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The pathogenesis of corticosteroid-resistant immune thrombocytopenia (ITP), a clinically challenging condition in which patients exhibit either no response to corticosteroids or are corticosteroid-dependent, remains poorly underst...
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The pathogenesis of corticosteroid-resistant immune thrombocytopenia (ITP), a clinically challenging condition in which patients exhibit either no response to corticosteroids or are corticosteroid-dependent, remains poorly understood. Murine studies suggest that bone marrow (BM) endothelial progenitor cells (EPCs) play a crucial role in regulating megakaryocytopoiesis. However, little is known regarding the number and function of BM EPCs or how to improve impaired BM EPCs in corticosteroid-resistant ITP patients. In the current case-control study, we evaluated whether the BM EPCs in corticosteroid-resistant ITP differed from those in corticosteroid-sensitive ITP. Moreover, whether atorvastatin could enhance the number and function of BM EPCs derived from corticosteroid-resistant ITP patients was investigated in vitro and in vivo. Reduced and dysfunctional BM EPCs, characterized by decreased capacities of migration and angiogenesis as well as higher levels of reactive oxygen species and apoptosis, were observed in corticosteroid-resistant ITP patients. In vitro treatment with atorvastatin quantitatively and functionally improved BM EPCs derived from corticosteroid-resistant ITP patients by downregulating the p38 MAPK pathway and upregulating the Akt pathway, and rescued the impaired BM EPCs to support megakaryocytopoiesis. Subsequently, a pilot cohort study showed that atorvastatin was safe and effective in corticosteroid-resistant ITP patients. Taken together, these results indicate that reduced and dysfunctional BM EPCs play a role in the pathogenesis of corticosteroid-resistant ITP, and the impaired BM EPCs could be improved by atorvastatin both in vitro and in vivo. Although requiring further validation, our data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in corticosteroid-resistant ITP patients.
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摘要 :
Prolonged isolated thrombocytopenia (PT) is a serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to murine studies, endothelial progenitor cells (EPCs) play a crucial role in t...
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Prolonged isolated thrombocytopenia (PT) is a serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to murine studies, endothelial progenitor cells (EPCs) play a crucial role in the regulation of hematopoiesis and thrombopoiesis in the bone marrow (BM) microenvironment. We previously showed that the reduced frequency of BM EPCs was an independent risk factor for the occurrence of PT following allo-HSCT. However, the functional role of BM EPCs and methods to improve the impaired BM EPCs in PT patients are unknown. In the current case-control study, we investigated whether the BM EPCs in PT patients differed from those in good graft function patients. Moreover, we evaluated whether N-acetyl-L-cysteine (NAC, a reactive oxygen species [ROS] scavenger) could enhance BM EPCs from PT patients in vitro and in vivo. The PT patients exhibited dysfunctional BM EPCs characterized by high levels of ROS and apoptosis and decreased migration and angiogenesis capabilities. In vitro treatment with NAC improved the quantity and function of the BM EPCs cultivated from the PT patients by downregulating the p38 MAPK pathway and rescued the impaired BM EPCs to support megakaryocytopoiesis. Furthermore, according to the results of a preliminary clinical study, NAC is safe and effective in PT patients. In summary, these results suggested that the reduced and dysfunctional BM EPCs are involved in the occurrence of PT. The defective BM EPCs in the PT patients can be quantitatively and functionally improved by NAC, indicating that NAC is a promising therapeutic approach for PT patients following allo-HSCT.
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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 hemato...
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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 BMEPCs 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 ofBMEPCs 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 BMEPCs 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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Exploring sustainable chemistry for renewable energy plays a key role in meeting the ever increasing energy demand without sacrificing the environment. In this study, two novel diketopyrrolopyrrol(DPP)-based pi-conjugated oligomer...
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Exploring sustainable chemistry for renewable energy plays a key role in meeting the ever increasing energy demand without sacrificing the environment. In this study, two novel diketopyrrolopyrrol(DPP)-based pi-conjugated oligomers (named as TPE-DPP4 and BP-DPP4) have been readily synthesized via a ligand-free Pd-catalyzed sequential activation of C-H bond in two steps with good yields starting from simple building blocks. Poly(3-hexylthiophene) is employed as an electron donor to blend with the new DPP-derived electron acceptors for the fullerene-free bulk heterojunction organic photovoltaics. The power conversion efficiency of 2.49% has been achieved, corresponding with an open-circuit voltage of 1.16 V, which is among the highest open-circuit voltages for the single junction organic photovoltaics. The facilely accessible electron acceptors blended with cost-effective poly(3-hexylthiophene) donor for fullerene-free organic photovoltaics opens a new pathway to access renewable solar energy via sustainable chemistry. (C) 2016 Elsevier Ltd. All rights reserved.
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Patients with prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) are known to have a poor prognosis. However, there is no standard treatment for PT. The present study aimed to investigat...
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Patients with prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) are known to have a poor prognosis. However, there is no standard treatment for PT. The present study aimed to investigate the potential effect of a novel recombinant human thrombopoietin (rhTPO) in a cohort of patients with PT following allo-SCT. A total of 24 patients with PT (including delayed platelet engraftment and secondary failure of platelet recovery) were treated with rhTPO from July 1, 2016 to May 31, 2017. rhTPO injections were administered at 300 IU/kg/d for 28 consecutive days or until platelet counts were ? 50???10(9)/L, independent of platelet transfusion. Response was defined as platelet recovery to ? 20???10(9)/L for seven consecutive days without transfusion support during or within 7?days of the end of rhTPO treatment. All patients completed the 28?days of treatment, and none were withdrawn due to adverse effects. The overall response was 45.8%, which was significantly higher than historical data (12.2%, p 收起
摘要 :
Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) immune microenvironment are involved in the pat...
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Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) immune microenvironment are involved in the pathogenesis of PT remains unknown, however. Twenty patients with PT, 40 matched patients with good graft function (GGF) after allo-HSCT, and 20 healthy donors (HD) were enrolled in this nested case-control study. Th1, Th2, Tc1, Tc2, Th17, and Treg cells were analyzed by flow cytometry, and IFN-gamma, IL-4, IL-17, IL-6, IL-21, and thrombopoietin levels in BM plasma were evaluated with a cytometric bead assay and ELISA. Relative to GGF patients and HD controls, PT patients had significantly higher proportions of Th1 and Tc1 cells, resulting in higher Th1/Th2 and Tc1/Tc2 ratios in the BM microenvironment. In addition, the excessive polarization of Th17 was observed in patients with PT. Changes in BM plasma cytokines were consistent with our cellular findings. These results suggest that dysregulated T cell responses in the BM microenvironment might play an important role in the pathogenesis of PT. (C) 2017 American Society for Blood and Marrow Transplantation.
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