28 results on '"QIAN SUN"'
Search Results
2. High-Dose Idarubicin Plus Busulfan As Conditioning Regimen to Autologous Stem Cell Transplantation Improves Prognosis in Patients with Favorable and Intermediate-Risk AML
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Ming Hong, Wenjie Liu, Qian Sun, Sixuan Qian, and Jianyong Li
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. The Role of Metagenomics Next-Generation Sequencing (mNGS) in Early Diagnosis of Bloodstream Infection in Hematologic Patients with Febrile Neutropenia: A Multicenter Prospective Study
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Yu-Qian Sun, Jing-Rui Zhou, Yue Yin, Jian-Ping Zhang, Mei-Xiang Zhang, Yun He, and Xiao-Jun Huang
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. The Prognostic Significance of the Stage of Reaching MRD-Negative for Patients with Multiple Myeloma Received ASCT
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Qian Sun and Juan Li
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,MRD Negative ,Internal medicine ,medicine ,Stage (cooking) ,business ,Multiple myeloma - Abstract
Objective: To explore the prognostic significance of the stage of reaching MRD-negative for patients with newly diagnosed multiple myeloma (NDMM) patients who received autologous hematopoietic stem cell transplantation (ASCT). Methods: A retrospective analysis of 186 NDMM patients who received "induction therapy-ASCT-maintenance therapy" in our center and reached MRD-negative, according to the stage when the patient's MRD status turned negative (induction therapy, 3 months after ASCT, maintenance therapy) is divided into three stages, A, B, and C (Figure 1). We compared the clinical characteristics and prognosis of patients in the three stages. Results: The median time to progress (TTP) of 186 patients was not reached, the median overall survival (OS) was 113.8 months, and the median follow-up time was 67.6 months; the number of cases in the three stages of A, B, and C was 73 (39.2%), 42 (22.6%), and 71 (38.2%), respectively (Figure 2). The median TTP of the patients in the three stages was not reached (P=0.013), and the median OS was not reached, not reached, and 71.2 months, respectively (P=0.026). Among the 124 standard-risk cytogenetics patients, the median TTP of the three stages of patients was not reached (P=0.121), and the median OS was not reached, not reached, and 99.6 months, respectively (P=0.091) (Figure 3). Among the 38 high-risk cytogenetics patients, the median TTP of patients in the three stages were unreached, 53.9 months, and 35.8 months (P=0.060), and the median OS was not reached, 71.2 months, and 60.2 months (P=0.625) (Figure 4). Among the 157 R-ISS Ⅰ-Ⅱ patients, the median TTP of the three stages was not reached (P=0.174), and the median OS was not reached, not reached, and 99.6 months (P=0.186) (Figure 5). Among 29 cases of R-ISS Ⅲ, the median TTP of the 3 stage patients was unreached, unreached, and 35.1 months (P Conclusion: For the same patients with MRD negative, the prognosis of patients reaching MRD-negative at different stages is different. The stage of reaching MRD-negative can predict the prognosis of patients with R-ISS stage Ⅲ, but cannot predict the prognosis of patients with R-ISS Ⅰ-Ⅱ. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
5. Prevalence and Risk Factors of Antibodies to Class I and II Human Leukocyte Antigens in Haploidentical Allograft Candidates: A Prospective Study on 3805 Subjects
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Xiao-Hui Zhang, Lan-Ping Xu, Fei-Fei Tang, Yu Wang, Ying-Jun Chang, Chen-Hua Yan, Kai-Yan Liu, Huan Chen, Wei Han, Ning Ma, Yu-Qian Sun, Yan-Rong Liu, Xiao-Dong Mo, and Xiao-Jun Huang
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biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biochemistry ,Class (biology) ,biology.protein ,Medicine ,Antibody ,business ,Prospective cohort study - Abstract
The aim of this study is to investigate the prevalence and risk factors of anti-human leukocyte antigen (HLA) antibodies in haploidentical candidates. This study was completed at Peking University People's Hospital, Beijing China. We performed a prospective analysis of patients with hematological diseases concerning the prevalence and risk factors of anti-HLA antibodies. Patients were enrolled between July 2015 - December 2019. Serum was collected for PRAs test within 1 month before haploidentical transplantation. The risk factors, such as age, sex, total transfusion, red blood cell (RBC) transfusion, platelet (PLT) transfusion, pregnancy, disease duration and diagnosis were collected. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factors of anti-HLA antibodies. Six hundred and eighty (17.9%) patients were positive for panel reactive antibodies (PRA)-class I, 360 (9.5%) for class II, 768 (20.2%) class I or II, and 272 (7.1%) positive for class I and II both. Multivariate analysis indicated that female was related to higher risk of having PRAs for class I (P = 0.011), class I or II (P = 0.009), anti-HLA-A (P = 0.015), anti-HLA-DP (P = 0.048) and also for having higher mean fluorescence intensity (MFI) (2000 or more) of PRAs in class I (P = 0.020) and class I or II (P = 0.005). Compared to patients with myelodysplastic syndrome (MDS), patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), aplastic anemia (AA) had a lower incidence for PRAs in class I, class II, class I or II, class I and II, anti-HLA-A. anti-HLA-B, anti-HLA-C, anti-HLA-DQ, anti-HLA-DR, anti-HLA-DP (Table 1). Prior pregnancy was a risk factor for PRAs (P < 0.001), and no previous pregnancy group having lower MFI of PRAs in class I (P = 0.001) and class I or II (P = 0.004). PLT transfusion (more than 4 times) rleted with a higher prevalence of PRAs (P < 0.001), and also had a higher MFI of PRAs in class II (P < 0.001), class I and II (P < 0.001). Patients with RBC transfusion (more than 3 times) had a higher prevalence of PRAs in class I (P = 0.001), class II (P = 0.029), class I or II (P < 0.001), anti-HLA-A (P = 0.001), anti-HLA-B (P < 0.001), anti-HLA-C (P = 0.007), anti-HLA-DQ (P < 0.001) and anti-HLA-DR (P = 0.011). In addition, diseases duration (8 months or more) was also associated with higher MFI of PRAs in class I (P = 0.023) and class I or II (P = 0.004). Subgroup analysis showed that 11.7% of pediatric patients were positive for PRAs in class I; 19.2% of adults, 17.9% of elder patients; 12.4% of males; 26.1% of females; 21.0% of patients with AML; 10.5% of patients with acute lymphoblastic leukemia (ALL); 18.9% of patients with AA; 30.3% of patients with MDS; 16.6% of patients with other hematological diseases. The positive rate of class II PRAs in children was 4.3%; 11.1% for adults; 9.5% for elder patients; 5.5% for males; 15.4% for females; 11.4% for patients with AML; 5.2% for patients with ALL; 10.3% for patients with AA; 17.2% for patients with MDS; 6.6% of patients with other hematological diseases. Multivariate analysis showed that, in children, PLT transfusion and diagnosis were the two main risk factors of PRAs in class I and class II (P < 0.001, P = 0.017). In adults, diagnosis (P = 0.003), transfusion (P < 0.001) and pregnancy (P < 0.001) were the three main factors associated with PRAs in class I and transfusion (P < 0.001) and pregnancy (P < 0.001) were the two main factors associated with PRAs in class II. In males, PLT transfusion (P < 0.001) and diagnosis (P < 0.001) were the two main factors associated with PRAs in class I and class II. In ALL subgroup, gender (P = 0.026, P = 0.048), pregnancy (P < 0.001) and transfusion (P < 0.001) were the three main factors associated with PRAs in class I and II. In AA subgroup, gender (P = 0.004) and PLT transfusion (P < 0.001) were risk factors for class I PRAs, pregnancy (P = 0.008) and PLT transfusion (P = 0.003) were risk factors for class II PRAs. In elder patients, females, AML, MDS and other diseases subgroup, transfusion and pregnancy were the two main factors associated with PRAs in class I and class II. Our results indicated that female sex, diagnosis, pregnancy, transfusion, disease duration were independent risk factors of anti-HLA antibodies in haploidentical allograft candidates, which provided evidence for best haploidentical donor selection. The risk factors of anti-HLA antibodies were different among total patients and those of cases in different subgroups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
6. The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation
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Chen-Hua Yan, Zhi-Dong Wang, Zhao Xiangyu, Xiao-Jun Huang, Yu Wang, Jing-Zhi Wang, Jun Kong, Gao Mengge, Yan Hong, Feng-Rong Wang, Yu-Qian Sun, and Xiao-Su Zhao
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medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biology ,medicine.disease ,Biochemistry ,Pathogenesis ,surgical procedures, operative ,Graft-versus-host disease ,medicine ,Invariant (mathematics) - Abstract
Background & Purpose: Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAITs) are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT in the occurrence of gut aGVHD in the human body. Methods & Cases: In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells (MAITs) and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyse the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAITs. The number and distribution of MAITs in intestinal tissues were analysed by immunofluorescence technology. We prospectively studied the enrolled 150 consecutive patients who underwent allo-HSCT in our institute. Results: The number and frequency of MAITs in infused grafts in gut aGVHD patients were lower than those in non-gut aGVHD patients (Figure). Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early post-transplantation period (+14 days). At the onset of gut aGVHD, the number of MAITs decreased in peripheral blood, and the activation marker CD69, chemokines CXCR3 and CXCR4 and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAITs secreted more granzyme B, TNF-α and IFN-γ under the stimulation of IL-12/IL-18 (non-TCR signal) and secreted most of the IL-17 under the stimulation of CD3/CD28 (TCR signal). MAITs inhibited the proliferation of CD4+ T cells in vitro. Conclusions: In conclusion, the lower number of MAITs in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAITs in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAITs and promoted the secretion of intestinal protective factors to affect the occurrence of gut aGVHD in humans. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
7. The Prognosis of Intermediate- and High-Risk Young AML Patients Who Did Not Receive Allo-HSCT Treated with Intensive Chemotherapy Is Not Superior to That of Elderly AML Patients Treated with the D-CAG Regimen
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Jianyong Li, Wenjie Liu, Yu Zhu, Han Zhu, Ming Hong, Qian Sun, and Si-Xuan Qian
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Allo hsct ,Cell Biology ,Hematology ,Intensive chemotherapy ,CAG regimen ,business ,Biochemistry - Abstract
Introduction: AML is an extremely heterogenous disease which poses fundamental challenges in developing effective treatment regimens, while simultaneously highlighting the critical need for more personalized therapy. This investigation explores AML patients who would benefit the most from the relatively low intensive regimen D-CAG or intensive therapy. Methods: A total of 331 patients with AML who were treated with intensive chemotherapy (young patients, n=179) or D-CAG regimen (older patients, n=152) were enrolled in this study.The young patients received IA regimen (idarubicin 10-12 mg/m 2 on days 1 to 3 and cytarabine 100 mg/m 2/d on days 1 to 7) as induction. A total of 37 patients were recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 27 patients were recipients of autologous HSCT. Patients who were unsuitable for HSCT were subjected to post-remission therapy consisting of 2-4 courses of intermediate to high dose cytarabine (cytarabine 2-3 g/m 2 twice daily on days 1-3). The D-CAG regimen (decitabine 15 mg/m 2 intravenously on days 1-5, cytarabine 10 mg/m 2 subcutaneous injection twice daily on days 3-9, aclarubicin 8-10 mg/m 2/d on days 3-6, and G-CSF 300 μg/d for priming until white blood cell count was >20×10 9/L) was given to the older patients. An additional 4-6 cycles of D-CAG were administered to those who achieved CR. Those who failed to obtain CR after two cycles of D-CAG were given the option of palliative care or alternative treatments. None of the patients in this subgroup received allo- or auto-HSCT.Clinical outcomes were retrospectively analyzed for patients belonging to the two treatment arms. Results: The median age was 67 (range, 60 to 86 years) and 36 years (range, 14 to 59 years) in D-CAG and IA cohort, respectively. In the D-CAG cohort, there were significantly more patients demonstrating an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2-3 in contrast to the IA cohort (17.1% vs. 2.2%, P< 0.0001). Conventional cytogenetic examination was conducted in all patients. However, sufficient metaphase data was not available for 15 of these patients. Based on the 2017 ELN cytogenetic risk classification, patients were risk stratified based on the presence of molecular and cytogenetic aberrances upon diagnosis. A total of 114 patients (34.4%) were determined to possess favorable-risk, 106 patients (32.0%) were intermediate-risk and 96 patients (29.0%) were poor-risk. There were significantly more patients in the favorable-risk category and less in the poor-risk category in the IA cohort as in contrast to the D-CAG cohort (favorable-risk: 47.5% vs. 19.1%, P< 0.0001; poor-risk: 21.2% vs. 38.2%, P=0.001). Older patients harbored significantly more complex, monosomal karyotypes and abnormalities in chromosomes 5 and/or 7 (-5/5q- and/or -7/7q-) in comparison to young patients. Clinical features of gender, white blood cell (WBC), hemoglobin and platelet count at diagnosis as well as percentage of blasts in bone marrow, were similar between the two cohorts. Our data revealed that the young patients had significantly better complete remission (CR) rate (80.4% vs.67.1%, P=0.0051) and median overall survival (OS) (38 vs. 15 months, P Conclusions: Intensive chemotherapy had little effect on the prognosis of intermediate- or high-risk young patients who did not undergo allo-HSCT. Patients harboring FLT3-ITD, DNMT3A, IDH2, TP53 and DNA methylation associated mutations were found to benefit more from the D-CAG regimen in comparison to intensive chemotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
8. Superiority of Leukemic Stem Cell-Based Minimal Residual Disease Assay to Traditional Multiparameter Flow Cytometry-Based Method for Relapse Prediction in AML Patients: A Prospective Study with Randomized Training and Validation Sets
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Ying-Jun Chang, Huan Chen, Wei Han, Xiao-Hui Zhang, Xiao-Dong Mo, Feng-Rong Wang, Yu-Hong Chen, Fei-Fei Tang, Yu-Qian Sun, Meng Lyu, Lan-Ping Xu, Yu Wang, Xiao-Jun Huang, Chen-Hua Yan, Kai-Yan Liu, and Si-Qi Li
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Minimal residual disease ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Leukemic Stem Cell ,Multiparameter flow cytometry ,business ,Prospective cohort study - Abstract
Background: Minimal/measurable residual disease (MRD) determined by multiparameter flow cytometry (MFC) is an important variable for relapse prediction and treatment approach selection in patients with acute myeloid leukemia (AML). We aimed to investigate whether leukemia-stem cell (LSC)-based assay is superior to traditional MFC methods, including LAIP and D-F-N assays, for MRD evaluation in predicting clinical outcomes. Methods: In this cohort study, a total of 360 AML patients who received allogeneic stem cell transplantation (allo-SCT) between July 2018 and November 2019 were prospectively enrolled. The patients were randomized (1:1) and classified into a training set (n=180) and a validation set (n=180). Posttransplantation MRD were according to LSC based assay, mainly including a cocktail of CD7, CD11b, CD22, CD56, Tim-3, and CLL-1 on CD34 +CD38 - cells, and traditional assay determined by MFC, respectively. Findings: In the training set, patients were classified as LSC positive group (group A) and LSC negative group (group B) according to a cutoff value of CD34 +CD38 -cocktail + LSCs as 0.004%. Subjects in group A had a higher cumulative incidence of relapse (CIR, 42.7% vs. 2.6%, P Interpretation: Our data suggest the superiority of LSC-based MRD assays such as higher sensitivity, low false negativity, and longer time for MRD positivity to relapse to traditional MFC MRD methods for outcome prediction in AML patients received allograft. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
9. An Accurate Prognostic Index Model for Adult HLH (HHLWG-HPI): A Multicenter Retrospective Analysis in China
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Kailin Xu, Wei Sang, Yingliang Jin, Qian Sun, Ziyuan Shen, Jianlin Qiao, Shuiping Huang, and Linyan Xu
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medicine.medical_specialty ,Index (economics) ,business.industry ,Internal medicine ,Immunology ,medicine ,Retrospective analysis ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cut-off points of continuous variables; univariate and multivariate Cox analysis were used for variables selection, and Kaplan-Meier curve was used to analyze the value of variables on prognosis. The C-index, brier score and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in derivation and validation cohort by using bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
10. Comparison of Transplant Donor and Third-Party Donor Derived CMV-Specific T Cells for CMV Infection after Allogenic Stem Cell Transplantation
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Meng Lv, Xuefei Liu, Xiao-Dong Mo, Lan-Ping Xu, Xiao-Jun Huang, Xiao-Hui Zhang, Yu Wang, Ying-Jun Chang, Xu-Ying Pei, Yu-Qian Sun, and Xiang-Yu Zhao
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Transplantation ,Third party ,business.industry ,Immunology ,Medicine ,chemical and pharmacologic phenomena ,Donor derived ,Cell Biology ,Hematology ,Stem cell ,business ,Biochemistry - Abstract
Background: Cytomegalovirus (CMV) infection is a major and potentially life-threatening complication after allogenic hematopoietic stem cell transplantation (allo-SCT). Adoptive transfer of CMV-specific T cells (CTL) from original transplant donor or third-party donor has both emerged as an effective method for CMV infection after allo-SCT. The potential advantages of third party CTL versus transplant donor CTL includes that it is not limited by donor viral immune and can be banked in advance for clinical use. However, as the expansion and persistent of transfused third-party CTL in vivo was considered to be shorter when compared with donor CTL, can third-party CTL provide comparable long-term antiviral efficacy as transplant donor CTL? In fact, the safety and efficacy of these two kinds of CTL have not been compared directly. In addition, the mechanisms driving sustained antiviral immunity induced by these two kinds of CTL remains to be established and compared. Methods: i) We established humanized CMV-infected mouse model and tumor-infiltration mouse model, and compared the antiviral ability of transplant donor and third-party donor derived CTL for CMV infection in mouse models. We comparatively investigated the in vivo recovery of CMV-specific immunity and analyzed the underlying mechanisms driving sustained antiviral immunity induced by these two types of CTL therapy. ii) We collected data from 31 patients who received third-party CTL and selected matched pairs of 62 patients who received donor CTL for refractory CMV infection after allo-SCT, and compared the safety and efficacy of these two kinds of CTL for CMV infection in clinical patients. We also track the infused CTL populations and evaluated the recovery of virus-specific immunity in clinical patients after donor and third-party CTL therapy. Results: i) In mouse models, we observed that adoptively infused donor and third-party CTL could both migrated to the virus or tumor infiltration organs, and contributed to comparable diminishing in CMV pathology and viral burden in target organs. The kinetics of CMV-specific immunity recovery was comparable in donor and third-party CTL group, which further conferred the comparable antiviral response of these two kinds of CTL for CMV infection. When performed a detailed analysis of the recovered source of CTL, we observed a preferential proliferation and expansion of graft-derived endogenous CTL in both donor and third-party CTL therapy group. ii) In clinical patients, adoptive therapy with donor or third-party CTL had comparable clinical response without significant therapy-related toxicity. The cumulative CR rates at 4 th weeks after CTL infusion was 80.6% in donor group and 83.1% in third-party group. We also observed strong expansion of CD8 + tetramer + T cells both after donor and third-party CTL infusion, which were associated with a reduced or cleared viral load. Conclusion:Adoptive therapy with transplant donor or third-party CTL had comparable antiviral response for CMV infection by promoting the restoration of CMV-specific immunity. Our data suggest that both transplant donor or third-party CTL may stimulate the recovery of graft-derived endogenous CMV-specific immunity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
11. The Prognostic Significance of Wilms' Tumor Gene 1 in Adult AML with Different Risk Stratification Following Allo-HSCT
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Xiao-Jun Huang, Chen-Hua Yan, Yu-Qian Sun, Yu Wang, Xiao-Su Zhao, Ke Wang, and Songhai Zhou
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Receiver operating characteristic ,business.industry ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Wilms' tumor ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Transplantation ,Leukemia ,Internal medicine ,medicine ,Cumulative incidence ,business - Abstract
INTRODUCTION: Wilms' tumor gene 1 is a "pan-leukemic marker" for evaluating measurable residual disease (MRD) in leukemia. The prognostic value in prediction of relapse following chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been recognized. However, there lack relevant guidelines for WT1 gene quantification as a MRD assessment for patients with acute myeloid leukemia (AML) undergoing allo-HSCT. The optimal monitoring time and threshold of WT1 expression level for MRD assessment following allo-HSCT are still unclear. METHODS: We retrospectively investigated the dynamic change of WT1 expression level in bone marrow in 151 adult patients with AML following allo-HSCT. All patients were divided into two subgroup including complete remission (CR) and non-remission (NR), which was based on the disease status before HSCT. WT1 expression levels were compared between two subgroups. Meanwhile, Receiver operating characteristic (ROC) curve analysis was performed on WT1 expression levels at different time points and the highest value of WT1 before relapse-related intervention to find the cutoff values for relapse prediction. Furthermore, the cutoffs were tested by cumulative incidence of relapse (CIR), overall survival (OS) and disease-free survival (DFS), which were analyzed through the Kaplan-Meier method. RESULTS: Compared with complete remission (CR) subgroup, non-remission (NR) subgroup has a trend of a higher expression baseline and a rapidly increasing from 2 to 3 months after allo-HSCT. ROC curve analysis results showed that 0.6% was the optimal cutoff value for relapse prediction at 3 months after allo-HSCT. The cutoff level 0.6% was effective in identifying patients in CR and NR group. Among the patients with CR status (n=131), patients with WT1≥0.6% had a significantly higher 5-year cumulative incidence of relapse (CIR, 27.3% vs. 6.0%; p=0.006), than patients with WT10.05). Moreover, ROC analysis was performed using the highest value of WT1 before relapse-related intervention, which showed that 2.25% was the upper threshold for predicting relapse after transplantation. The upper cutoff 2.25% was only effective in CR group. In CR group, patients with WT1≥2.25% had a significantly higher 5-year cumulative incidence of relapse (CIR, 100% vs. 7.1%; p CONCLUSION: Our results suggest that the relapse predictive WT1 level is different in patients with different risk stratification before HSCT and the 3th months after allo-HSCT is the most meaningful time point for WT1-based MRD monitoring and relapse intervention. Different intervention thresholds should be used according to the pre-transplant disease status. Patients in NR before transplant should strictly use 0.6% as the threshold, while for patients in CR can be appropriately widened. Disclosures No relevant conflicts of interest to declare.
- Published
- 2020
12. Atorvastatin enhances endothelial cell function in posttransplant poor graft function
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Xiao-Hui Zhang, Min-Min Shi, Yuan Kong, Xiao-Jun Huang, Kai-Yan Liu, Yu-Qian Sun, Yu Wang, Yang Song, and Lan-Ping Xu
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Male ,0301 basic medicine ,Angiogenesis ,Antigens, CD34 ,Cell Count ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,0302 clinical medicine ,Bone Marrow ,Atorvastatin ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Cells, Cultured ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Endothelial stem cell ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,embryonic structures ,cardiovascular system ,Female ,lipids (amino acids, peptides, and proteins) ,Stem cell ,circulatory and respiratory physiology ,Adult ,endocrine system ,medicine.medical_specialty ,Adolescent ,Immunology ,Colony-Forming Units Assay ,Young Adult ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Progenitor cell ,Protein Kinase Inhibitors ,business.industry ,Endothelial Cells ,Cell Biology ,Transplantation ,030104 developmental biology ,Endocrinology ,Case-Control Studies ,Bone marrow ,Reactive Oxygen Species ,business - Abstract
Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant.
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- 2016
13. Haploidentical Hematopoietic Stem Cell Transplantation May Improve Prognosis in Non-Infant Children with t(v;11q23)/MLL-Rearranged B-Acute Lymphoblastic Leukemia
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Pan Suo, Huiren Chen, Yu Wang, Xiao-Jun Huang, Yu-Hong Chen, Chen-Hua Yan, Ai-Dong Lu, Yue-Ping Jia, Wei Han, Yi-Fei Cheng, Lan-Ping Xu, Xiang-feng Tang, Kai-Yan Liu, Jun Wu, Huan Chen, Jing-Bo Wang, Ying-Xi Zuo, Le-Ping Zhang, Yu-Qian Sun, and Lu Bai
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Lymphoblastic Leukemia ,Immunology ,Allopurinol ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,surgical procedures, operative ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Allogeneic hematopoietic stem cell transplant ,B Acute Lymphoblastic Leukemia ,business ,Burkitt's lymphoma ,Neoadjuvant therapy ,medicine.drug - Abstract
Background: B-acute lymphoblastic leukemia (B-ALL) with t(v;11q23)/MLL-rearrangement (MLL-r) in children (1 year or older) is rare, and its outcome and optimal treatment options remain controversial. This study aimed to analyze the clinical characteristics and outcomes of these patients, and to explore the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially haploidentical HSCT (haplo-HSCT) in the treatment of these patients. Methods: At the time of the last follow-up (July 1, 2019), we retrospectively analyzed clinical data of 42 non-infant children with t(v;11q23)/MLL-r B-ALL. Comparison of outcomes was made between patients received allo-HSCT in the first complete remission (CR1) and chemotherapy only. Results: The median follow-up was 41 (1-106) months. The median age at diagnosis was 4.5(1-14) years and the median leukocyte count was 56.0 (2.2-735.2)×109/L. One was excluded for death during induction. For the remaining 41 patients, the complete remission rate after induction therapy was 40/41 (97.6%), the estimated 4-year probabilities of overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 59.7%, 51.6% and 43.4%, respectively. 19 patients received allo-HSCT in CR1 (HSCT in CR1 cohort), notably, 18/19 cases in this cohort received haplo-HSCT, and the remaining 22 patients continued the consolidation therapy (Non-HSCT in CR1 cohort). The estimated 4-year probabilities of OS, EFS and CIR in the HSCT in CR1 cohort were 86.6%, 89.2% and 5.3%, respectively. Meanwhile, the estimated 4-year probabilities of OS, EFS and CIR in the Non-HSCT in CR1 cohort were 37.5%, 19.9% and 75.6%, respectively. They were considered to be statistically significant. Of the 17 patients who relapsed during consolidation chemotherapy, 9 patients who underwent chemotherapy only (Non-HSCT after relapse cohort) all died within 44 months. For the remaining 8 patients who chose allo-HSCT (HSCT in CR2 cohort) when they achieved the second complete remission (CR2), the estimated 4-year probability of OS was 47.6% (P=0.002). Multivariate analysis showed that HSCT in CR1 was the only independent protective factor for OS, EFS and CIR, and age at diagnosis (≥10 years) was an independent risk factor of OS. Conclusions: Allo-HSCT (especially haplo-HSCT) in CR1 may reduce the risk of relapse and improve prognosis in non-infant children with MLL-r B-ALL. In addition, allo-HSCT also seemed to be an effective approach to improve the prognosis of relapsed patients. Thus, haplo-HSCT could be an alternative approach for non-infant children with MLL-r B-ALL. Disclosures No relevant conflicts of interest to declare.
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- 2019
14. Rituximab for Desensitization during HLA-Mismatched Stem Cell Transplantation in Patients with a Positive Donor Specific Anti-HLA Antibody: A Prospective Study
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Chen-Hua Yan, Yu Wang, Huan Chen, Wei Han, Xiao-Jun Huang, Xiao-Hui Zhang, Ming-Rui Huo, Lan-Ping Xu, Yu-Hong Chen, Feng-Rong Wang, Xiao-Dong Mo, Kai-Yan Liu, Ying-Jun Chang, Yu-Qian Sun, Fei-Fei Tang, and Xiang-Yu Zhao
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business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Biochemistry ,Transplantation ,Medicine ,Rituximab ,In patient ,Stem cell ,business ,Prospective cohort study ,medicine.drug ,Desensitization (medicine) - Abstract
A prospective, clinical trial in non-manipulated haploidentical allografts was initiated to define the efficacy of a single dose of 375 mg/m2 rituximab as a desensitization regimen for donor-specific anti-HLA antibody (DSA)-positive patients with 2,000 ≤ mean fluorescence intensity (MFI) < 10,000. In the clinical cohort, compared to pretransplantation [median, 4791, n=28], the median MFI levels at day 7 [0], 14 [0], 21 [0], 30 [0], and 45 [0] following transplantation were significantly decreased (P This study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
15. The Low Number of Mucosal-Associated Invariant T Cells in the Graft Was Associated with Occurrence of Gut Graft-Versus-Host Disease
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Xiao-Su Zhao, Yu Wang, Gao Mengge, Yan Hong, Jun Kong, Xiao-Jun Huang, Chen-Hua Yan, Yu-Qian Sun, and Zhi-Dong Wang
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Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Mucous membrane ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Mucosal associated invariant T cell ,medicine.disease ,Biochemistry ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Graft-versus-host disease ,Intestinal mucosa ,immune system diseases ,medicine ,Bone marrow ,Stem cell ,business - Abstract
Background & Purpose: Gut graft-versus-host disease (GVHD) is a serious complication after hematopoietic stem cell transplantation (HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAIT) are a group of innate-like T cells enriched in the intestine, which may alter the composition of the intestinal microflora or exert a certain immunomodulatory effect to protect the intestinal mucosa from further damage for the inflammatory response. However, little is known about the regulatory role of MAIT cells in development and progression of gut GVHD. Infused MAIT in grafts will facilitate the reconstruction of MAIT after transplantation. Thus, we aimed to investigate the correlation between the number of MAIT cells in the graft and the occurrence of gut GVHD. Methods & Cases: Our transplantation setting used the graft composed of bone marrow stem cells (BMSC) and peripheral blood stem cell (PBSC). We prospectively studied 60 patients undergoing allo-HSCT and 9 healthy donors in our institute. In our study, the number of MAIT cells in the graft was evaluated by multiparameter flow cytometry (FCM). MAIT cells were defined as a group of cells expressing CD3+CD161hiVa7.2+. To better compare the specific changes in the number of MAIT cells in the graft in groups of healthy donors, no GVHD patients, skin GVHD patients, and gut GVHD patients, we chose a group of non-MAIT cells that express CD3+CD161-Va7.2+ as a reference(Fig.1A). We compared the number and frequency of MAIT and non-MAIT cells in the 4 groups. Results: In the 60 transplanted patients, 9 patients developed into gut GVHD and 6 patients developed into skin GVHD. In patients with gut GVHD, the frequency of MAIT cells in the graft of PBSC was lower compared to that of no GVHD (No GVHD vs. gut GVHD, P=0.045. Fig.1B), but no difference was detected in the graft of BMSC among these groups (No GVHD vs. gut GVHD, P=0.191; Healthy vs. gut GVHD, P=0.298; Skin GVHD vs. gut GVHD, P=0.071. Fig.1C). The total number of infused MAITs in the graft of gut GVHD patients was significantly lower than that of no GVHD and skin GVHD patients (no GVHD vs. gut-GVHD, P=0.001. Fig.1D). In addition, the frequency and number of MAIT cells in the graft were not different between no GVHD and skin GVHD patients (P>0.05, Fig.1B, C and D). Finally, in the graft of patients with no GVHD, skin GVHD and gut GVHD, the difference in the frequency and number of non-MAIT cells was not significant (all P>0.05, Fig.1E and Fig.1F). Conclusions: In conclusion, gut GVHD was more likely to occur in patients who were infused with a smaller number of MAIT cells in grafts. In addition, the number of MAIT cells in the graft had no significant correlation with the occurrence of skin GVHD. These results suggested the potential functional effects of MAIT cells on gut GVHD. However, the specific biological role of MAIT cells in maintaining the homeostasis of intestinal tract and how MAIT cells would influence the onset of gut GVHD are still unclear. It may function through direct immunosuppression or regulation of intestinal microflora, which needs to be confirmed by further mechanical studies. Figure 1 Disclosures No relevant conflicts of interest to declare.
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- 2019
16. Sarcopenia As a Significant Prognostic Factor in Acute Myeloid Leukemia: Validation of a Novel Scoring System
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Jianyong Li, Qian Sun, Hong Ming, and Si-Xuan Qian
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Prognostic factor ,Scoring system ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,musculoskeletal system ,medicine.disease ,Biochemistry ,Giemsa stain ,Leukemia ,Sarcopenia ,Cancer research ,Medicine ,medicine.symptom ,business ,Myopathy ,human activities ,Protein p53 - Abstract
Background: Acute myeloid leukemia (AML) is a malignant hematologic disease mainly occurs in the elderly. Sarcopenia is a muscle disease (muscle failure) common among adults of older age but can also occur earlier in life. This study indicates to investigate the prognostic value of sarcopenia in AML patients. Methods: From January 2014 to April 2019, a total of 100 patients diagnosed with de novo AML according to the WHO classification were included in this study. Clinical data and biological characteristics were collected. Giemsa R-banding method was used to detect the karyotype of metaphase bone marrow cells. Targeted gene sequencing was taken to test a total of 23 gene mutations including DNMT3A, IDH1, IDH2, ASXL1, RUNX1, NPM1, CEBPA, FLT3, KIT, and TP53, etc. Bioelectrical impedance analysis (BIA) of human body before treatment was used to calculate the Body Mass Index (BMI), Appendicular Skeletal Muscle Mass (ASM), SMI (ASM/height2), Fat Mass (FM), Fat-free Mass (FFM), and FFMI (FFM/height2), etc. The diagnosis of sarcopenia was based on the consensus report of the Asian Working Group for Sarcopenia. Results: Sixteen AML patients were diagnosed as sarcopenia. Patients with sarcopenia had significantly lower weight (P=0.049), BMI (P=0.039), ASM (P=0.002), SMI (P Conclusion: Sarcopenia is common in AML patients, and BIA offers a useful objective tool for identifying these patients. We illustrated a marked clinical impact of sarcopenia on patients with AML, and presented a novel prognostic scoring system. In elderly patients, the presence of sarcopenia before treatment may offer a useful factor for avoiding intensive therapeutic strategies for AML. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
17. Myeloid-Derived Suppressor Cells (HLA-DR-/lowCD16-CD33+) Expanded By Granulocyte Colony-Stimulating Factor Can Prevent Acute Graft-Versus-Host Disease in Humanized Mouse and Patients Following HSCT
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Pan Suo, Zhi-Dong Wang, Yan Hong, Ke Wang, Yu Wang, Dan Liu, Yuan-Yuan Zhang, Xiang-Yu Zhao, Meng Lv, Lan-Ping Xu, Shu-Zhen Zhai, Xiao-Su Zhao, Xiao-Jun Huang, Yu-Qian Sun, Yang Zhou, Xiao-Hui Zhang, Kai-Yan Liu, and Ying-Jun Chang
- Subjects
education.field_of_study ,business.industry ,medicine.medical_treatment ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Colony-stimulating factor ,Biochemistry ,Granulocyte colony-stimulating factor ,Graft-versus-host disease ,Humanized mouse ,medicine ,Myeloid-derived Suppressor Cell ,Stem cell ,business ,education - Abstract
Introduction Myeloid-derived suppressor cells (MDSCs) are proposed to control graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the definition of human MDSCs has not yet reached consensus. Granulocyte colony-stimulating factor (G-CSF) has been routinely used to mobilize stem cells to peripheral blood in healthy donors. It was also recognized as a novel mediator of T-cell tolerance. However, the effects of G-CSF administration on donor-derived MDSCs and the further regulatory effects of these MDSCs on GVHD remained unclear. Amis The aim of this study is to evaluate the in vitro and in vivo effects of G-CSF expanded, donor-derived MDSCs (HLA-DR-/lowCD16-CD33+) in preventing acute GVHD after allo-HSCT. Methods The frequency and cell numbers of different kinds of MDSCs in peripheral blood before and after G-CSF administration from 10 healthy donors were analyzed by flow cytometry. Cells morphological features were detected by May-Grünwald-Giemsa cytospin. Secondly, the suppressive and regulatory functions of HLA-DR-/lowCD16-CD33+ population on CD3+ T cells were assessed via in vitro experiments. A humanized xenogeneic acute GVHD model was established to determine whether this population could prevent acute GVHD in vivo. Furthermore, a clinical prospective cohort study enrolled one hundred consecutive transplant recipients was performed to assess the effects of HLA-DR-/lowCD16-CD33+ contained in HSC grafts on the occurrence of acute GVHD. Results The findings of this study include: First, a novel phenotype of HLA-DR-/lowCD16-CD33+ MDSCs with suppressive function and morphological features similar to those of immature monocyte was identified. The median of percentages of this subset were significantly increased both in peripheral blood (PB, 6.5% vs. 4.6%, P=0.0122) and peripheral blood stem cells harvest (PBSCs, 15.5% vs. 4.6%, P Conclusion Our results suggest that MSDCs with HLA-DR-/lowCD16-CD33+ phenotype in G-CSF-mobilized PBSCs have monocytic features and immune-regulatory properties, which could alleviate acute GVHD in the allo-HSCT settings. Key words: Myeloid-derived suppressor cells; granulocyte colony-stimulating factor; graft-versus-host disease Figure Figure. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
18. Prophylactic Intervention with N-Acetyl-L-Cysteine before Allotransplant Could Reduce the Occurrence of Poor Hematopoietic Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation
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Lan-Ping Xu, Min-Min Shi, Yu Wang, Xiao-Hui Zhang, Yu-Qian Sun, Ying-Jun Chang, Yuan-Yuan Zhang, Kai-Yan Liu, Xiao-Dong Mo, Xiao-Jun Huang, and Yuan Kong
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medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Allopurinol ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Pancytopenia ,Acetylcysteine ,Haematopoiesis ,medicine.anatomical_structure ,Biopsy ,medicine ,Cancer research ,Platelet ,Bone marrow ,business ,medicine.drug - Abstract
Background Poor hematopoietic reconstitution including poor graft function (PGF), characterized by pancytopenia, and prolonged isolated thrombocytopenia (PT), defined as the engraftment of all peripheral blood cells other than platelets, remains a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the clinical management is challenging. Endothelial cells (ECs) play a crucial role in regulating hematopoiesis in bone marrow (BM) microenvironment. N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger, is clinical used as a mucolytic drug. In this regard, we reported that PGF and PT patients had impaired BM ECs post-HSCT (BBMT 2013; BMT2016;Blood 2016; AJH2018). Recently, we reported in vitro treatment with NAC could improve the defective HSCs through repairing the impaired BM ECs of PGF and PT patients (Blood 2016; AJH2018). However, our previous studies evaluated BM ECs in PGF and PT patients at +3 month(M) post-HSCT. Therefore, whether BM ECs dysfunction in PGF and PT patients is responsible for the defective hematopoiesis, or vice versa, requires to be further clarified. Moreover, prophylactic intervention to improve the impaired BM ECs and HSCs remains unidentified. Aims In order to investigate whether the defective BM ECs pre-HSCT is the risk factor for the occurrence of PGF and PT post-HSCT. Moreover, to evaluate whether prophylactic NAC intervention could repair the impaired BM ECs and reduce the incidence of PGF and PT. Methods Two registered prospective clinical trials were included. The first trial compared the dynamic reconstitution of the BM ECs pre- and post-HSCT among PGF, PT, and good graft function (GGF) patients at Peking University People's Hospital. Multivariate analyses were performed to identify the risk factors for the occurrence of PGF and PT. Receiver operating characteristic (ROC) curves were used to identify the cut-off percentage of BM ECs pre-HSCT to predict high risk patients for PGF and PT. Subsequently, the second trial was performed to investigate whether prophylactic NAC intervention could reduce the incidence of PGF and PT and its underlying mechanism. The quantity and function of BM ECs were evaluated at -14 day (D), 0D pre-HSCT, and +1M, +2M post-HSCT in the patients who were willing to provide BM samples after the written consent. Results In the first trial, 15 patients of the enrolled 68 patients developed PGF or PT, whereas the remaining 53 patients were GGF at +2M post-HSCT. PGF and PT patients demonstrated impaired BM ECs at -14D pre-HSCT and defective dynamic reconstitution at +1M, +2M post-HSCT. Moreover, the BM ECs impairment positively correlated with their ROS levels. Multivariate analysis identified BM EC The second trial enrolled EC Summary / Conclusion: BM EC Disclosures No relevant conflicts of interest to declare.
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- 2018
19. 98% IGHV Gene Identity Is Still the Optimal Cutoff to Predict the Prognosis of Chronic Lymphocytic Leukemia Patients in China
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Li Wang, Chun Qiao, Jianyong Li, Wei Xu, Ke Shi, Hua-Yuan Zhu, Yi Xia, Qian Sun, and Lei Fan
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Oncology ,medicine.medical_specialty ,Optimal cutoff ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,medicine ,Immunoglobulin Variable Region ,IGHV@ ,Gene ,Protein p53 - Abstract
Background: Immunoglobulin heavy chain variable region (IGHV) has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. 98% being a cut-off value for IGHV is a mathematical choice and researches on the best cut-off value have never been stopped. Chinese CLL patients are known to differ from Caucasian CLL patients on both clinical and genetical features. However, the optimal cutoff for IGHV mutational status has not yet been studied in this particular ethnic group. Method: We carried out a study on 595 Chinese CLL patients in order to find out whether 98% is the best cut-off value for IGHV in Chinese CLL patients. Genomic DNA from peripheral blood or bone marrow was subjected to PCR amplification following the IGH Somatic Hypermutation Assay v2.0 protocol (InVivoScribe). Sequences were aligned to ImMunoGeneTics/V-QUEry and Standardization (IMGT/-VQUEST) database. Result: 600 sequences were received after IGHV rearrangement sequencing. IGHV3-23, IGHV4-34, IGHV3-7, IGHV4-39 and IGHV1-69 were the most frequently used IGHV genes. 352 (58.7%) cases were IGHV-mutated while 248 (41.3%) cases were IGHV-unmutated if the classical 98% classification by ERIC was used. In order to determine the optimal cut-off value, we used 1% as the interval to divide the entire cohort into 7 groups according to the mutational rate, which were Conclusion: 98% is the optimal cutoff value for IGHV mutational status to predict the prognosis of CLL patients in China. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
20. Lysosomal Cell Death and Apoptosis Crosstalk - Synergistic Role in Bcl-2 Inhibitor (ABT-263) Mediated Cell Death in B-Cell Precursor Acute Lymphoblastic Leukemia
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Klaus-Michael Debatin, Stefanie Enzenmüller, Lüder-Hinrich Meyer, and Qian Sun
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Programmed cell death ,biology ,Chemistry ,Immunology ,Intrinsic apoptosis ,Cell Biology ,Hematology ,Mitochondrion ,Biochemistry ,Cathepsin B ,medicine.anatomical_structure ,Apoptosis ,medicine ,Cancer research ,biology.protein ,Viability assay ,B cell ,Caspase - Abstract
Although improved treatment of pediatric Acute Lymphoblastic Leukemia (ALL) has become increasingly successful with cure rates of up to 90%, leukemia reoccurrence is clearly associated with inferior prognosis. Treatment failure and resistance in leukemias are considered to involve defects in apoptosis signaling, which forms the basis for apoptogenic treatment approaches such as the use of Bcl-2 inhibitors. Identification of alternative cell death programs like lysosomal membrane permeabilization-induced cell death may provide a novel strategy for the treatment of ALL. Previous studies showed that lysosomal activity, as well as their traffic properties are greatly altered during tumorigenesis. Intralysosomal hydrolases such as cathepsin B, L and D have been implicated in cancer progression and high expression levels are generally associated with poor prognosis. Lysosomotropic agents modulating lysosomal integrity may overcome cell death resistance and might therefore also improve the outcome of high risk or ALL relapse patients. In this study, we investigated the efficacy of the lysosomotropic compound B10, a derivative of Betulinic acid, as well as its combination with the Bcl-2 inhibitor ABT-263 in B-cell precursor- (BCP-) ALL. In BCP-ALL cell lines, B10 showed induction of cell death combined with increased DNA fragmentation. Interestingly, additional treatment with the pan-caspase inhibitor zVAD.fmk only partially rescued B10 triggered loss of cell viability, indicating that B10 is not exclusively inducing caspase-dependent apoptosis, but also induces an additional alternative cell death program. B10 permeabilized lysosomes as indicated by the significant decrease of LysotrackerRED positive populations detected by flow cytometry, and treatment with E-64d, a potent inhibitor of thiol proteases and cathepsins, reduced B10-induced cell death, thus emphasizing the cathepsin-dependent effect of B10. To exclude that B10-induced lysosomal permeabilization might represent a secondary effect, a panel of different substances was tested for their activity on lysosomal membrane integrity. While treatment with dexamethasone, chloroquine, vincristine and asparaginase also showed lysosomal permeabilization, co-treatment with E-64d did not reduce cell death indicating a secondary effect of these compounds on lysosomes. In addition to cell lines, we tested the effect of B10 on 15 primary leukemia samples isolated from ALL bearing mice of established patient-derived NOD/SCID/hu BCP-ALL xenografts. In a majority of these individual patient-derived leukemias, B10 induced cell death that could be inhibited by E-64d, thus demonstrating a lysosomal protease-dependent death program also in primary ALL. In addition to its classical role in triggering the intrinsic mitochondria dependent apoptosis pathway, the pro-apoptotic Bcl-2 family member Bax was previously described to be involved in the regulation of lysosomal membrane integrity, pointing to a possible synergistic effect of B10 and BH3-mimetics. Intriguingly, in cell fractionation assays we observed increased Bax recruitment to lysosomal membranes when B10 is present. Interestingly, co-treatment with the Bcl-2 inhibitor ABT-263, which displaces Bcl-2 from its inhibitory binding to Bax, led to increased lysosomal permeabilization, loss of mitochondrial membrane potential, and caspase activation indicating involvement of the intrinsic apoptosis pathway. The importance of lysosomal Bax recruitment for the activity of ABT-263 and its concomitant effect on lysosomal membrane permeabilization was further supported by Bax knockdown experiments, since induction of lysosomal disruption, release of cathepsins and their subsequent effect on cell death activation by B10 was reduced. Taken together, our findings suggest an important role of lysosomal membrane permeabilization-induced cell death for the activity of Bcl-2 inhibitors such as ABT-263. The combination of BH3 mimetics with lysosomotropic compounds may provide the basis for novel molecular directed treatment strategies. Disclosures No relevant conflicts of interest to declare.
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- 2016
21. Dysfunction of Bone Marrow Endothelial Progenitor Cells from Subjects with Poor Graft Function Following Allogeneic Hematopoietic Stem Cell Transplantation Can be Improved By Atorvastatin
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Yuan Kong, Xiao-Jun Huang, Lan-Ping Xu, Xiao-Hui Zhang, Yu Wang, Min-Min Shi, Kai-Yan Liu, Yang Song, and Yu-Qian Sun
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Tube formation ,medicine.medical_specialty ,business.industry ,Atorvastatin ,Immunology ,CD34 ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,Haematopoiesis ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,cardiovascular system ,Medicine ,lipids (amino acids, peptides, and proteins) ,Bone marrow ,Progenitor cell ,Stem cell ,business ,medicine.drug - Abstract
Background Poor graft function (PGF) is a serious complication post allo-HSCT. The definition is a hypo- or aplastic bone marrow with 2 or 3 of the following: (1) neutrophils ≤0.5×10E+9/L; (2) platelets ≤20×10E+9/L; and/or (3) hemoglobin concentration ≤70 g/L for at least 3 consecutive days after day +28 post-HSCT. The mechanisms of PGF remain poorly understood. Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells (HSCs) in the bone marrow (BM) microenvironment. In addition, our previous prospective, nested case-control study found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. Atorvastatin is widely used in the treatment of dyslipidemia and associated vascular abnormalities. Furthermore, atorvastatin has been reported to improve the mobilization and function of circulating EPCs in a number of diseases, such as heart disease, diabetes and others. Nevertheless, no previous studies have focused on the roles of atorvastatin on bone marrow-derived EPCs in subjects with poor graft function following allo-HSCT. Aims To evaluate the function of BM EPCs in subjects with PGF. Moreover, to investigate the effect of atorvastatin on the number and function of cultivated BM EPCs derived from subjects with PGF and its underling molecular mechanisms. Methods Three cohorts were included: subjects with PGF (N=23), subjects with good graft function (N=23), defined as persistent successful engraftment after allotransplant, and transplant donors as normal controls (N=23). Atorvastatin (0.5nM,50nM,500nM) was administrated to the 5 day cultivated BM EPCs from subjects with PGF until tested on day 7. The number and functions of CD34(+)/CD133(+)/KDR(+)EPCs were evaluated by flow cytometry, cell counting, DiI-Ac-LDL and FITC-lectin-UEA-1 double staining, migration, tube formation test and apoptosis. Reactive Oxygen Species (ROS) level was evaluated by flow cytometry. Cell proliferation was determined by cell counting kit-8 assay. Protein expression for ERK,JNK, p38, Akt was measured by flow cytometry and western blots. EPCs-CD34+ co-culture system and Colony-forming unit (CFU) assays were used to evaluate the supporting effect that atorvastatin exposure on hematopoietic progenitors in vitro. Results Human BM EPCs was characterized by the spindle shape and expression of CD34, CD309 and CD133 at day 7 of cultivation. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cAMP-responsive element-binding protein (CREB) were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through down-regulation of the p38 mitogen-activated protein kinase (MAPK) pathway. The colony-forming unit plating efficiency in CD34+ BM cells was also improved by atorvastatin when co-cultured with BM EPCs from subjects with PGF. Atorvastatin demonstrated similar improvement effects on the number and function of bone marrow EPCs as ROS inhibitor and p38 inhibitor from subjects with PGF. Conclusion In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through down-regulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF post-allotransplant. Disclosures No relevant conflicts of interest to declare.
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- 2016
22. The Efficacy of CT-Diagnostic-Driven Antifungal Strategy with Voriconazole for Invasive Aspergillosis in Patients with Hematological Diseases: A Multicenter, Prospective Study
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Yu Ji, Yu-Qian Sun, Chen-Hua Yan, Xiao-Jun Huang, Dai-Hong Liu, and Qifa Liu
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,030106 microbiology ,Immunology ,Population ,Hematopoietic stem cell transplantation ,Neutropenia ,Aspergillosis ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,education ,Halo sign ,Voriconazole ,education.field_of_study ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,medicine.symptom ,business ,Fluconazole ,Febrile neutropenia ,medicine.drug - Abstract
Background The frequency of invasive fungal disease (IFD) has increased in recent two decades and has emerged as an important cause of life-threatening infections in immunocompromised patients, especially in those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). Empirical antifungal therapy has been the standard of care used to decrease the number of deaths due to IFD among neutropenic patients who have persistent or recurrent fever despite broad-spectrum antibacterial treatment. However, about two thirds of these patients may be potentially exposed to unnecessary empirical antifungal treatment with associated potential toxicity and considerable financial burden. It was demonstrated that high-resolution computerized tomography (HRCT) had early predictive value for fungal infection, and the major signs on chest CT scans generally precede the positive outcome of serum galactomannan test. It was also shown that the diagnosis-based treatment strategy only based on HRCT results could reduce more than a half use of antifungal agents in HSCT patients who had persistent febrile neutropenia. Thus, we would like to explore the feasibility of this new strategy for hematological patients with IA in China. Method This was a prospective and single-arm study. Up to now, 24 neutropenic patients after intensive chemotherapy or HSCT with high risk factors for IFD from three hospitals were enrolled. After recruitment, HRCT of thorax will be conducted within 24h. If HRCT shows any new changes suspicious of fungal infection, including halo sign, cavity, air-crescent sign, or other non-specific signs, voriconazole would be given intravenously for two weeks, followed by oral voriconazole. Six weeks after initiation of antifungal therapy, the outcome was evaluated by clinicians according to the patients' imagining and microbiological evidences and clinical conditions, and complete or partial responses were defined as successful outcome of antifungal therapy. Result The median age of this population was 38.5 years (range from 19 to 78). Four of 24 patients were the recipients of HSCT, and the others received intensive chemotherapy. There were four patients had history of IFD, and 7 take fluconazole orally for antifungal prophylaxis. At the beginning of antifungal therapy with voriconazole, 12 had non-specific infiltrates on pulmonary HRCT, 8 had dense lesions with halo sign, and 4 had cavity. At the end of six-week follow-up, 5 patients were diagnosed with possible IA, 6 with probable IA and 1 with proven IA. The total successful rate of antifungal therapy with CT-diagnostic-driven strategy was 50.0% (12/24). Notably, efficacies of the antifungal treatment in patients with specific IA signs on pulmonary HRCT were significant higher than that in patients with non-specific signs (75.0% vs. 25.0%, P=0.043). Conclusion The CT-diagnostic-driven antifungal strategy was effective and suitable for patients with hematological malignancies. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
23. Abnormalities of the Bone Marrow Immune Microenvironment in Patients with Prolonged Isolated Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation
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Yuan Kong, Min-Min Shi, Yu-Qian Sun, Xiao-Jun Huang, Lan-Ping Xu, Xiao-Hui Zhang, Yu Wang, and Yang Song
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business.industry ,medicine.medical_treatment ,T cell ,Immunology ,FOXP3 ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,medicine.anatomical_structure ,Megakaryocyte ,Medicine ,Peripheral blood cell ,IL-2 receptor ,Bone marrow ,business ,CD8 - Abstract
Background:Prolonged Isolated Thrombocytopenia (PT), is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and defined as the engraftment of all peripheral blood cell lines other than a PLT count ≤20×10E+9/L or dependence on PLT transfusions for more than 90 days after allo-HSCT. Nevertheless, the mechanisms underlying PT remain unclear. Recent studies have presumed that the mechanism of PT might be similar, at least in part, to that of Immune Thrombocytopenia (ITP). BM immune microenvironment is considered to be involved in the regulation of hematopoiesis, and also influence the production of platelets. There is growing evidence that activated CD8+ T cells in the bone marrow (BM) of patients with ITP might suppress megakaryocyte apoptosis, leading to impaired platelet production. In our previous study, we also found the deregulated T cells responses in BM were associated with ITP patients. Therefore, we hypothesized aberrant immune microenvironment may also influence the production of platelet after allo-HSCT, contributing to the occurrence of PT, so we conducted a study to analyze the alteration of T cell subpopulations and cytokines in BM micro-environment of allotransplant patients. Aims:To compare the cellular compositions and function of T cells in BM microenvironment between patients with PT and good graft function (GGF) after allo-HSCT. Methods:Using a prospective nested case-control study, the T cell subpopulations in BM were analyzed by flow cytometry in 15 patients with PT, 30 matched patients with GGF after allo-HSCT, and 15 healthy donors (HDs). The fractions of T cells, including Th1, Tc1,Th2, Tc2 ,Th17 and Treg were identified as CD3+CD8-IFN-gama+, CD3+CD8-IFN-gama+, CD3+CD8+IL4+, CD3+CD8+IL-4+, CD3+CD8-IL17A+ and CD3+CD4+CD25+Foxp3+, respectively. The levels of IFN-gama, IL-4 and IL-17A in BM plasma were detected by cytometric beads assay. Results: The demographic and clinical characteristics were similar between allo-HSCT patients with PT and those with GGF. The T cell subset analysis revealed that the proportion of CD8+ T cells in BM was higher in PT patients. The in vitro cytokine stimulated tests demonstrated a significant higher proportion of Th1 in PT patients (29.8% ±13.0% vs. 21.7%±12.2%, P=0.01), and we also found an elevated percentage of Tc1 in PT patients when compared with GGF (39.3% ±19.3% vs. 23.0% ± 14.0%, P=0.01). Meanwhile, the similar percentage of Th2 and Tc2 were found in PT patients. The type-1/ type-2 response ratio was calculated by the percentages of Th1/Th2 and Tc1/Tc2. A significant elevation in the ratio of Tc1/Tc2 (37.3 vs. 22.1 vs. 15.6, P Summary/Conclusion: Our study demonstrated that the abnormal BM immune microenvironment including the higher percentage of Th1, Tc1, and Th17 cells in patients with PT, suggesting that the dysfunction of T cells response in BM immune microenvironment may contribute to the occurrence of PT after allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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- 2016
24. Eltrombopag mobilizes iron in patients with aplastic anemia.
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Zhen Zhao, Qian Sun, Sokoll, Lori J., Streiff, Michael, Zhe Cheng, Grasmeder, Sophie, Townsley, Danielle M., Young, Neal S., Dunbar, Cynthia E., and Winkler, Thomas
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- *
APLASTIC anemia , *CANCER chemotherapy , *DRUG therapy - Published
- 2018
- Full Text
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25. Effective in Vivo Targeting of BCP-ALL in a NOD/SCID/huALL Mouse Model By CD70 Directed Immunotherapy
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Chiara Borga, Geertruy te Kronnie, Lüder Hinrich Meyer, Klaus-Michael Debatin, and Qian Sun
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Antibody-dependent cell-mediated cytotoxicity ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Immunotherapy ,Biology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Leukemia ,medicine.anatomical_structure ,Acute lymphocytic leukemia ,medicine ,biology.protein ,Bone marrow ,Antibody ,B cell - Abstract
Acute lymphoblastic leukemia (ALL) is the most frequent malignant disorder in children and adolescents. Despite successful treatment, relapse of the disease remains a major problem and is associated with poor prognosis. This emphasizes the need for novel treatment strategies to be applied in addition to established chemotherapy regimens without increasing general toxicity. Previously, we described a strong association of leukemia cell engraftment of primary patient B cell precursor (BCP) ALL samples transplanted in a NOD/SCID/huALL mouse model and patient outcome. Rapid onset of leukemia related morbidity (time to leukemia, TTLshort) is indicative for patient relapse and characterized by a specific gene expression profile. Among the top differentially regulated genes, the gene coding for CD70 was identified to be significantly up-regulated in TTLshort/high risk ALL. CD70 is a member of the tumor necrosis factor (TNF) family expressed on activated B- and T-lymphocytes and dendritic cells. Binding of CD70 to its receptor CD27 is involved in regulation of T- and B-cells including priming and generation of memory and plasma cells. CD70 has been described to be constitutively expressed on different cancers including hematological malignancies. However, expression and targeting of CD70 in B- cell precursor lymphoblastic leukemia has so far not been investigated. In this study, we addressed expression of CD70 in patient-derived primograft leukemia samples and primary patient specimens obtained at diagnosis from pediatric patients. Furthermore, we evaluated CD70 as a therapeutic target for directed immunotherapy in vitro and in our BCP-ALL xenograft system in vivo. Flow cytometric analyses of CD70 surface expression in all together 19 patient-derived xenograft samples (TTLshort n= 7, TTLlong n=12) revealed a higher expression of CD70 on ALL cells with a TTLshort/early relapse phenotype compared to TTLlongsamples. We also investigated expression of the CD70 receptor CD27 and found no significant difference in surface expression between both TTL subgroups. Moreover, we investigated the transcript expression levels of 198 BCP-ALL specimens obtained at diagnosis. Interestingly, we found a heterogenous expression of CD70 with no association to cytogenetic subgroups, minimal residual disease (MRD) risk classes or patient outcome. Importantly, a significant higher CD70 expression was found in leukemia samples compared to healthy bone marrow controls indicating a general over-expression in BCP-ALL. CD27 however, did not show different transcript expression including healthy bone marrow controls. To take advantage of increased CD70 expression in BCP-ALL, we addressed CD70 as therapeutic target for immunotherapy. Co-culture in vitro experiments of primograft ALL cells with NK cells in the presence of specific anti-CD70 antibodies revealed five-fold increased antibody-dependent cell-mediated cytotoxicity (ADCC) as compared to the respective isotype control. To evaluate the efficacy of CD70 directed immunotherapy, we assessed leukemia development in NOD/SCID mice upon transplantation of primograft ALL with high CD70 expression either incubated with anti-CD70 antibody or the respective isotype control. Most importantly, a marked reduction of leukemia load in peripheral blood, bone marrow and spleens of the animals was detected in anti-CD70 treated cases. This indicates, that CD70 provides an immunotherapeutic target on ALL cells inducing ADCC by NK cells present in NOD/SCID mice. Most interestingly, this effect could be abrogated both by NK-cell depletion (pre-treatment with anti-mouse CD122 antibodies) in the recipient animals and by using NK-cell deprived NSG mice as recipients, confirming that decreased in vivo leukemia growth upon anti-CD70 treatment is mediated by NK-cell induced cytotoxicity of anti-CD70 bearing CD70 positive ALL cells. Taken together, we identified significantly up-regulated CD70 expression in BCP-ALL with varying expression among molecular and prognostic subgroups. BCP-ALL samples with high surface expression of CD70, as detected by flowcytometry, can be targeted by directed immunotherapy with anti-CD70 antibodies leading to efficient NK-cell dependent lysis of leukemia cells in vitro and decreased growth in an in vivo BCP-ALL model. Thus, CD70 provides a novel target for directed immunotherapy of BCP-ALL. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
26. Risk-Stratification Directed Prophylaxis with Additional Low-Dose of Methylprednisolone Can Reduce Acute Graft-Versus-Host Disease for Patients with Hematological Malignancies after Allogeneic SCT: A Randomized, Controlled, Clinical Trial
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Xiao-Dong Mo, Xiao-Jun Huang, Huan Chen, Fei-Fei Tang, Dai-Hong Liu, Yu-Hong Chen, Feng-Rong Wang, Ying-Jun Chang, Lan-Ping Xu, Yu Wang, Wei Han, Yu-Qian Sun, Kai-Yan Liu, Chen-Hua Yan, and Xiao-Hui Zhang
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medicine.medical_specialty ,Basiliximab ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Group A ,Gastroenterology ,Group B ,Surgery ,Transplantation ,Graft-versus-host disease ,Methylprednisolone ,Internal medicine ,medicine ,Cumulative incidence ,business ,medicine.drug - Abstract
The major complication of allogeneic HSCT-graft-versus-host disease (GVHD)-remains lethal and limits use of this important procedure, especially after unmanipulated haploidentical HSCT. Several studies have provided evidence that universal addition of corticosteroids for prophylaxis of GVHD can reduce the risk for acute GvHD grade II-IV in HLA-matched transplantation. However, corticosteroid, a non-specific immunosuppressive agent, may also contribute to high rates of infections. Our previous data suggest that the ratio of CD4/CD8 in allografts from haploidentical donors can stratify patients into high-risk and low-risk ones who will develop GVHD after transplantation. Recently, we indicated that low-dose of methylprednisolone (MP, 0.5 mg/kg/day) might be a well-tolerated, effective and inexpensive regimen in combination of MTX for therapy of GVHD, suggesting that low-dose corticosteroid may be used for the prophylaxis of GVHD without increasing infection. To investigate whether risk-stratification directed prophylaxis strategy can reduce the incidence of GVHD and improve survival in a hemogenous patient population who underwent unmanipulated haploidentical HSCT, we performed a prospective, randomized, controlled, clinical trial. A total of 228 patients were enrolled in this trial. All of the patients completed the study and were stratified as high-risk (n=145) and low-risk arms (n=83) according to the ratio of CD4/CD8 in allografts. Patients of the high-risk arms were randomly assigned in a 1:1 ratio to additional low-dose glucocorticoid prophylaxis group (Group A, n=72) and control group (GroupB, n=73). The groups were balanced with respect to patient and donor characteristics. Our results showed that the cumulative incidence of grade II-IV acute GVHD on day 100 was 20.9%±4.8% in Group A, which was comparable to Group C (25.5%±4.8%, P=0.430) and both of which were significantly lower than that of Group B (48.1%±5.9%, P<0.001). In addition, the onset time of grade II-IV acute GVHD was 25 (16-50) days, 15 (9-57) days, and 21 (10-58) days, respectively in Group A, Group B, and Group C (P<0.05, Group A vs. Group B or Group C). There were no significant difference in grade Ⅲ-IV acute GVHD among these three groups. The ratio of patients who developed glucocorticoid refactory acute GVHD and treated with basiliximab (anti-CD25 antibody) were 13.9% (10/72), 17.8% (13/73), and 22.9% (19/83), respectively, in Group A, Group B, and Group C, there is a trend that the incidence of basiliximab treated patients in Group C is higher than that of Group A (P=0.109). The median time for myeloid engraftment in Group A was 11 days (range: 10-21 days), which was significantly faster that those of Group B (13 days, range from 10 to 33 days, P<0.05) and Group C (13 days, range from 10 to 33 days, P<0.05). The median time for platelet engraftment in Group A was 12 days (range: 10-22 days), which was significantly faster that those of Group B (17 days, range from 6 to 255 days, P<0.01) and Group C (19 days, range from 8 to 260 days, P<0.01). In addition, risk-stratification directed prophylaxis with additional low-dose of MP did not increase the incidence of CMV, EBV reactivation, PTLD, relapse and TRM, as well as delay immune recovery after unmanipulated haploidentical HSCT. The 100 day cumulative incidence relapse and transplant-related mortality was not significantly different among patients in Group A, Group B, and Group C, respectively. The 100 day probabilities of LFS and OS were comparable among these three patient groups. In conclusion, we for the first time demonstrated that risk-stratification directed prophylaxis for GVHD with additional low-dose of MP could significantly decrease the incidence and delay the onset of grade II-IV acute GVHD without increasing infections and delaying immune recovery. Our data indicated that addition of glucocorticoid early after unmanipulated haploidentical transplantation could also accelerate hematopietic recovery [This study was registered at http://clinicaltrials.gov/ NCT01607580]. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
27. Functional Alterations of Lin−CD34+CD38+ Progenitors in Chronic Myelomonocytic Leukaemia and on Progression to Acute Leukaemia
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Li Chong Chan, Thomas S.K. Wan, Chi-Chiu So, Sze-Fai Yip, Qian Sun, and Edmond S. K. Ma
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education.field_of_study ,Myeloid ,Immunology ,Population ,CD34 ,Bone Marrow Stem Cell ,Cell Biology ,Hematology ,CD38 ,Biology ,Biochemistry ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Cancer research ,medicine ,Bone marrow ,Stem cell ,Progenitor cell ,education - Abstract
Chronic myelomonocytic leukaemia (CMML) is a clonal bone marrow stem cell disorder based on the presence of trilineage involvement, the association of myelodysplastic and myeloproliferative features and its ability to transform into acute myeloid leukaemia. The objectives of our study are to identify the cell population and its functional characteristics involved in evolution from CMML phase to acute myeloid leukaemia. We analysed Lin−CD34+ stem/progenitor population and performed cell proliferation, apoptotic assays, self-renewal ability and differentiation potential studies in purified populations of Lin−CD34+CD38− stem cells and Lin−CD34+CD38+ committed progenitors from peripheral blood of 16 patients with CMML and in six of the 16 after transformation to acute myeloid leukaemia (AML-t). We observed an expansion of the stem cell/progenitor pool (Lin−CD34+ cells) in AML-t comprising mainly of Lin−CD34+CD38+ committed progenitors within Lin−CD34+ cells. The Lin−CD34+CD38+ committed progenitors displayed highly proliferative activity in CMML and in AML-t; and additionally acquired resistance to apotosis and myeloid colony self-renewing ability in AML-t. Impairment of dendritic cell (DC) differentiation was observed with complete block in AML-t. Our findings suggest Lin−CD34+CD38+ committed progenitors instead of Lin−CD34+CD38− stem cells could be the target(s) of secondary genetic lesions underpinning progression from CMML to AML. These results have implications for the further study of the biology of leukaemic transformation and the design of new strategies for the effective treatment of CMML.
- Published
- 2007
28. Atorvastatin enhances endothelial cell function in posttransplant poor graft function.
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Min-Min Shi, Yuan Kong, Yang Song, Yu-Qian Sun, Yu Wang, Xiao-Hui Zhang, Lan-Ping Xu, Kai-Yan Liu, and Xiao-Jun Huang
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- *
HEMATOPOIETIC stem cell transplantation , *ATORVASTATIN , *ENDOTHELIAL cells , *BONE marrow physiology , *CELL proliferation , *ADENOSINE monophosphate - Abstract
Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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