bluuebunny/crossref_metadata_2025_split huggingface dataset:
R4 Rgs Subfamily Proteins Negatively Regulates SDF-1/CXCR4 Signaling in CD34+ Hematopoietic Stem and Progenitor Cells
Authors: Leung Kam Tong , Wong Yorky Tsin Sik , Li Karen , Chan Kathy Yuen Yee , Zhang Xiao-Bing , Leung Ting Fan , Ng Pak Cheung , Li Chi Kong 
Published: October 2019

Abstract
RGS family proteins are known to negatively regulate G-protein-coupled receptor signaling through their GTPase-accelerating activity. In several types of hematopoietic cells (e.g., B lymphocytes and megakaryocytes), responses to stromal cell-derived factor-1 (SDF-1) are subjected to regulation by R4 subfamily RGS proteins. However, their expression patterns and functional roles in hematopoietic stem and progenitor cells (HSC) are poorly characterized. Here, we showed that human CD34+ HSC derived from cord blood (CB, n = 10) expressed 7 out of 10 R4 RGS proteins at mRNA level (RGS1-3, 5, 13, 16 and 18), whereas expressions of RGS4, 8 and 21 were undetectable. Exposure of CB CD34+ cells to SDF-1 significantly increased RGS1, 2, 13 and 16 expressions and decreased RGS3 and 18 expressions (P ≤ 0.0402, n = 5). Expressions of RGS1, 13 and 16 were significantly higher in bone marrow (BM, n = 10) CD34+ cells when compared to mobilized peripheral blood (MPB, n = 5) CD34+ cells (P ≤ 0.0160), while RGS3 and 18 expressions were lower in BM CD34+ cells (P ≤ 0.0471), suggesting a SDF-1- and niche-dependent regulation of RGS expressions. To investigate the potential involvement of RGS proteins in SDF-1-mediated homing-related functions, we introduced RGS overexpression constructs into CB CD34+ cells by lentiviral transduction. With >80% transduction efficiency, we showed that overexpression of RGS1, 13 and 16 but not RGS2 significantly inhibited migration of CD34+ cells to a SDF-1 gradient (P ≤ 0.0391, n = 4-5). Similarly, RGS1, 13 and 16 overexpression suppressed SDF-1-induced Akt phosphorylation (n = 2), but none of them affected SDF-1-mediated actin polymerization (n = 3). In the NOD/SCID mouse xenotransplantation model, preliminary results showed that bone marrow homing was impaired in RGS1- (16.3% reduction), RGS13- (12.7% reduction) or RGS16-overexpressing CD34+ cells (33.7% reduction). Taken together, we provided the first evidence that expressions of R4 RGS proteins are regulated by the SDF-1/CXCR4 axis in human CD34+ HSC. We also presented evidence that specific R4 RGS proteins (RGS1, 13 and 16) negatively regulate in vitro SDF-1-mediated responses and in vivo homing of CD34+ cells, suggesting that RGS proteins may serve as a feedback mechanism to regulate SDF-1/CXCR4 signaling. Strategies to inhibit RGS signaling could thus be a potential method for enhancing efficiency of HSC homing and long-term engraftment, which is particularly important in the setting of CB transplantation.

Disclosures
No relevant conflicts of interest to declare.
Clinical Observation for the Treatment of Umibilical Cord Mesenchymal Stem Cells(UCMSC) on Severe Aplastic Anemia(SAA)
Authors: Liu Qingchi , Zheng Zhuanzhen 
Published: October 2019

Abstract
Objective To investigate the safety and the efficacy of Umibilical cord mesenchymal stem cells(UCMSC) on severe aplastic anemia(SAA).
Methods 30 cases who diagnosed SAA in our department from October 2013to January 2016 and treated with UCMSC on the basis of conventional treatment,were enrolled in this study prospectively.The cultured UCMSC using Serum-free culture system in vitro were given to patients with AA, interval of 15 days, 3 times for a course.the conventional treatments include CsA,male hormone and Chinese herb.Observed the changes of Th / Ts before and after treatmen ,Clinical efficacy and UCMSC infusion adverse reactions. Compared the efficacy of UCMSC therapy with conventional therapy of 30 cases of SAA at the same time.
Results:Among 30 cases using umbilical cord mesenchymal stem cell infusion with UCMSC each infusion volume 3.2 × 106 / kg ~ 4.2 × 106 / kg, the average of 2.9 × 106 / kg, the average influsinon three times , 8 cases acquired basic cure, 8 cases acquired remission , 6 cases acquired significant progress in 6 cases, 8 cases were ineffective,with an effective rate of 73.3%.Before UCMSC treatment Th / Ts 0.67 ± 0.41, after1.33 ± 0.45, there was significant difference (P <0.05). There were 4 patients experienced transient fever during the influsion ,disappeared after symptomatic treatment, no other serious adverse reactions.Among 30 cases of SAA recived conventional therapy at the same period , 3cases acquired basic cure, 5cases acquired remission ,8cases acquired significant progress in 6 cases, 14 cases were ineffective,with an effective rate of 53.3%.The difference was significant (P <0.05).
Conclusions:In vitro serum-free culture system can be used to culture and expand clinical scale UCMSC.UCMSC infusion can improve the SAA patient's Th / Ts proportion of T lymphocyte subpopulation , can improve the efficacy of new SAA, also more secure, no serious adverse reactions.

Disclosures
No relevant conflicts of interest to declare.
Either Scl or Lyl1 Is Required to Maintain Primitive Erythropoiesis
Authors: Chiu Sung Kai , Tremblay Cedric , Saw Jesslyn , Curtis David J. 
Published: October 2019

Abstract
SCL (TAL1) and LYL1 are the predominant bHLH transcription factors expressed in erythropoiesis. Using a conditional allele of Scl, we have previously demonstrated redundancy of Scl in adult erythropoiesis. Similarly, adult erythropoiesis is maintained in Lyl1-deficient mice. To determine if these factors can compensate for each other, we deleted Scl with Cre recombinase under the control of the Epo receptor, which is active in late erythroid progenitors from embryonic day 8.5. Embryos lacking Scl in erythroid progenitors (EpoR-Cre SclD/D) were born at the expected Mendelian frequency with only a mild anemia in adult mice, indicating Scl was not required for primitive or definitive erythropoiesis. In contrast EpoR-Cre SclD/D mice lacking Lyl1 died at e11.5 due to erythropoietic collapse. Gene expression profiling of yolk sacs prior to the loss of erythrocytes (E9.5) revealed reduced Gata1, Fog1, Klf1 and the primitive b-globins. In contrast, expression of Gata2 and Runx1 were increased despite absence of Scl and Lyl1. Development of embryonic stem cells from these mice will determine if Gata1 is key downstream target of the Scl/Lyl1 complex for primitive erythropoiesis.

Disclosures
No relevant conflicts of interest to declare.
Demonstration of Pharmacokinetic and Pharmacodynamic Equivalence in Healthy Volunteers for B12019, a New Proposed Pegfilgrastim Biosimilar
Authors: Roth Karsten , Gastl Barbara , Lehnick Dirk , Jacob Karin , Jankowsky Ruediger 
Published: October 2019

Abstract

B12019 is being developed as a biosimilar to Neulasta® (INN pegfilgrastim), a long-acting, pegylated form of recombinant human granulocyte-colony stimulating factor (r-metHuG-CSF, INN filgrastim) for the prevention of chemotherapy-induced neutropenia. A comprehensive analytical, functional and preclinical comparability program has already demonstrated a high degree of similarity of B12019 as compared to Neulasta®. In order to confirm the similarity on the clinical level, a pharmacokinetics/pharmacodynamics (PK/PD) study was conducted with B12019 in comparison to EU-authorised Neulasta®.
The study was designed as a single-dose, randomized, double-blind, two-way crossover study. The study statistics were based on a two-stage design derived from to Potvin et al, 2007 to address potential high variability for the PK endpoints. 172 healthy male volunteers were enrolled in stage 1 of the study, whereas stage 2 would allow the recruitment of additional 102 subjects. The subjects received B12019 as well as Neulasta®. The primary PK endpoints were the Area Under the Curve for concentration (AUC0-last) and maximum concentration (Cmax). The primary PD endpoint was the Area Under the Effect Curve (AUEC) for Absolute Neutrophil Count (ANC). PK endpoints were assessed with a 94.32% confidence interval (CI) accounting for the two-stage study design, whereas the PD endpoint was assessed with a 95% CI. Furthermore, safety and immunogenicity were investigated.
161 subjects were eligible to contribute to the model-based PK and PD comparison based upon the first stage of the study. For the PK endpoints, the 94.32% CIs for the geometric mean ratios were 86.60-104.73% for AUC0-last and 84.36-102.18% for Cmax. Both PK endpoints fulfilled the predefined acceptance criteria of being within the range of 80-125%. For the PD endpoint, the 95% CI for the geometric mean ratio of the ANC AUEC was 98.67-101.75%, also falling within the predefined acceptance criteria of 80-125%. Since the primary PK endpoints were met in stage 1 of the study, stage 2 was not required. The safety profile of B12019 did not show any clinically meaningful difference as compared to Neulasta®. Neither anti-G-CSF nor neutralising antibodies were detected for both, B12019 and Neulasta®.
The study demonstrated PK and PD comparability as well as comparable safety and immunogenicity profiles of B12019 as compared to EU-authorised Neulasta®. No clinically meaningful differences were detected between B12019 and Neulasta®. The high analytical and functional similarity of B12019 was confirmed on clinical level.

Disclosures
Roth: Cinfa Biotech: Employment. Gastl:Cinfa Biotech: Consultancy. Lehnick:Nuvisan GmbH: Employment. Jacob:Cinfa Biotech: Employment. Jankowsky:Cinfa Biotech: Employment.
TP53-Induced Glycolysis and Apoptosis Regulator Protects from Spontaneous Apoptosis and Predicts Poor Prognosis in Chronic Lymphocytic Leukemia
Authors: Hong Ming , Xia Yi , Zhu Yu , Zhao Huihui , Xie Yue , Fan Lei , Wang Li , Miao Kourong , Wu Wei , Zhu Huayuan , Chen Yaoyu , Xu Wei , Qian Sixuan , Li Jianyong 
Published: October 2019

Abstract
The circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, CLL cells' recurrent contact with the stromal microenvironment leads to an increase of aerobic glycolysis and the cells' overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. Here, we investigated correlation between TIGAR expression and apoptosis in CLL primary cells, along with its relationship with the clinical characteristics and prognosis in 102 newly diagnosed CLL patients. Our data showed TIGARoverexpression correlated with protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with briefer treatment-free survival (median: 3 months vs. 51 months, p = 0.0108) and worse overall survival (median: 74 months vs. not reached, p = 0.0242), as well as their diverse responses to fludarabine based chemotherapy. TIGAR expression of the patients who were resistant to chemotherapy was significantly higher than those who were sensitive to chemotherapy (mean: 0.3859±0.1710 vs. 0.0974±0.0291, p = 0.0290). Taken together, our findings depict how bioenergetics characteristics could be therapeutically exploited in CLL.

Disclosures
No relevant conflicts of interest to declare.
Selective Advantage of the Recurrent Isodicentric Chromosome 20 in Myeloid Disease
Authors: Schleede Justin B , Papenhausen Peter , Schwartz Stuart , Gadi Inder K. 
Published: October 2019

Abstract
Interstitial deletion of the long arm of chromosome 20 is a common genomic imbalance associated with myeloid hematologic disorders. Originally identified by conventional cytogenetics and fluorescent in situ hybridization, it has been hypothesized that deletion of 20q results in haploinsuffciency of tumor suppressor gene(s) causing a proliferative advantage. The advent of microarray analysis has revolutionized the detection of copy number gains and losses associated with a variety of oncogenic mechanisms. Initial studies using microarray analysis have shown significant heterogeneity in the breakpoints associated with interstitial deletions of 20q, ruling out the possibility of a recurrent genomic fusion, but establishing a critical region which appears to support a tumor suppressor gene loss model. We have documented six individuals, referred for microarray analysis of myelodysplasia, with alterations of chromosome 20 involving a similar complex rearrangement. The rearrangement is an isodicentric chromosome 20 consisting of 1) a deletion of the majority of the short arm pter to p11.1, 2) retention of the region flanking the centromere from p11.1 to q11.21, and 3) an adjacent interstitial deletion of the long arm that can vary in size similar to the common 20q deletion. The breakpoints of the region flanking the centromere at 20p11.1 are within a block of segmental repeats and virtually identical in all 6 cases while the break points in 20q11.21 are within ~1.1 MB (30,785,977-31,887,129). In addition, one of the six cases shows additional copies of the region flanking the centromere from p11.1 to q11.21 consistent with supernumerary marker chromosomes found by conventional cytogenetics. These results suggest that there is a selective advantage associated with a gene(s) within the chromosome 20p11.1->q11.21 segment. The PDRG1 gene is localized to 20q11.21and has been shown to be upregulated in number of malignant cell types including colon, rectum, ovary, lung, stomach, breast and uterus. As our results show, PDRG1 is duplicated or amplified in all 6 cases with the isodicentric chromosome 20. Therefore, these results suggest PDRG1 upregulation may contribute to the pathogenicity of myelodysplasia by conferring a selective advantage in individuals with the isodicentric chromosome 20.

Disclosures
No relevant conflicts of interest to declare.
Apatinib Inhibits Proliferation and Induces Apoptosis of Acute Myeloid Leukemia Stem/Progenitor like Cell Line(kg1α cells) By Inhibition PI3K/AKT Signal Pathway
Authors: Xu Bing , Li Zhi-feng , Deng Man-man , Zha Jie , Zhou Yong , Fang Zhi-hong 
Published: October 2019

Abstract
OBJIECTIVE To investigate the effect of apatinib, a small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, on the proliferation and apoptosis of acute myeloid leukemia stem/progenitor like cell (kg1α) and its molecule mechanism. METHODS The kg1α cells were treated with a serial of concentrations of apatinib for 48 h and 72 h, the inhibitory ratio was measured by CCK8 assay, the apoptosis percent was measured by flow cytometry. Western bolt was used to analyzed AKT/p-AKT、p-Raf and p-PTEN expression after treatment with 0、10 and 20μM apatinib. RESULTS ①After treatment with a serial of apatinib (2.5、5、10、20、40μM) on AML stem-like cell line(kg1α)for 48 and 72 hours, the cell proliferation were significantly inhibited in a dose- and time-dependent mode. For treating with 48h, the cell viability were respectively (92.32±0.82) %、 (80.59±4.95) %、 (61.75±0.47) %、 (51.51±4.10) %、 (26.42±4.20) %, and all the differences had statistical significance compared with control group, and with the 50% inhibitory concentration(IC50) value of (16.98±0.08) μM; However, the viability were respectively (88.42±2.91) %、 (70.83±4.45) %、 (47.87±1.59) %、 (31.41±3.57) %、 (13.26±1.96) % for 72h, and with the 50% inhibitory concentration(IC50) value of (10.05±0.08) μM .②The results of Annexin V/PI showed that various concentration of apatinib induced significantly apoptosis on kg1α cells. After the treatment of 10、20、30 and 40μM apatinib for 48 hours, the apoptosis percentage was significantly higher than control group (6.12±1.26) %, respectively (4.57±1.16) %、 (12.6±2.34) %、 (16.37±4.38) % and (19.77±2.55) % ,and the differences(except for 10μM) had clearly significance compared with control group(F=18.85,P<0.001);for 72h, the apoptosis percentage of 10、20、30 and 40μM apatinib were seperately 10.83±2.96 (%、 (15.38±2.78) %、 (24.95±2.70) % and (35.17±1.36) %, compared with untreated group (5.03±1.11) % had obviously significance(F=79.425,P<0.001). Western blot results indicated decrease the expression of AKT/p-AKT and p-Raf, however, upregulated the level of p-PTEN. CONCLUSION Apatinib can inhibit the proliferation and induce the apoptosis of kg1αcells. Its mechanism may be related with the PI3K/AKT signal pathway.

Disclosures
No relevant conflicts of interest to declare.
Anti-CD 19 and Anti- CD 20 Chimeric Antigen Receptor-Modified T Cells for B-Cell Malignancies: A Systematic Review and Meta-Analysis
Authors: Riaz Irbaz Bin , Husnain Muhammad , Kamal Muhammad Umar , McBride Ali , Hua Anh , Geoge Laeth , Hamadani Auon Abbas , Rahman Bushra , Ali Zeeshan , Sipra Qurat-ul-Ain Riaz , Zahid Umar , Raina Ammad , Saleh Ahlam , Anwer Faiz 
Published: October 2019

Abstract
Background:
Chimeric antigen receptor (CAR) modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. CD19 and CD20 targeted CAR constructs from several different institutions have demonstrated consistently high anti-tumor efficacy in children and adults with relapsed B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL). We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 CAR-T therapy for B-cell hematologic malignancies.
Methods:
Literature search was performed using MEDLINE (Ovid SP and PubMed), EMBASE, The Cochrane Library, Scopus and Web of Science. We conducted meta-analysis using random effects model using Comprehensive Metaanalysis 3.0. Heterogeneity was assessed using Q-statistic and it was quantified using I2statistic.
Results:
After a comprehensive literature search 4476 studies were identified and finally 15 eligible studies involving 121 patients were included in the final systematic review. The infused CAR T-cell dose was in the range of 0.76 x 106 to 3 x 107 cells/kg in seven trials and in the range of 0.8 x 107 cells to 3.3 x 109 cells/m2in 6 trials. Among 106 patients, the overall response to treatment after CAR T-cell infusion were 33% complete remission (CR), 30 % partial remission (PR), 21% stable disease (SD), and 8% progressive disease (PD). Three studies described response to immunotherapy as minimal residual disease negative (MRD-) and as no evidence of disease (NED) and after including it, the overall CR was 38%. Major adverse events included fever (38%), hypotension (23%), chills (29%), rigor (28%), fatigue 17% and dyspnea 10%. One patient died from cytokine release syndrome, which is potentially serious complication. Neurological symptoms require prompt recognition and management.
Conclusion:
CAR T cell therapy is a promising treatment for refractory and relapsed hematological malignancies. The durable responses of CAR T cell therapy help integrate it in standard treatment protocols. Patients who are refractory to standard salvage chemotherapy or relapse after allo - HSCT have overall poor prognosis and can potentially achieve remission again with CAR T cell therapy.

Disclosures
McBride: Sanofi: Research Funding. Anwer:Seattle Genetics: Other: Advisory Board Participant; Incyte: Speakers Bureau.
TIM3 Dynamically Expressed on Peripheral Blood NK Cells in Acute Myeloid Leukemia Patients: The Expression Decreased When Untreated, and Restored While Disease Improved
Authors: Li Caixia , Chen Xiaochen , Gu Caihong , Wang Tong , Zou Qiu , Yang Dan , Wu Depei 
Published: October 2019

Abstract
Objective: Preliminary study the expression and clinical significance of TIM3 on peripheral blood NK cells in patients with acute myeloid leukemia (AML). Methods: We investigated the expression characteristics of TIM3 on the peripheral blood NK cells of newly diagnosed AML patients and its clinical significance. Peripheral blood was obtained from 50 patients with newly diagnosed AML before intervention, with peripheral blood from 30 cases of healthy volunteers collected as normal control. Expression levels of TIM3 on the peripheral blood NK cells and subsets were assayed with flow cytometry. Then the expression of gamma interferon in Tim3+CD56+NK cells and Tim3-CD56+NK cells were analyzed by intracellular immunofluorescence labeling and flow cytometry. Results: Compared with the normal control, in the newly diagnosed AML patients, the NK cells percentage and the proportion of CD56dimNK/CD56+NK reduced, while the proportion of CD56brightNK/CD56+NK increased significantly, and the proportions of Tim3+CD56+NK/CD56+NK and Tim3+CD56dimNK/CD56dimNK decreased significantly. However, in AML patients with complete remission after chemotherapy, the proportion of peripheral blood NK cells and cell subsets recovered. Furthermore, compared with Tim3-CD56+NK cells, IFN-γsecretion level of Tim3+CD56+NK cells in the newly diagnosed AML patients is increased significantly. Conclusion: The dynamic expression of TIM3 on NK cell and its cell subsets before and after chemotherapy in AML patients suggest that Tim3 and NK cells may play an important role in the occurrence and development of AML.

Disclosures
No relevant conflicts of interest to declare.