017 and 2019, failed or intolerated to the preemptive antiviral therapy, and were switched to CDV therapy. Also, another 9 (CDV-front line treatment, FT group) patients with CMV infection were preemptively treated with CDV. CDV was used at a dose of 5 mg/kg per week until CMV-DNA negative twice with quantification polymerase chain reaction (qPCR) detection or disease progression.
23/28(82.1%) patients achieved treatment response with a median response time of 9(2-23) days and 20/28(71.8%) obtained complete response (CR) in CDV-ST group. While 6/8(75.0%) acquired CR with a median time of 6 (4-25) days in CDV-FT group. Higher response rate was seen in CDV treatment groups, though not significantly different, when being compared with those in CT groups (66/95(69.5%), 7 (2-34) days, 65(68.4%, respectively, all P-value &gt;0.05). Also, there was not statistical difference in CMV-related mortality among the three groups (P-value &gt;0.05). With a median follow-up of 10 (1-28) months, cumulatively 8/22(36.3%) patients experienced CMV reactivation in CDV-ST group, while 23/62(37.0%) happened in CT group, there was not significant difference (P&gt;0.05). Whereas none with CMV recurrence was observed in the CDV-FT group. CDV-related toxicities were recorded in a total of 13/40 (32.5%) patients, shown as 7(17.5%) with I~II° gastrointestinal side effects, 6(15%) presenting reversible nephrotoxicity.
Taking together, salvage treatment with CDV shows no worse efficacy than ganciclovir or foscarnet does in the front line treatment of CMV infection in haplo-HSCT recipients. Also, CDV-related toxicity is tolerated.
Keywords: cidofovir, CMV infection, haplo-hematopoietic stem cell transplantation, efficacy, safety

Disclosures
No relevant conflicts of interest to declare.