bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thromboxane a2 Exerts Promoting Effects on the Proliferation of Multiple Myeloma Cells By Reducing G2/M Phase Arrest through the Activation of p38/JNK MAP Kinase Pathway
Authors: Xiong Hong , Yu Yu 
Published: October 2019

Abstract
Background: Multiple myeloma is a kind of frequent hematological malignancy and its effective cure is still deficiency. Whether TXA2/TP affects the proliferation of MM through the MAPK signaling pathway are still uncovered.
Results: SQ29548 inhibits the proliferation of MM cells by arresting cells at the G2/M phase through attenuating cyclin B1/CDK1 expression and p38 MAPK/JNK activation, and inducing cell apoptosis.
Conclusion: SQ29548 has potential as a novel agent to target kinase cascades for MM therapy.
Significance: We have defined a novel physiological role for TXA2/TP in MM cells.
Multiple myeloma (MM) is a plasma cells malignant proliferation disease, and a satisfactory cure is unavailable till now. Thromboxane A2 (TXA2)/TXA2 receptor (TP) has involved the modulations of some carcinomas progression, while their effects on the proliferation of MM cells remain unclear. In this study, we detected cyclooxygenase enzymes (COX) downstream prostaglandin (PG) profiles in human myeloma cell lines U266 and RPMI8226, analyzed the effect of COX-1/-2 inhibitors, SC-560 and NS-398 on the MM cells proliferation. The observations showed that COX-2 involved in the modulation of cell growth. Then, MM cells were incubated with 4 antagonists of DP2, EP2, EP4 and TP receptors which were chosen according to their high transcriptions, and only TP antagonist, SQ29548, suppressed MM cells proliferation. Moreover, SQ29548 promoted MM cells G2/M phase arrest accompanied by reducing cyclin B1 and CDK1 expression at mRNA and protein levels. We also found TP agonist, U46619, activated JNK and p38 MAPK by phosphorylation, and JNK inhibitor, SP60015, and p38 MAPK inhibitor, SB203580, depressed U46619-induced proliferation and protein expressions of cyclin B1 and CDK1. In addition, SQ29548 leaded to MM cells apoptotic rate increasing with improving caspase 3 activity. Taken together, our results suggest that TXA2/TP promote the proliferation of MM cells by reducing cells at the G2/M phase through elevating cyclin B1/CDK1 expression and p38 MAPK/JNK activation, and reducing cell apoptosis. It has potential as a novel agent to target kinase cascades for MM therapy.

Disclosures
No relevant conflicts of interest to declare.
Identification of a CLL Cancer Stem Cell
Authors: Kellner Joshua , Yvon Eric , Gordon Veronica , McNiece Ian K. 
Published: October 2019

Abstract
To date cancer research and therapeutic approaches have mainly targeted the cellular mechanisms of aberrant proliferation. These treatments do shrink tumors, but after a remission of variable length, most patients relapse with frequent drug resistance and metastatic dissemination. These features indicate that within a tumor exists a population of cells that is inherently resistant to therapies and are able to reinitiate tumor growth and development. This is the basis of the cancer stem cell (CSC) theory. Targeted elimination of CSCs is actively being explored as a new therapeutic approach in hemato-oncology with a focus on cell surface antigens expressed on CSCs for antibody- or ligand-based therapeutic approaches. Most studies have defined CSCs functionally by their tumor initiating ability, when inoculated into immune-deficient (NSG) mice. These xenograft models have been powerful preclinical tools in a number of malignancies, with the notable exception of chronic lymphocytic leukemia (CLL).
We have recently isolated a primary cell line from the bone marrow BM of a patient with CLL, which we have termed MDA-BM5, and have successfully passaged this line through six serial transplants in NSG mice. The mice die of disease around 1 month post transplant and analysis of organs has demonstrated the presence of CD19+CD5+ cells with Ig light chain restricted to lambda which is consistent with the original patient samples. BM cells from tertiary transplant NSG mice demonstrate a stem cell phenotype; including expression of CD34 and aldehyde dehydrogenase (ALDH). Treatment of MDA-BM5 cells in vitro with inbrutinib is effective in killing 99% of cells, however, continued culture after removal of ibrutinib results in propagation of a "resistant" subpopulation. Based upon these data we propose that the novel cell line (MDA-BM5) contains a CSC subpopulation which replicates human CLL in NSG mice. Further characterization of the CLL-CSC is ongoing to identify potential therapeutic targets.

Disclosures
No relevant conflicts of interest to declare.
The Targeting Repair of UC-MSCs Homing on Immune Inflammatory Microenvironment and Thrombophilia in CIA Rats
Authors: Cai Xinzhen , Ni Jun , Wu Wei , Shi Qingqing , Li Zou , Gu Wei , Gu Jian , Depei Wu 
Published: October 2019

Abstract
Introduction
To preliminary study the repair effect of umbilical cordmesenchymal stem cells (UC-MSCs) homing on local and systemic inflammatory microenvironment and immune inflammatory thrombophilia states of the CIA rata by observing the distribution of the UC-MSCs in the CIA rate and the influence of the UC-MSCs on the expression of the inflammatory cytokines IL-10, TNF-α IL-6, IFN-γ and the thrombosis indicators TF, VWF, DD, FIB's.
Methods
The clean grade, female, 5-week-old SD rats were randomly divided into a control (C) group, model (M) group, UC-MSCs treatment (SU) group, adding AMD3100 to labled UC-MSCs therapy (ASU) group. Except for control group, the other rats were induced as CIA rats model. Treatment group were injected UC-MSCs suspension by tail vein. The rats were sacrificed in the first, the third and the fifth week after transplantation. HE staining was used to observe the pathological changes of joint tissues. The distribution of UC-MSCs in the joint tissue was detected by FISH. ELISA assay was used to observe the expression of inflammation and thrombosis indicators in peripheral blood. The expression of inflammatory factors in the joint tissue were detected by western blot.
Results:
1. One week after injection, the expression of SDF-1 in the injuried joint of the group SU was significantly increased compared with the control group, at the same time, the large number of UC-MSCs occured in injured sites. While, adding AMD3100 to labled UC-MSCs were not expressed in the joint tissue. The expression of SDF-1 in the labled UC-MSCs treating group decreased over time, and the number of UC-MSCs reduced in the inflammatory joints.
2. After given UC-MSCs treatment, the levels of pro-inflammatory cytokines IL-6, TNF-α, IFN-γ in the knee and serum were conspicuously reduced compared with the group M since the first week. While the level of anti-inflammatory cytokine IL-10 was increased (p <0.05). After adding AMD3100, the expression of above indicators in the group ASU showed no significant difference compared to the group C.
3. After given UC-MSCs treatment, the levels of TF in serum and DD, FIB, VWF in plasma were conspicuously reduced compared to the group M since the first week (p <0.05). The expression of the above indicators in the group ASU showed no significant difference compared to the group C.
Conclusion:
1. UC-MSCs homing to the injured joint tissue is influnced by the local inflammation environment, which is an important way to play its role of immune regulation to improve the immune inflammatory thrombophilia state in CIA rsts.
2. SDF-1/CXCR4 axis is important to the UC-MSCs homing, the antagonist AMD3100 can suppress the UC-MSC homing to the injured site.
Funded by Jiangsu Provincial Special Program of Medical Science (BL2012005)

Disclosures
No relevant conflicts of interest to declare.
HO-1-Transduced Mesenchymal Stem Cells Attenuate aGVHD By Inhibiting HIF-1α /ROR-γt and then Down-Regulate Proportion of TH17/Treg
Authors: Wang Jishi , Yu Meisheng , Chen Shuya , Zhao Jiangyuan , Zhang Yaming , Lin Xiaojing , Zhe Nana , Fang Qin 
Published: October 2019

Abstract
Background. In acute graft versus host disease, the balance pattern of Treg/Thl7 cells are destroyed, leading to a series of inflammation and damage to the body, greatly affect the survival of allogeneic hematopoietic stem cell transplantation patients. Mesenchymal stem cells can regulate the body's balance of TH17/Treg cells, clinically used to prevent and treat aGVHD.But between immune adjustment ability of mesenchymal stem cells in clinical trials have not been shown to efficiently prevent and treatment of GVHD. HO - 1 as a significant anti-inflammatory and immunosuppressive molecules in rats and human MSC played a crucial role in immune suppression function.In this article, we discuss slow virus in mice mediated transfection MSC HO-1 key nuclear transcription factor can inhibit the TH17 STAT3 activation to further decline, the proportion of TH17/Treg and whether more effectively adjust the related the secretion of cytokines to alleviate aGVHD caused by inflammation of the target organ damage, in addition to observe the clinical patients undergoing allogeneic transplantation patients occurred aGVHD HO-1 high expression and the relationship between the expression of STAT3 and the secretion of peripheral blood serum of TH17/Treg related factors.
Methods.Lentivirus transfection raised for rat mesenchymal stem cells between the expression of HO-1, trailing edge vein injection of mice treated, fluorescence microscopy MSC colonize the target organs of mice, pathological biopsy to detect target organ damage, immunohistochemical detection of target organs and the spleen and the expression of pSTAT3, HO-1 flow cytometry to detect the spleen, drainage of lymph node ratio of TH17/Treg cells, Realtime PCR and ELISA to detect the related inflammatory factor levels.
Results. The mouse in accepting HO-1 high expression of mesenchymal stem cells after infusion, significantly reduce aGVHD, immunohistochemical results show that the main target organs damage in the expression of HO-1 is inversely proportional to the expression of STAT3 and spleen pSTAT3 protein and total level of STAT3 protein was lower than other groups, the spleen and lymph nodes of TH17/Treg proportion are lower than other groups, IL-17 A, ROR-ϒt mRNA level and serum concentration is lower than other groups, FOXP3, TGF-β mRNA and serum concentration is higher than in the rest of the group.
Conclusions. These results suggest that activation of HO - 1 May improve the anti-inflammatory and immune suppression ability of MSC, and perhaps by inhibiting the phosphorylation of STAT3, cut ratio of TH17/Treg cells, promote reduce aGVHD.

Disclosures
No relevant conflicts of interest to declare.
Stem Cell Mobilization after Various Induction Regimens in Patients with Multiple Myeloma
Authors: Radocha Jakub , Maisnar Vladimir , Lanska Miriam , Hanousek Jiri , Machalkova Katerina , Beranova Katerina , Zavrelova Alzbeta , Motyckova Monika , Zak Pavel 
Published: October 2019

Abstract
Stem cell mobilization after various induction regimens in patients with multiple myeloma
Introduction: Rapid development of novel therapies for multiple myeloma has led to a significant improvement in response to the treatment. Stem cell mobilization before autologous stem cell transplantation is a source of considerable costs of transplant procedure. Whether modern induction regimens affect outcome of stem cell mobilization has not been extensively studied.
Aim: The goal of this study was to compare efficacy of stem cell mobilization after different induction regimens in patients with multiple myeloma. The primary goal was to compare CTD (cyclophosphamide, thalidomide, dexamethasone), CVD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone) and regimens in terms of succesful stem cell collection.
Methods: All patients with multiple myeloma who have been planned for stem cell collection and were treated with one of the above mentioned regimens were included in this retrospective analysis. The demographic data, amount of stem cells collected, number of days needed to reach the target collection were recorded. All patients received high dose cyclophosphamide 2,5 g/m2 prior to stem cell collection and were primed with G-CSF twice daily from day 5. The collection was started at day 10. Collection goal was 8x106/kg CD34+ cells.
Results: 15 patients received CTD, 25 patients CVD and 16 patients VTD regimen before stem cell collection. Groups were comparable according to age, gender and myeloma stages. Mean collected cells at the end of collection were 9.2 (SD 2.8) for CTD, 12.3 (SD 5.6) for CVD and 10.1 (SD 2.1) for VTD (p=0.066). Mean daily harvest was 3.4, 8.0 and 7.6 x106/kg respectively (p=0.01). Mean days needed to reach desired harvest were 3, 2.25 and 1.6 days (p=0.001). No collection failure was observed.
Conclusion: The best collection results were seen in patients after induction with CVD or VTD regimen. VTD regimen also required the least days for collection and seems to be most beneficial for cost of collection. CTD regimen shows the least efficacy in stem cell collection before autologous transplantation. All patients managed to harvest for at least one stem cell transplant.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Chemotherapy Combined with Granulocyte Colony Stimulating Factor (G-CSF) for Mobilization of CD34+ Cells in Lymphoma and Multiple Myeloma Patients
Authors: Zheng Gaofeng , Zheng Yanlong , Luo Yi , Shi Jimin , Zheng Weiyan , Wei Guoqing , Sun Jie , Huang He , Cai Zhen , He Jingsong 
Published: October 2019

Abstract
Objective: To investigate and analyze factors which effect autologous stem cell collection in patients with lymphoma and multiple myeloma (MM) during chemotherapy combined with G-CSF mobilization, for improving quality and effectiveness of autologous stem cell transplantation.
Methods: A retrospective analysis was performed from April 1, 2006 to October 31, 2013 in our hospital and 128 lymphoma and MM patients whose autologous peripheral blood stem cells (PBSCs) were collected including 75 patients with malignant lymphoma,7 cases of Hodgkin's lymphoma and 68 non-Hodgkin's lymphoma (NHL) cases as well as 53 MM patients were enrolled. The stem cells of all patients were mobilized by chemotherapy combined with G-CSF and collected via a continuous flow cell separation instrument (COBE Spectra, Lakewood, CO). Mobilize failure was defined when the amount of CD34 + cells was less than 2.0 x 106 / kg, whereas ≥2.0 * 106 / kg was defined as successful mobilization. More than 5.0x 106 cells / kg or more was considrered as ideal mobilization. Univariate and multivariate regression analyses of factors for mobilization failure, successful mobilization and ideal mobilization acquisition were performed.
Results: There were more CD34+ cells in MM patients than in lymphoma patients (P = 0.064). The collection rates of CD34 + cells in MM patients were ≥ 2.0 x106 / kg in 64.8% (83 cases) and ≥ 5.0 x 106 / kg in 35.2% (45 cases). MM patients with a success collection ratio was 73.6 % (39/53) and the ideal collection rate was 43.4% (23/53), which was higher than in the NHL group with a success rate and ideal rate of 58.7% (44/75) and 30.7% (23/75). A total of 35.2 % (45 cases, including 31MM cases and 14 lymphoma cases) a mobilization was not successful.
Conclusion: In different chemotherapy regimens in patients with lymphoma, remission, ever use MTX and/or Ara-c treatment and collecting the outer peripheral hematocrit could significantly affect the success rate of stem cell collection; In MM patients, who received lenalidomide treatment and multiple courses of treatment, still not got CR, which these reasons were the factors of non- successful mobilization.Although Plerixafor and peripheral blood CD34-positive cell counts could help to improve the success collection rate and predict collection rate, but there is still a need for further improvement of the current mobilization protocols, recognizing the ideal stem cell collection dynamics, efficiency and cost in order to select the appropriate mobilization protocols.

Disclosures
No relevant conflicts of interest to declare.
Reconstitution of Memory T -Cells after Allogeneic Stem Cell Transplantation in Patients with Post-Transplantation Cyclophosphamide As Tolerance Induction
Authors: Vasilyeva Vera , Parovichnikova Elena N. , Kuzmina Larisa A. , Drokov Mikhail , Mikhaltsova Ekaterina , Koroleva Olga , Dubnyak Daria , Galtseva Irina , Savchenko Valeri G. 
Published: October 2019

Abstract
Introduction.
Nowadays high-dose post-transplantation cyclophosphamide (CY) replace standard immunosuppression (IST). Thereby, the investigation of T-cells reconstitution after post-transplant-CY doesn't reach appropriate level, and probably it's very different from what we see after standard IST. We studied the reconstitution of memory T-cells on day of engraftment (WBC>1000 cells\us) after allogenic hematopoietic stem cell transplantation (allo-HSCT) with post-transplant-CY and standard immunosuppression therapy.
Patients and methods.
During 2 years, 29 patients with different hematological malignancies were included in this study. Median of age was 36 years (24-60 years). 16 patients were males, 13 - females. 22 received RIC, 7 - myeloablative regime. Match unrelated donor (MUD) was in 17 cases, "Mismatch" MUD - 2, Match related donor (MRD) - 9, "Mismatch"MRD - 1. 4 patients were in relapse or disease progression. CY as alternative IST was administrated to 6 patients. Standard immunosuppression consisted of CSA, MMF or MTX at standard dose. Peripheral blood samples were collected in EDTA-tubes at day of engraftment after allo-HSCT (Me= 20 day (14-35)). Isolation of mononuclear cells from human peripheral blood was made by standard protocol using Lympholyte®-M Cell Separation Media (Cedarlane Labs). The anti-CD4- APC-Cy7 antibody (Becton Dickinson, USA) and FSC/SSC were used for determine population of CD4+T-cells. Anti-CD45R0- FITC (Becton Dickinson, USA) antibody were used to determine memory T-cells as subpopulation of CD4+ T-cells. Due to cyto- and lymphopenia 1,000,000 events was analyzed.
Results.
Mann-Whitney U test was used to test for differences between memory T-cells (CD4+ CD45R0+) after post-transplant-CY alone and in a group with standard IST. The percent of memory T-cells in CD4+ cell population at day of engraftment after post-transplant CY alone was statistically higher (74,3% ± 5,1% ,p=0.048*) than in patients with standard immunosuppression (49,4%±6,7%).
Conclusion.
We may conclude that patients with post-transplant CY had a different "T cell reconstitution profile". Reported data show us that probably post-transplant CY spares memory T-cells in contrast with standard IST, and also probably that CY is more selectively immunosuppressor than "gold standard" (such as CSA, MMF and etc.) not only on effector T-cells population. Despite the fact that the analyzed group is small, obtained data is important and needs further investigation.

Disclosures
No relevant conflicts of interest to declare.
Thymoglobulin Does Not Impact Relapse or Survival after Matched Unrelated Transplantation for AML/MDS Compared to Matched Related Donor Transplantation without Thymoglobulin Use
Authors: Khaled Yasser , Patel Rushang D. , Mori Shahram , Ahmed Wesam B. , Solh Melhem 
Published: October 2019

Abstract

Thymoglobulin does not impact relapse or survival after matched unrelated transplantation for AML/MDS compared to matched related donor transplantation without Thymoglobulin use.
Background: Thymoglobulin has been used customarily after matched related (RD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) to decrease risk of GVHD and graft rejection. However, its use has been implicated in increasing the risk of relapse. As matched sibling related donors considered the best available donor source for patients with AML /MDS, we hypothesized that production of outcomes (Relapse/Survival) after MUD transplant with use of thymoglobulin similar to RD transplantation without the use of thymoglobulin, would justify the use of thymoglobulin after MUD HCT in AML/MDS.
Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan based conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC) with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/Kg single daily dose for 4 days (AUC 4200-5000). GVHD prophylaxis for FIC was Tacrolimus/mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only regardless the conditioning intensity.
Results: With median follow up 696 days (RD 746 days, MUD 676 days), the overall survival at 1 year was 75% +/- 8% and 74% +/- 5% for RD and MUD respectively, P=0.66. All patient engrafted except two patients in FIC MUD group. The cumulative incidence of relapse at 1 year was 31% +/- 8% and 23% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) was 3.5% +/- 3% and 10% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-1V was 29% in RD and 49% in MUD. Grade III-IV acute GVHD was 14% in Both RD and MUD recipients. Higher cumulative incidence of extensive chronic GVHD was observed in MUD recipients of 28% vs 20% in RD recipients.
Conclusion: The addition of thymoglobulin to MUD HCT did not increase the cumulative incidence of relapse compared to RD HCT patients who did not receive thymoglobulin. RD HCT remained associated with lower TRM than MUD HCT despite the addition of thymoglobulin. MUD HCT with thymoglobulin produced similar overall survival to RD HCT without thymoglobulin. Our data suggest continued use of low dose thymoglobulin with MUD HCT while avoiding its use with matched RD HCT.Table 1.PatientsRelated DonorUnrelated DonorNumber2969AML2261MDS78Graft Failure02Age (Range)53 (35-71)56 (25-73)Reduced Intensity825Full Intensity2144CR11747CR245Relapsed/Refractory817

Disclosures
No relevant conflicts of interest to declare.