bluuebunny/crossref_metadata_2025_split huggingface dataset:
10-Day Low Dose Decitabine Regimen for Elderly Acute Myeloid Leukemia Patient Maintenance Treatment
Authors: Liu Jia , Peiyan Kong , Gao Li , Zhang Cheng , Liu Yao , Yan Hongju , Zhu Lidan , Gao Shichun , Lei Gao , Zeng Defu , Zhang Xi 
Published: October 2019

Abstract
Background
Acute myeloid leukemia (AML) is a malignant hematologic disease with high incidence in the elderly peoples. The median age of onset is 65 years. There is no standard chemotherapy regimen for elderly AML, especially for AML patients older than 70 years old. Six to eight courses of low-dose or reduced-dose chemotherapy were commonly used in clinical treatment. However, most patients. However, most patients relapsed within six months after chemotherapy. How to prolong the survival of elderly patients with AML is a realistic problem that needs to be urgently solved.
Patients and Methods
From Jan 2017 to May 2018, six elderly patients with AML in our center include in the study. The median age was 74 (70-78) years. According to cytogenetics and molecular mutation, 1 patient were favorable risk with t (8, 21) and AML1-ETO, 3 patients were intermediate risk with karyotype abnormality, and 2 patients were unfavorable risk with complex karyotype and FLT3-ITD mutation. One patient received complete remission (CR) after IA induce scheme, and then, he received 4 courses of DA regimen for consolidation therapy. At last, he stopped chemotherapy because of severe atrial fibrillation and heart failure. Other 5 patients treated with 4-8 courses of decitabine (Dec) +CAG or HAG regimen. Minimal residual disease (MRD) of four patients were negative and two patients were positive before include in the study. Six patiens were given 10-day low dose Dec regimen treatment (5mg/m2/day×10 days) for every six weeks, until AML progress.
Results
For 2 MRD positive patients, after 10-day low dose Dec regimen treatment, one patient MRD turn to negative, one patient MRD remained positive, and died after 4 months. Till Jul 2018 (median observation time 10 months), 5/6 patients remained CR and survival with better quality of life. the most common treatment-emergent adverse events (TEAEs) were related to hematocytopenia. The most significant reduction of blood cells was hypoleucocytosis, and mainly in the first 2 courses of G-Dec treatment.
Conclusion
Preliminary research shows 10-day low dose Dec regimen treatment has Significant effect and mild side effect on the survival of elderly AML patients. The multicenter, randomized controlled clinical study will conduct to further verify its effectiveness and safety.

Disclosures
No relevant conflicts of interest to declare.
Lncrna RP1-68D18.2 Promotes K562 Cell Line Resistance to Imatinib through CD44 and Its Downstream Signal Molecules
Authors: Yan Tianyou , Gong Yuping 
Published: October 2019

Abstract
As the first-generation tyrosine kinase inhibitor specifically targeting the BCR-ABL oncoprotein, imatinib has been successfully used in the therapy for chronic myelogenous leukemia (CML) with a significant response and good compliance. However, imatinib resistance becomes the main reason for failure of the treatment of CML. In addition to the common BCR-ABL dependence of imatinib resistance, e.g. BCR-ABL kinase domain mutations and BCR-ABL gene amplification, BCR-ABL independence also plays important roles, which involves alteration of dynamics of drug import and efflux, persistent or compensatory activation of signaling pathways etc. Recently, several studies have reported the correlation of lncRNA with resistance of chemotherapeutic drugs in many cancers. Here, we report, for the first time, discernible overexpression of lncRNARP1-68D18.2 and CD44 mRNA in the imatinib resistant chronic myelogenous leukemia cell line K562R, using lncRNA and mRNA microarray, and further verify it using qPCR. Knockdown of RP1-68D18.2 in K562R cell lines increased their sensitivity to imatinib, and simultaneously caused a decrease in CD44 and c-Myc protein levels. Correspondingly, overexpression of RP1-68D18.2 in K562, a sensitive cell line, led to a slightly decrease in imatinib sensitivity and partially reverse downregulation of c-Myc, p-ERK and p-MEK caused by imatinib treatment. Analysis of correlations revealed positive correlation between RP1-68D18.2 and CD44 mRNA expression in the primary CML blasts and hematological malignant cell lines. We conclude that overexpression of RP1-68D18.2 could promote imatinib resistance in the K562R cell line through the regulation of CD44 and its downstream signal molecules.

Disclosures
No relevant conflicts of interest to declare.
hnRNP K: A Regulator of Global Transcription and Translation That Drives Lymphomagenesis
Authors: Malaney Prerna , Gallardo Miguel , Hornbaker Marisa J , Zhang Xiaorui , Link Todd , Shah Vrutant , Alybayev Sanzhar , Wu Meng-Han , Pageon Laura R , Ma Huaxian , Jacamo Rodrigo , Yu Li , Xu-Monette Zijun Yidan , Steinman Haley , Lee Hun Ju , Sarbassov Dos , Rapado Inmaculada , Barton Michelle , Martinez-Lopez Joaquin , Bueso-Ramos Carlos E. , Young Ken H. , Post Sean M 
Published: October 2019

Abstract
hnRNP K is an RNA binding protein that controls a multitude of cellular processes and is aberrantly expressed in cancers. We have previously shown that hnRNP K functions as a haploinsufficient tumor suppressor in AML patients with 9q deletions. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon. We have recently discovered that hnRNP K overexpression in patients with diffuse large B-cell lymphoma correlates with dismal outcomes and directly resulted in the development of lymphomas in transgenic mice.
To understand the mechanistic basis for the oncogenicity of hnRNP K overexpression and to identify therapeutic vulnerabilities, we performed RNA-sequencing, RNA immunoprecipitation following by sequencing (RIP-Seq), mass spectrometry, and polysome assays. We observed that hnRNP K regulates both global transcription and translational processes within the cell via modulation of 7SK and translation initiation proteins (such as the eIFs and PABP), respectively. Consequently, we hypothesized that aberrant hnRNP K expression primarily perturbs oncogenes with short half-lives. Mechanistically, we identified that hnRNP K binds to the RNA and regulates the expression of a plethora of critical oncogenes and tumor suppressors involved in hematologic malignancies such as c-Myc, RUNX1, and Cyclin D1. As proof of concept for clinical applications, we have demonstrated that hnRNP K-driven c-Myc overexpression renders tumors susceptible to bromodomain inhibition.
Given that hnRNP K directs global transcription and translation, it is likely that hnRNP K overexpressing tumors will also be sensitive to transcriptional and translational inhibitors such as CDK9 inhibitors and omacetaxine mepesuccinate, respectively. However, since hnRNP K also regulates a plethora of additional cellular processes that extend far beyond mRNA and protein synthesis, there is a need to develop hnRNP K-specific inhibitors that will only target these activities. Thus, we have recently begun to identify small molecule compounds that can directly inhibit hnRNP K-RNA binding function on specific targets using an in vitro fluorescent binding assay. Using this assay, we are currently screening a library of 70,000 small molecule compounds to identify agents that can prevent hnRNP K-RNA interactions.
In summary, we have established that hnRNP K is a bona fide oncogene that drives lymphomagenesis. Global analyses have revealed therapeutic vulnerabilities of hnRNP K overexpressing tumors. Furthermore, using our in vitro RNA binding assays, we anticipate identification of novel hnRNP K-specific inhibitors.

Disclosures
No relevant conflicts of interest to declare.
Building Capacity for Relapsed/Refractory ALL Patients Needing CAR-T Cells: How Do We Prepare?
Authors: Khalife Roy , Montroy Joshua , Limvorapitak Wasithep , Broady Raewyn , Fergusson Dean , Atkins Harold , Holt Robert , Lalu Manoj , Kekre Natasha 
Published: October 2019

Abstract
Introduction: The prognosis of relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) remains poor in adults. Response rates and survival following anti-CD19 chimeric antigen receptor (CAR) T-cells in r/r ALL have exceeded those of other available agents, but comparative studies are still lacking. Although this therapy shows great promise, it involves complex and expensive manufacturing and administration. Our study seeks to understand the response and survival outcomes of a cohort of Canadian patients with ALL treated with current standard therapies to help the Canadian health care system build capacity for anti-CD19 CART therapies for r/r ALL.
Methods: We conducted a retrospective chart review of all patients diagnosed with ALL at 2 large Canadian academic hospitals between 2010 and 2015 (Ottawa and Vancouver). All patient, therapy and outcome-based factors were extracted. Included patients were then cross-checked against the eligibility criteria for completed anti-CD19 CART cell trials in r/r ALL, but with an upper age cut-off of 75.
Results: 173 patients were diagnosed with ALL over a 5-year period, with median age of 50 (range 16-88). 159 (92%) patients had CD19 reported by flow cytometry, of which 141 were positive at diagnosis. 124 patients (72%) achieved complete remission with induction chemotherapy and 74 patients (43%) relapsed after a median of 11.8 months (range 1-85.6) from diagnosis, of which 29 patients (17%) experienced a second relapse. A total of 63 patients (36%) had an allogeneic stem cell transplant, of which 22 (13%) relapsed after transplant. Patients who relapsed at any point in time survived 5.4 months (range 0.2-55.4). A total number of 62 patients (35.8%) would have been eligible for currently approved anti-CD19 CAR T cell therapy. Reasons for ineligibility were not limited to remission status, but also included CNS involvement, previous solid malignancy, undocumented CD19 status or CD19 negativity, and evidence of kidney or liver dysfunction. The median event-free and overall survival for patients who would have been eligible for FDA-approved anti-CD19 CART cells were 10.3 months (range 0.4-52.3) and 17.3 months (range 0.4-72.6), respectively.
Conclusion: Anti-CD19 CAR T cell therapy has shown very promising results based on early phase data in patients with r/r ALL. Canadian patients are expecting this therapeutic option to be available soon, but our health care system needs to prepare for the complexity of this therapy. Our study helps provide "real-world" eligibility and outcomes of adult patients with r/r ALL. This data suggests that about one-third of cases of ALL could be eligible for this new therapy and should help centers build capacity according to how many new cases of ALL are seen per year.

Disclosures
No relevant conflicts of interest to declare.
Vitamin C Stabilizes CD8iTregs and Enhances Their Therapeutic Potential in Controlling GvHD and Leukemia Relapse
Authors: Iamsawat Supinya , Daenthanasanmak Anusara , Yu Xue-Zhong 
Published: October 2019

Abstract
Graft-versus-host disease (GvHD) remains a leading cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). The imbalance between T effector (Teffs) and regulatory cells (Tregs) is a defined characteristic of GvHD. Therefore, promoting Tregs for controlling GvHD has drawn an intense interest in preclinical and clinical studies of allo-HCT. Although CD4 Tregs (CD4+Foxp3+) have been shown to effectively prevent GvHD, they impaired graft-versus-leukemia (GVL) effect. Our lab has previously demonstrated that CD8 iTregs (CD8+Foxp3+) not only suppressed allogeneic T-cell responses, but also possessed the GVL activity themselves. However, instability of Foxp3 in CD8 iTregs is a major obstacle to translate this Treg population into clinic application.
Vitamin C has been reported to promote Foxp3 stability by accelerating its demethylation. In the current study, we asked whether vitamin C could stabilize CD8 iTregs and enhance their therapeutic potential in controlling GvHD. Addition of vitamin C in the culture significantly increased the generation of allo-reactive CD8 iTregs in vitro (Fig. 1A). These CD8 iTregs generated with vitamin C had strikingly increased demethylation on Foxp3 CpGs (Fig. 1B) and superior suppressive activity (data not shown) compared to control-treated CD8 iTregs. We further evaluated the capability of vitamin C-treated CD8 iTregs in preventing GvHD in allo-HCT. Using a MHC-mismatched murine BMT model, vitamin C-treated CD8 iTregs could significantly alleviate GvHD reflected by a marked reduction of recipient mortality (Fig. 1C) and clinical scores (data not shown).
To determine the Foxp3 stability in vivo, we analyzed the transferred CD8 iTregs and allogeneic Teffs in recipient spleens 7 days after allo-HCT. Vitamin C-treated CD8 iTregs (Ly5.2+) remarkably suppressed Teff (Ly5.1+) expansion and maintained higher Foxp3 expression compared to the control iTregs (Fig. 1D). To address a critical question whether vitamin C-treated CD8 iTregs can preserve the GVL activity, we performed a haploidentical transplant with a leukemia relapse model, and found that vitamin C-treated CD8 iTregs not only attenuated GvHD severity, but also prevented recipients from tumor relapse (Fig. 1E). In conclusion, our studies provide a rationale and mean to use stabilized CD8 iTregs with vitamin C for controlling GvHD and leukemia relapse in the clinic.

Disclosures
No relevant conflicts of interest to declare.
Bendamustine Conditioning Alters Host Dendritic Cell Composition and Function
Authors: Molina Megan Stanley , Stokes Jessica , Hoffman Emely , Katsanis Emmanuel 
Published: October 2019

Abstract
Background
A largely understudied strategy for reducing graft-versus-host disease (GvHD) is the modification of conditioning regimens. We have demonstrated that pre-transplant bendamustine (BEN) used in combination with total body irradiation (TBI) significantly reduces GvHD compared to the more commonly used cyclophosphamide (CY) + TBI. The short half-lives of BEN/CY (<4h), which are given 48h prior to transplant, indicate that these drugs do not directly affect the donor cells. Therefore, the striking improvement in GvHD by substituting CY with BEN must be due to differential effects on the host cells. Conditioned host immune cells diminish over time, but are the majority early after transplant and are able to critically interact with the infused donor cells at the earliest stages of GvHD pathogenesis.
Methods
Using an MHC-mismatched murine model of bone marrow transplantation (BMT) with C57BL/6 donors into BALB/c recipients (H2Kb into H2Kd), we evaluated the differential effects of BEN conditioning on host dendritic cells (DCs) early after transplant, as compared to CY conditioning. Transplant recipient mice were conditioned with BEN or CY on day -2 pre-BMT, and supplemented with 400cGy of total body irradiation on day -1. On days 1, 3, and 5 post-BMT, splenic pan-DCs were isolated and analyzed by flow cytometry to evaluate host (H2Kb-) DC phenotype and activation state. Further, on day 0 (without BMT), circulating leukocytes and splenic pan-DCs were isolated from conditioned mice and analyzed by flow cytometry, qPCR and allogeneic mixed leukocyte reactions.
Results
We found that BEN-conditioned pan DCs are less stimulatory of allogeneic T-cells than CY-treated DCs. BEN conditioning significantly alters host DC composition compared to CY conditioning, resulting in a significantly higher frequency and number of host CD8α+ DCs on days 1 and 3 post-BMT. BEN-conditioned CD8α+ DCs also display a highly regulatory phenotype (CD80highCD86low) and have greater suppressive ability compared to CY-conditioned CD8α+ DCs. Analysis of host DCs on day 0 (without BMT) revealed a significantly greater percentage of BEN-conditioned DCs positively expressing the Flt3 receptor compared to CY.
Conclusions
These findings advocate a potential role of Flt3L-dependent DCs, particularly CD8α+ DCs, in the mechanism by which BEN alters GvHD pathogenesis to limit morbidity and mortality. Thus, BEN may have advantages as an alternative agent to CY for pre-transplant conditioning in allogeneic BMT.

Disclosures
No relevant conflicts of interest to declare.
ERV-9 LTR Retrotransposon Modulates Globin Gene Switching
Authors: Tuan Dorothy 
Published: October 2019

Abstract
In the human beta-globin gene locus, an LTR retrotransposon derived from ERV-9 human endogenous retrovirus is located near the locus control region (LCR) far upstream of the globin genes. In transgenic mice carrying the 100 kb human globin gene locus, deleting the ERV-9 LTR by cre-loxP mediated in situ recombination inactivates transcription of beta-globin gene by ~50% and activates that of gamma-globin gene by up to 5 fold, to at least 20% the level of beta-globin mRNA in both fetal and adult erythroid cells. Chromosome-conformation-capture (3C) shows that the ERV-9 LTR preferentially loops with beta-globin gene, even in fetal erythroid cells where gamma-globin gene is predominantly transcribed. Unique in the locus, the ERV-9 LTR contains high density of CCAAT motifs that strongly bind transcription factor (TF) NF-Y critical for assembling the LTR enhancer complex but no CCNCNCCC motifs that bind master erythroid TF KLF1, while the beta-globin promoter contains two tandem CCNCNCCC motifs that bind KLF1 but a CCAAT motif that only weakly bind NF-Y. However, both the LTR and beta-globin promoter associate in vivo with high levels of NF-Y and KLF1 in ChIP assays. Protein immunoprecipitation shows that neither NF-Y nor KLF1 associates with transcription co-regulator Ldb1, which has been reported to mediate chromosome looping of the LCR with the globin genes. Thus, the Ldb1/LMO2/GATA -1, -2 complex potentially assembled by the GATA motifs distributed throughout the locus does not appear to mediate the preferential looping of ERV-9 LTR with beta-globin promoter. Through interaction of NF-Y and KLF1 mediated by the to be identified co-regulator, the ERV-9 LTR interacts with and activates beta-globin gene, and suppresses gamma-globin gene by a competitive mechanism. Deletion of the ERV-9 LTR removes the competitive advantage of beta-globin gene, thus re-activating gamma-globin gene. Our findings suggest that deleting the ERV-9 LTR from the globin locus by genome-editing could provide a potential new therapy for beta-hemoglobinopathies.

Disclosures
No relevant conflicts of interest to declare.
Prothrombin Complex Concentrate Is Safe and Effective for Achieving Hemostasis in the Setting of Urgent Surgery for Patients Treated with Direct Xa Inhibitors
Authors: Barzilai Merav , Kirgner Ilya , Steimatzky Arza , Salzer Gotler Dalit , Belnick Yulia , Avivi Irit , Varon David , Shacham Adi , Yahalom Vered , Nakav Sigal , Yussim Ethan , Bahar Gil , Rozovski Uri , Spectre Galia 
Published: October 2019

Abstract
Introduction: Patients treated with direct Xa inhibitors may require an urgent surgery. A reversal agent for Xa inhibitors was recently approved for major bleeding but not prior to urgent surgery. Administration of prothrombin complex concentrate (PCC) in this setting is a common practice; however, it is based on limited experience in healthy volunteers.
Objective: To characterize the population receiving PCC for apixaban/rivaroxaban reversal prior to an urgent surgery/procecdure and evaluate its efficacy and safety.
Methods: A retrospective study in two tertiary hospitals. Bleeding was evaluated by surgical reports, hemoglobin drop and use of packed red blood cells or additional PCC during 48h. Safety measures were thrombotic complications and 30-day mortality.
Results: Sixty-two patients, aged 80.7±9, received PCC prior to urgent invasive procedures ;39 (63%) received apixaban and 23( 37%) rivaroxaban. Ninety percent of them received anticoagulation due to atrial fibrillation. Most urgent procedures were abdominal surgery (61%), orthopedic surgery (13%) or transhepatic cholecystostomy insertion (10%). Mean dose of PCC was 26.6±8 U/kg. Fourteen patients (23%) received 1 gram of tranexamic acid. Bleeding was reported by surgeons in 3(5%) patients and no patient required additional PCC. Sixteen (26%) patients received packed cells (median 1 unit, range 1-5). Thirty day mortality and thrombosis were 13(21%) and 2(3%) respectively. Cause of death was related to the primary disease or sepsis. No patient died due to bleeding/thrombosis.
Conclusions: PCC is safe and effective for the reversal of Xa inhibitors prior to an urgent surgery/procedure.

Disclosures
No relevant conflicts of interest to declare.
Medium-Dose VP-16 Intensified Conditioning Regimen Is Effective in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia
Authors: Sun Feifei , Fang Xiaosheng , Yujie Jiang , Sui Xiaohui , Liu Xin , Wang Xianghua , Li Ying , Wang Na , Zhen Changqing , Qu Huiting , Fan Juan , Xu Hongzhi , Wang Xin 
Published: October 2019

Abstract
Objective: Retrospectively analysing the outcome of additional medium-dose etoposide (VP-16 30mg/kg) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL).
Methods: From 2010.10.1 to 2018.6.30, 53 ALL patients received allo-HSCT in Shandong provincial hospital. 20 conditioning with medium-dose VP-16 (15 in CR , 5 in refractory and/or relapse disease) (VP-16 group), 33 conditioning without medium-dose VP-16 (32 in CR and 1 in refractory and/or relapse disease) (control group) . The basic conditions of the primary disease, treatment-related toxicity, leukemia-free survival (LFS), overall survival (OS), graft-versus-host disease (GVHD) and relapse-free survival (GRFS), non-relapse mortality (NRM), relapse incidence (RI), GVHD and so on were compared between the two groups.
Results: The VP-16 group included more R/R(refractory and/or relapse disease) patients and was associated with improved 3-year-LFS (70.7% vs. 56.5%, p= 0.565) and 3-year-OS (68% vs. 59.4%, p=0.825), although there was no statistical difference. Moreover, the additional of VP-16 lead to reduced incidence of aGVHD (II,III,IV) (10% vs. 30.7%, p=0.146) and cGVHD (9.1% vs 24%, p=0.25), resulting in improved GRFS (63.6% vs. 48.7%, P=0.343). RI was similar between the two group (29.3% vs 27.2%, p=0.76). Meanwhile, the addition of VP-16 enhanced the intensity of conditioning regimen, its NRM was relatively lower than control group (0% vs. 20.2%, P=0.371).
Conclusion: The intensified conditioning regimen with medium-dose VP-16 did not increase NRM and GVHD, with tendency to increase OS and LFS, may become an effective pre-treatment scheme in allo-HSCT for ALL.

Disclosures
No relevant conflicts of interest to declare.