180 results on '"Hong Yan"'
Search Results
2. Evaluate Dynamics of IL-6 Release during Step-up Dosing of Subcutaneous Administration of Odronextamab Via a Quantitative Systems Pharmacology Modeling Approach
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Masood Khaksar Toroghi, Min Zhu, Srikanth R. Ambati, Hesham Mohamed, Aafia Chaudhry, Hong Yan, John D. Davis, and A. Thomas DiCioccio
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Optimization of Intravenous Odronextamab Step-up Regimen for Reducing the Risk of High-Grade Cytokine Release Syndrome
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Min Zhu, Jurriaan Brouwer-Visser, Srikanth R. Ambati, Hesham Mohamed, Vladimir Jankovic, Fang Wang, Hong Yan, Jingxian Cai, Carolina Leite De Oliveira, Melanie Ufkin, John D. Davis, Aafia Chaudhry, and Masood Khaksar Toroghi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Selection of Odronextamab Pediatric Dosing Regimens for Aggressive Non-Hodgkin Lymphoma Via a Modeling and Simulation Approach
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Min Zhu, Michael Dodds, Srikanth R. Ambati, Hesham Mohamed, Jason Chittenden, Hong Yan, Aafia Chaudhry, and John D. Davis
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. Modeling and Simulation in Support of Odronextamab Subcutaneous Dose Selection for Adult Patients with Indolent or Aggressive Non-Hodgkin Lymphoma
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Min Zhu, Srikanth R. Ambati, Hesham Mohamed, Masood Khaksar Toroghi, Hong Yan, Aafia Chaudhry, and John D. Davis
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. Endothelial Cell Dysfunction Is Involved in the Progression of Myelodysplastic Syndromes
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Xing, Tong, primary, Lyu, Zhong-Shi, additional, Duan, Cai-Wen, additional, Wen, Qi, additional, Zhao, Hong-Yan, additional, Tang, Shu-Qian, additional, Zhang, Yuan-Yuan, additional, Lv, Meng, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Huang, Xiao-Jun, additional, and Kong, Yuan, additional
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- 2021
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7. Restoring Dysfunctional Bone Marrow Endothelial Cell Alleviates Aplastic Anemia
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Tang, Shu-Qian, primary, Yao, Wei-Li, additional, Zhao, Hong-Yan, additional, Wen, Qi, additional, Zhang, Yuan-Yuan, additional, Lyu, Zhong-Shi, additional, Xing, Tong, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Huang, Xiao-Jun, additional, and Kong, Yuan, additional
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- 2021
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8. 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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Mengge, Gao, primary, Hong, Yan, additional, Xiangyu, Zhao, additional, Sun, Yuqian, additional, Kong, Jun, additional, Wang, Zhidong, additional, Wang, Fengrong, additional, Wang, Jingzhi, additional, Yan, Chenhua, additional, Wang, Yu, additional, Huang, Xiaojun, additional, and Zhao, Xiaosu, additional
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- 2021
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9. TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements
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Du, Hong-Yan, Pumbo, Elena, Ivanovich, Jennifer, An, Ping, Maziarz, Richard T., Reiss, Ulrike M., Chirnomas, Deborah, Shimamura, Akiko, Vlachos, Adrianna, Lipton, Jeffrey M., Goyal, Rakesh K., Goldman, Frederick, Wilson, David B., Mason, Philip J., and Bessler, Monica
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- 2009
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10. Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells
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Fagerli, Unn-Merete, Holt, Randi U., Holien, Toril, Vaatsveen, Thea K., Zhan, Fenghuang, Egeberg, Kjartan W., Barlogie, Bart, Waage, Anders, Aarset, Harald, Dai, Hong Yan, Shaughnessy, John D., Jr, Sundan, Anders, and Børset, Magne
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- 2008
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11. Endothelial Cell Dysfunction Is Involved in the Progression of Myelodysplastic Syndromes
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Yu Wang, Qi Wen, Tong Xing, Xiao-Jun Huang, Yuan-Yuan Zhang, Yuan Kong, Shu-Qian Tang, Zhong-Shi Lyu, Meng Lv, Xiao-Hui Zhang, Lan-Ping Xu, Hong-Yan Zhao, and Cai-Wen Duan
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Endothelial stem cell ,business.industry ,hemic and lymphatic diseases ,Myelodysplastic syndromes ,Immunology ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry - Abstract
Background: Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis, refractory anemia, and a tendency to transform to acute myeloid leukemia (AML). Ineffective hematopoiesis progression and immune deregulation are dominating pathophysiological process of MDS. Emerging evidences showed the role of bone marrow (BM) microenvironment in MDS. In MDS murine model, integral BM microenvironment contributes to inferior hematopoietic function and disease progression. As an important component of BM microenvironment, the relationship between endothelial cells (ECs) and MDS progression remains largely unknown. Although ECs from MDS patients have been identified to have decreased supporting ability to normal hematopoietic stem cells (HSCs), the supporting ability of ECs in different clinical stages of MDS remains to be elucidated. In addition, the role of BM ECs from MDS patients in supporting leukemia cells and their immunomodulatory ability remains unclear. Aims: To determine the number and functions of BM ECs in different subtypes of MDS patients. Moreover, to explore the correlation between BM ECs and MDS progression, which may represent a potential therapeutic target for MDS patients. Methods: In the prospective cohort study, patients with multilineage dysplasia (MDS-MLD, N=15), MDS with excess blasts (MDS-EB, N=15), or AML(N=15) and healthy donors (HD, N=15) were enrolled. BM ECs were analyzed in HD and patients by flow cytometry and in situ histological analyses. The functions of BM ECs were analyzed by migration, angiogenesis capacities, levels of apoptosis and reactive oxygen species (ROS). To evaluate the supporting abilities of BM ECs on HSCs, leukemia cells and T cells, in vitro co-culture strategies were used. The levels of apoptosis, ROS and colony-forming unit-plating (CFU) efficiency of CD34+ and HL-60 cells were investigated. T cell subsets were analyzed by flow cytometry as previously reported. To further investigate the underlying mechanism of dysfunctional ECs, RNA sequencing (RNA-Seq) analyses and real time-PCR (qRT-PCR) were performed in BM ECs from HD and MDS patients with different subtypes. Results: In the current study, gradually increased BM ECs were observed from MDS-MLD, MDS-EB to AML patients. Furthermore, dysfunctional BM ECs were found with MDS progression, characterized by increased levels of migration, angiogenesis capacities, apoptosis and ROS. More importantly, BM ECs from MDS patients exhibited decreased supporting ability of HSCs whereas increased supporting ability of leukemia cells in vitro with MDS progression. After coculture with ECs, levels of apoptosis and ROS in CD34+ cells were increased whereas their CFU efficiency reduced. On the other hand, levels of apoptosis and ROS of HL-60 cells were decreased. The proliferation capacity and leukemia CFU efficiency of HL-60 cells after co-cultured with ECs were enhanced with MDS progression. Furthermore, following coculture with BM ECs, deregulated differentiation was demonstrated in T cell subsets, characterized by elevating proportion of Th2 and Treg and decreasing proportion of Th1 and Th17 with MDS progression. RNA-Seq showed that the expression profile of BM ECs from MDS-EB was closer to MDS-MLD, whereas that of MDS-EB was closer to AML. Different gene expression profiles indicated the expression of hematopoiesis and immune related genes increased in BM ECs with MDS progression. Mechanistically, the mRNA levels of CX CL12, SCF and NFKB of ECs were increased with MDS progression. Summary/Conclusion: In summary, the number of BM ECs gradually increased, BM EC dysfunction more and more severe, and the supporting abilities of BM ECs on HSCs decreased, whereas on leukemia cells increased with MDS progression. Moreover, ECs regulated the differentiation of T cells into immune tolerant cells with MDS progression. Although further validation is required, these findings indicated that the improvement of BM ECs may represent a potential therapeutic approach for MDS patients. Keywords: Myelodysplastic syndromes, endothelial cells, disease progression, ineffective hematopoiesis, immune deregulation Disclosures No relevant conflicts of interest to declare.
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- 2021
12. Restoring Dysfunctional Bone Marrow Endothelial Cell Alleviates Aplastic Anemia
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Yuan Kong, Yu Wang, Tong Xing, Yuan-Yuan Zhang, Lan-Ping Xu, Shu-Qian Tang, Qi Wen, Xiao-Hui Zhang, Zhong-Shi Lyu, Wei-Li Yao, Xiao-Jun Huang, and Hong-Yan Zhao
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business.industry ,Immunology ,Dysfunctional family ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Endothelial stem cell ,medicine.anatomical_structure ,medicine ,Cancer research ,Bone marrow ,Aplastic anemia ,business - Abstract
Background Aplastic anemia (AA) is a life-threatening disease characterized by bone marrow (BM) failure and pancytopenia. Immunosuppressive therapy can rescue most patients with AA. However, the pathogenesis of AA is still not well elucidated and the new strategies need to be developed for AA patients. Increasing evidences suggested the dysfunctional BM microenvironment may be involved in the pathogenesis of AA. As important components of the BM microenvironment, endothelial cells (ECs) play a crucial role in supporting hematopoiesis and regulating immune. However, whether BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve the hematopoietic and immune status of AA patients remain to be elucidated. Aims To evaluate the quantity and function of BM ECs from AA patients. Moreover, to determine whether the dysfunctional BM ECs are involved in the occurrence of AA by affecting hematopoiesis and regulating immunity in vitro and in vivo. Finally, to uncover the therapeutic potential of repairing dysfunctional BM ECs to alter the hematopoietic and immunological status in AA patients. Methods This study enrolled 30 patients with AA and 30 healthy donors(HD). Flow cytometry and BM in situ immunofluorescence staining were used to analyze the proportion of ECs in BM of the two groups. The level of intracellular reactive oxygen species(ROS) and the proportion of apoptosis were detected by flow cytometry. The functions of BM ECs were evaluated by double-positive staining, migration and tube formation assays. To determine the effect of BM ECs on hematopoiesis and immunity, primary human BM ECs were separately cocultured with CD34 + and CD3 + cells. To further validate the role of BM ECs in the occurrence of AA, a classical AA mice model and VE-cadherin blocking antibody that could antagonize the function of BM ECs were used. Moreover, to explore potential approach of targeting the dysfunctional BM ECs, the exogenous EC infusion or N-acetyl-L-cysteine (NAC, a ROS scavenger) for repairing BM ECs were administrated to the AA mice. To further explore the repairing effect of NAC on BM ECs, the primary BM ECs from AA patients were treated by NAC in vitroand then the functions of BM ECs were evaluated. Results Compared with HD, BM ECs in AA patients were decreased and dysfunctional, which characterized by higher levels of ROS and apoptosis, impaired abilities of migration and angiogenesis. Furthermore, dysfunctional BM ECs from AA patients not only impaired their hematopoiesis-supporting ability but also promoted co-cultured T cells to polarize towards pro-inflammatory T cells in vitro, which resulted in an unbalanced T cell subsets. Consistently, AA mice demonstrated decreased BM ECs with increased level of intracellular ROS. Moreover, hematopoietic failure and immune imbalance in AA mice became more severe when the function of BM ECs was antagonized, whereas the administration of NAC or infusion of exogenous EC improved the hematopoietic and immunological status of AA mice via repairing BM ECs in vivo. In addition, we found the NAC treatment also restored the hematopoiesis-supporting ability and immunity-regulating ability of the primary ECs derived from AA patients in vitro. Summary/Conclusion Our study demonstrates for the first time that dysfunctional BM ECs with impaired hematopoiesis-supporting ability and abnormal immunomodulatory ability are involved in the pathogenesis of AA. Although further validation is required, restoring dysfunctional BM ECs via EC infusion or administration of ROS scavenger NAC might be a potential therapeutic approach for AA patients. Disclosures No relevant conflicts of interest to declare.
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- 2021
13. Different Subsets of Haematopoietic Cells and Immune Cells in Bone Marrow between Young and Old Donors
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Yao, Weili, primary, Wen, Qi, additional, Zhao, Hong-Yan, additional, Zhang, Yuan-Yuan, additional, Tang, Shuqian, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Huang, Xiao Jun, additional, and Kong, Yuan, additional
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- 2020
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14. M1 and M2 Macrophages Play Different Roles in the Pathogenesis of Acute Graft-Versus-Host Disease Post-Allotransplant By Modulating Immune Microenvironment
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Wen, Qi, primary, Zhao, Hong-Yan, additional, Lyu, Zhong-Shi, additional, Weili, Yao, additional, Han, Ting-Ting, additional, Chen, Yu-Hong, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Kong, Yuan, additional, and Huang, Xiao-Jun, additional
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- 2020
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15. M2 Macrophages, but Not M1 Macrophages, Support Megakaryopoiesis Via up-Regulating PI3K-AKT Pathway
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Zhao, Hong-Yan, primary, Wen, Qi, additional, Lyu, Zhong-Shi, additional, Tang, Shu-Qian, additional, Zhang, Yuan-Yuan, additional, Lyu, Meng, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Kong, Yuan, additional, and Huang, Xiao-Jun, additional
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- 2020
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16. M1 and M2 Macrophages Play Different Roles in the Pathogenesis of Acute Graft-Versus-Host Disease Post-Allotransplant By Modulating Immune Microenvironment
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Yao Weili, Ting-Ting Han, Xiao-Jun Huang, Xiao-Hui Zhang, Zhong-Shi Lyu, Yu-Hong Chen, Lan-Ping Xu, Hong-Yan Zhao, Qi Wen, Yu Wang, and Yuan Kong
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integumentary system ,business.industry ,Immune microenvironment ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Pathogenesis ,surgical procedures, operative ,immune system diseases ,hemic and lymphatic diseases ,Acute graft versus host disease ,Medicine ,business - Abstract
Background: Acute graft-versus-host disease(aGVHD) remains a major complication following allogeneic hematopoietic stem cell transplantation(allo-HSCT). The pathogenesis of aGVHD is commonly considered to be caused by exaggerated and undesirable immune responses. Macrophages (MΦs) are an important immune population that are essential for disease pathogenesis. MΦs are now commonly classified as either M1, which produce pro-inflammatory cytokines, or M2, which produce anti-inflammatory cytokines. Our recent study reported that patients who received an allograft with a higher M1/M2 ratio exhibited a higher incidence of grade 2-4 aGVHD(BMT, 2019). Moreover, an aberrant M1/M2 polarization was found in the colon of aGVHD mice, and regulating the polarization of MΦs cultured from aGVHD patients towards M2 phenotype modulated T cells favoring a type 2 response in vitro(Sci China Life Sci, 2020). However, the primary subsets and function of MΦs in aGVHD patients, and the precise roles of different MΦ subsets in the development of aGVHD remain to be elucidated. Aims: To determine the subsets and function of MΦs in primary peripheral blood(PB) of aGVHD patients. Moreover, to investigate whether M1 and M2 had different effects on the development of aGVHD, which may provide a potential therapeutic target for aGVHD patients after allo-HSCT. Methods: In this prospective case-control study, a total of 20 patients with aGVHD and 20 matched patients without aGVHD(non-aGVHD) after allo-HSCT were enrolled. MΦ subsets were analyzed in aGVHD and non-aGVHD patients by flow cytometry. M1 and M2 were identified as CD14+CCR2+CD68+ and CD14+CX3CR1+CD163+, respectively. In order to determine the function of MΦs in patients with aGVHD and non-aGVHD, the phagocytosis was analyzed using a DiI-AcLDL assay. The protein expressions for the costimulatory molecules and the cytokine production of MΦs were measured by flow cytometry. To further investigate its mechanism, RNA sequencing (RNA-Seq) was performed to analyze the gene expression profiles of MΦs. Subsequently, to explore the role of different subsets of MΦs in the development of aGVHD, M1 and M2 were infused into aGVHD mice, respectively. Mice were monitored for survival, weight, and aGVHD score. Histological scores of tissues from aGVHD target organs (liver, intestine, spleen and skin) were evaluated by HE staining. Results: When compared with non-aGVHD patients, MΦs in primary PB of aGVHD patients were polarized towards pro-inflammatory M1, characterized by an elevated proportion of M1 and a reduced proportion of M2. Furthermore, MΦs isolated from aGVHD patients exhibited lower phagocytic function, higher expression of TNF-α and IL-6 and higher expression of costimulatory molecules CD80 and CD86. Consistent with the increased activated MΦs from aGVHD patients, the mRNA levels of genes involved in the pro-inflammatory M1 polarization, antigen presenting and promoting the activation of T cells pathway were substantially elevated in MΦs of aGVHD patients compared to those in non-aGVHD patients. Importantly, in vivo infusion with pro-inflammatory M1 aggravated aGVHD response by modulating immune microenvironment of spleen and liver in mice, characterized by enhanced effector function of T cell, including elevated percentages of Tc1, Th1 and Th17 as well as increased proliferation of T cells from spleen and liver. By contrast, infusion with anti-inflammatory M2 alleviated aGVHD through down-regulating the activity of T cells derived from aGVHD mice, characterized by decreased proliferation and decreased percentages of Tc1, Th1 and Th17. Summary/Conclusion: The current study demonstrated that the primary MΦs in aGVHD patients preferentially polarize into pro-inflammatory M1. Moreover, M1 aggravate aGVHD whereas M2 ameliorate aGVHD by differently modulating immune microenvironment. Although further validation is required, modulating the polarization state of MΦs promises to be a novel therapeutic target for aGVHD patients after allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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- 2020
17. Different Subsets of Haematopoietic Cells and Immune Cells in Bone Marrow between Young and Old Donors
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Xiao-Hui Zhang, Wei-Li Yao, Yuan-Yuan Zhang, Hong-Yan Zhao, Yuan Kong, Shu-Qian Tang, Xiao-Jun Huang, Qi Wen, Lan-Ping Xu, and Yu Wang
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Myeloid ,Naive T cell ,T cell ,Immunology ,hemic and immune systems ,Cell Biology ,Hematology ,CD38 ,Biology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,medicine ,Progenitor cell ,Memory T cell ,CD8 - Abstract
Background Young donors are reported to be associated with better transplant outcomes than old donors in allo-HSCT, but the underlying mechanism is still uncertain. Successful allo-HSCT relies on the rapid reconstitution of donor-derived haematopoietic and immune systems in the recipient. Therefore, characterizing the differences in percentages of HSCs and progenitors and immune cell subtypes between young and old donors may help explain the disparities in transplant outcomes. In humans, HSCs give rise to multipotent progenitors (MPPs) that further segregate into either common myeloid progenitors (CMPs) or multipotent lymphoid progenitors (MLPs), which in turn segregate into either common lymphoid progenitors (CLPs) or granulocyte-macrophage progenitors (GMPs). CMPs further segregate into either megakaryocyte-erythroid progenitor (MEPs), or GMPs. However, differences in the frequencies of HSCs and their progenitors between young and old adults remain uncertain. In addition, aGVHD is generally considered to be associated with increased ratios of donor Th1/Th2, Tc1/Tc2 and M1/M2 macrophage. However, little is known about the cytokine-producing T cell subsets and macrophage subsets in BM between young and old donors. Aims To evaluate the different subsets of HSCs and their progenitors and immune cells among young (aged 45 years). Moreover, to analyze the association between donor characteristics and HSC frequency. M ethods In this prospective study, a total of 60 healthy adult donors, including 20 young donors, 20 middle-aged donors, and 20 old donors were enrolled. The frequencies and ROS levels of BM HSCs(CD34+CD38−CD90+CD45RA−) and progenitors including MPPs(CD34+CD38−CD90−CD45RA−), MLPs(CD34+CD38−CD45RA+), CLPs(CD34+CD38+CD7−CD10+CD45RA+), GMPs(CD34+CD38+CD7−CD10−CD45RA+), CMPs(CD34+CD38+CD7−CD10−CD135+CD45RA+), and MEPs(CD34+CD38+CD7−CD10−CD135−CD45RA−) were quantified by flow cytometry. Furthermore, T cell and macrophage subsets were analyzed in young, middle-aged and old donors by flow cytometry. Effector T cells, naïve T cells, effector memory T cells and central memory T cells were identified as CD45RA+CCR7−, CD45RA+CCR7+, CD45RA−CCR7−, and CD45RA−CCR7+. Th1, Th2, Tc1 and Tc2 were identified as CD3+CD8−IFN-γ+, CD3+CD8−IL-4+, CD3+CD8+IFN-γ+ and CD3+CD8+IL-4+, respectively. In addition, M1 and M2 were identified as CD14+CCR2+CD68+ and CD14+CX3CR1+CD163+. Moreover, the association of donor characteristics with HSC frequency was analysed by univariate and multivariate analysis. Results To determine the differences in HSCs and progenitors in different age donors, HSCs and six subpopulations were compared among young, middle-aged and old donors. The frequencies of HSCs and myeloid progenitors, including CMPs and MEPs in CD34+ cells were significantly lower and the frequencies of lymphoid progenitors including MLPs and CLPs in CD34+ cells were higher in the BM of young donors than in that of old donors. Significantly lower levels of ROS in HSCs and progenitors were observed in young donors than in the other donors. Furthermore, to investigate the differences in the differentiation potential from HSCs to immune cells in different age donors, T cell and macrophage subsets were compared among the three donor age groups. Young donors demonstrated a lower CD4+/CD8+ T cell ratio, lower memory T cell frequency and higher naïve T cell frequency in both CD4+ cells and CD8+ cells. Importantly, BM immune cells from young donors polarized towards less pro-inflammatory T cells characterized by Th1 and Tc1, and more immune suppressor cells, such as M2, than those from old donors. As a result, young donors had lower ratios of Th1/Th2, Tc1/Tc2 and M1/M2 in BM. In addition, multivariate analysis showed that age≥37 was independently correlated with a higher HSC frequency. Conclusion BM HSCs from young donors exhibited a lower frequency, balanced myeloid-lymphoid differentiation potential, lower ROS level and produced more immune suppressors and fewer immune effector cells than those from old donors. Donor age might be a good predictor of HSC frequency. Although further validation is required, the differences in the frequency and immune differentiation potential of HSCs in BM between young and old donors may partly explain the different outcomes of allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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- 2020
18. Glycolysis Restoration Attenuates Damaged Bone Marrow Endothelial Cells
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Lyu, Zhong-Shi, primary, Yao, Wei-Li, additional, Wen, Qi, additional, Zhao, Hong-Yan, additional, Tang, Fei-Fei, additional, Wang, Yu, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, Lee, Hsiang-Ying, additional, Huang, Xiao-Jun, additional, and Kong, Yuan, additional
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- 2019
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19. Autophagy in Endothelial Cells Regulates Their Hematopoiesis Supporting Ability
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Kong, Yuan, primary, Cao, Xie-Na, additional, Lyu, Zhong-Shi, additional, Mo, Xiao-Dong, additional, Wen, Qi, additional, Zhao, Hong-Yan, additional, Chen, Yu-Hong, additional, Wang, Yu, additional, Chang, Ying-Jun, additional, Xu, Lan-Ping, additional, Zhang, Xiao-Hui, additional, and Huang, Xiao-Jun, additional
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- 2019
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20. 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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Mengge, Gao, primary, Hong, Yan, additional, Sun, Yuqian, additional, Kong, Jun, additional, Yan, Chenhua, additional, Wang, Zhidong, additional, Wang, Yu, additional, Huang, Xiaojun, additional, and Zhao, Xiaosu, additional
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- 2019
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21. M2 Macrophages, but Not M1 Macrophages, Support Megakaryopoiesis Via up-Regulating PI3K-AKT Pathway
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Qi Wen, Shu-Qian Tang, Yuan Kong, Zhong-Shi Lyu, Hong-Yan Zhao, Meng Lyu, Yuan-Yuan Zhang, Lan-Ping Xu, Yu Wang, Xiao-Hui Zhang, and Xiao-Jun Huang
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Chemistry ,Immunology ,AKT1 ,Cell Biology ,Hematology ,Biochemistry ,Apoptosis ,Cancer research ,Tumor necrosis factor alpha ,Cytokine secretion ,Peripheral blood cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Megakaryopoiesis - Abstract
Background Megakaryopoiesis and platelets production intensely depend on bone marrow(BM) microenvironment. Our previous studies found that impaired BM microenvironment and dysfunctional megakaryopoiesis are responsible for the occurrence of prolonged isolated thrombocytopenia (PT), which is defined as the engraftment of all peripheral blood cell lines other than a platelet count less than 20×109/L or a dependence on platelet transfusions for more than 60 days following allo-HSCT(BBMT 2014; BBMT 2017; Brit J Haematol 2018; Am J Hematol 2018). As an important component of the BM microenvironment, macrophages (MՓs) are heterogeneous and polarized into classically activated (M1) MՓs and alternatively activated (M2) MՓs with distinct phenotypes and function. Although inconsistent effect of BM MՓs was reported on megakaryopoiesis, the functional role of M1 and M2 MՓs and related pathway in regulating megakaryopoiesis and its effect on PT patients post-allotransplant remain to be elucidated. Aims To address the roles of M1 MФs and M2 MФs in regulating megakaryopoiesis as well as PI3K-AKT pathway in the process. Moreover, polarization status and the function of BM MФs in regulating megakaryopoiesis were evaluated in PT patients. Methods This prospective nested case-control study enrolled 12 patients with PT, 24 matched patients with good graft function (GGF), defined as persistent successful engraftment after allotransplant, and 12 healthy donors (HD). BM standard monocyte subsets and M1/M2 MՓs polarization state were analyzed by flow cytometry. To generate M1 and M2 MՓs, both primary BM MՓs and THP1 cell lines were treated with LPS and IFN-γ or with IL-4 and IL-13. The functions of BM MՓs were evaluated by migration, phagocytosis and cytokine secretion assay. The sorted CD34+ cells from HD were co-cultured with BM MՓs from PT and GGF patients or M1 and M2 MՓs respectively for megakaryopoiesis. The quantification of the megakaryocytes(MKs), MKs apoptosis, MKs polyploidy distribution, colony-forming unit MK(CFU-MK) efficiency, and platelet production were analyzed in the coculture system. To understand the underlying mechanism of MՓs polarization in regulating MKs, RNA-seq analyses were performed in BM MՓs from PT and GGF patients. In addition, M1 and M2 MՓs were treated with the chemical inhibitors and lentivirus for PI3K-AKT pathway. Results Elevated intermediate and non-classical monocyte subsets were found in PT patients when compared with those in GGF patients. Moreover, PT patients displayed increased M1 and reduced M2 MՓs, resulting an unbalanced M1/M2 polarization, compared with GGF and HD. BM MՓs from PT patients, with high TNF-α levels and low TGF-β levels, showed decreased megakaryopoiesis-supporting ability. No significant differences in migration and phagocytosis function of MՓs among the three groups. RNA sequencing of BM MՓs showed down-regulated PI3K-AKT pathway in MՓs of PT patients compared with GGF. Consistently, the phosphorylation levels of AKT decreased significantly in MՓs of PT patients, suggesting that PI3K-AKT pathway may functionally regulate megakaryopoiesis-supporting ability of MՓs. Subsequently, BM-M2 and THP1-M2 showed superior effect on megakaryopoiesis-supporting ability compared with BM-M1 and THP1-M1. Specifically, the BM CD34+ cells cocultured with M2 MՓs demonstrated significant increased percentages of MKs and MK polyploidy, CFU-MK efficiency, and platelet count compared with those cocultured with M1 MՓs. Preventing PI3K-AKT pathway by PI3K inhibitor or Akt inhibitor significantly reduced the megakaryopoiesis-supporting ability of M2 MՓs. Moreover, knockdown of AKT1 induced the impairment of megakaryopoiesis-supporting ability via suppressing M2 MՓs polarization, which could be attenuated by AKT1 overexpression complementarily. Summary/Conclusion The current study demonstrated the polarization status of MՓs modulates their ability to support megakaryopoiesis. M2 MՓs, but not M1 MՓs, support megakaryopoiesis via up-regulating PI3K-AKT pathway. Defective M2 MՓs polarization via down-regulating PI3K-AKT pathway may be responsible for the pathogenesis of PT post-allotransplant, which provides a promising therapeutic target for PT patients. Disclosures No relevant conflicts of interest to declare.
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- 2020
22. Gene expression profile in human leukocytes
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Hashimoto, Shin-ichi, Nagai, Shigenori, Sese, Jun, Suzuki, Takuji, Obata, Aya, Sato, Taku, Toyoda, Nobuaki, Dong, Hong-Yan, Kurachi, Makoto, Nagahata, Tomoyuki, Shizuno, Ken-ichi, Morishita, Shinichi, and Matsushima, Kouji
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- 2003
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23. Glycolysis Restoration Attenuates Damaged Bone Marrow Endothelial Cells
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Wei-Li Yao, Xiao-Jun Huang, Yuan Kong, Hsiang-Ying Lee, Qi Wen, Yu Wang, Hong-Yan Zhao, Fei-Fei Tang, Xiao-Hui Zhang, Zhong-Shi Lyu, and Lan-Ping Xu
- Subjects
Tube formation ,Angiogenesis ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,GW501516 ,Transplantation ,Haematopoiesis ,Apoptosis ,Cancer research ,medicine ,Glycolysis ,Stem cell ,business - Abstract
Background: Bone marrow(BM) endothelial cells(ECs), a key component of BM microenvironment, is essential for the physiology and regeneration of hematopoietic stem cells (HSCs). The damage of ECs is recognized by us and other researchers as a mainstay in the pathophysiology of a serious of life-threatening complications after chemoradiotherapy and myeloablative hematopoietic cell transplantation(HSCT), including poor graft function (PGF) (2013BBMT, 2015BMT, 2016Blood, 2019Blood Advances). Despite numerous researches focused on the BM ECs contributing to HSC regeneration following myelotoxicity, the mechanisms underlying the injured BM ECs itself remain to be elucidated. Under physiological conditions, energy metabolism plays an instrumental role in maintaining EC function, and markedly perturbed of EC metabolism is linked to many pathologies, like cancer and diabetes. However, little is known about the metabolism state and its role in impaired BM ECs. Aims: The current study was performed to investigate the metabolism status in BM ECs after chemotherapy-induced injury. Moreover, we evaluated the metabolic state and its role in BM ECs of PGF patients post-allotransplant. Finally, we evaluated the therapeutical potential of anti-metabolic drugs to the dysfunctional BM ECs derived from PGF patients. Methods: Two EC injury models in vitro were established with the cultivated human BM ECs treated by 5-Fluorouracil (5-FU) and hydrogen peroxide. The findings from the above models were further validated by a prospective case-control study enrolled 15 patients with PGF, 30 matched patients with good graft function (GGF) and 15 healthy donors (HD). To determine the metabolic status of BM ECs, the expression of metabolism regulating genes was analyzed by qRT-PCR (mRNA level) and flow cytometry (protein level). Glucose metabolism levels were measured by glucose consumption and lactate production assays. To evaluate the functions of BM ECs, apoptosis, migration and tube formation assays were performed. To investigate the effect of anti-metabolic drugs to injured BM ECs, the glycolysis inhibitor 3PO and PPARd agonist GW501516 were administrated to the cultivated BM ECs treated by 5-FU , hydrogen peroxide or derived from PGF. Results: We demonstrated that the glycolysis in BM ECs could be induced by the treatment with either 5-FU or hydrogen peroxide in vitro, consistent with the dysfunction(impaired migration, angiogenesis, and higher level of apoptosis) of BM ECs, which could be attenuated by glycolysis restoration. Mechanistically, we revealed that the aberrant glycolysis and dysfunction of BM ECs could be triggered by PPARd knockdown in vitro, while the PPARd were down-regulated by either 5-FU or hydrogen peroxide treatment in vitro, Furthermore, PPARd agonist GW501516 treatment attenuated the perturbed function and number of injured BM ECs treated by either 5-FU or hydrogen peroxide. Subsequently, the prospective case-control study demonstrated elevated expressions of the glycolytic activator PFKFB3 and decreased PPARd were observed in BM ECs of PGF patients, when compared with those of GGF patients and HD, indicating that BM ECs of PGF patients have a hyper-glycolytic metabolism. Moreover, either glycolysis (PFKFB3) inhibitor 3PO or PPARd agonist GW501516 treatment reduced the aberrant glycolysis and improved the number and function of BM ECs derived from patients with PGF in vitro, revealing the critical role of defective glycolysis in the impaired BM ECs of PGF. Summary / Conclusions: These findings reveal that hyper-glycolysis mediated by PPARd inhibition is involved in the dysfunction of BM ECs after injury. Defective glycolysis may contribute to the pathobiology of BM ECs of PGF patients, which could be attenuated by glycolysis inhibitor 3PO or PPARd agonist GW501516 in vitro. Our findings might merit further consideration of targeting BM ECs glycolysis or PPARd as a promising therapeutic approach for PGF patients post-allotransplant in the future. Disclosures No relevant conflicts of interest to declare.
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- 2019
24. 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
- Author
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Wang, Ke, primary, Lv, Meng, additional, Chang, Ying-Jun, additional, Zhao, Xiang-Yu, additional, Zhao, Xiao-Su, additional, Zhang, Yuan-Yuan, additional, Sun, Yu-Qian, additional, Wang, Zhi-Dong, additional, Suo, Pan, additional, Zhou, Yang, additional, Liu, Dan, additional, Zhai, Shu-Zhen, additional, Hong, Yan, additional, Wang, Yu, additional, Zhang, Xiao-Hui, additional, Xu, Lan-Ping, additional, Liu, Kaiyan, additional, and Huang, Xiao-Jun, additional
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- 2018
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25. Serial Analysis of Gene Expression in Human Monocyte-Derived Dendritic Cells
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Hashimoto, Shin-ichi, Suzuki, Takuji, Dong, Hong-Yan, Nagai, Shigenori, Yamazaki, Nobuyuki, and Matsushima, Kouji
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- 1999
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26. Serial Analysis of Gene Expression in Human Monocytes and Macrophages
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Hashimoto, Shin-ichi, Suzuki, Takuji, Dong, Hong-Yan, Yamazaki, Nobuyuki, and Matsushima, Kouji
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- 1999
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27. The Clinical Significance of Monitoring Expression Level of Sil-TAL1 Fusion Gene after Allogeneic Hematopoietic Stem Cell Transplantation
- Author
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Zhao, Xiaosu, primary, Hong, Yan, additional, Qin, Yazhen, additional, Chang, Yingjun, additional, Zhang, Xiaohui, additional, Xu, Lanping, additional, and Huang, Xiao Jun, additional
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- 2016
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28. Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE
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Hong-Yan Dong, Takuji Suzuki, Jun Sakai, Kouji Matsushima, Nobuyuki Yamazaki, Nobuaki Toyoda, Taro Yamashita, Shigenori Nagai, Toshihiro Nukiwa, and Shin-ichi Hashimoto
- Subjects
Immunology ,CCL4 ,Cell Biology ,Hematology ,Biology ,CCL7 ,Biochemistry ,CCL8 ,Molecular biology ,CXCL2 ,CXCL10 ,Interleukin 19 ,CCL15 ,CCL13 - Abstract
Monocytes play a pivotal role in various human infectious and inflammatory diseases. To reveal a whole picture of pathophysiologic function of activated human monocytes, this study used the serial analysis of gene expression (SAGE) procedure in lipopolysaccharide (LPS)-stimulated human monocytes. A total of 35 874 tags corresponding to more than 12 000 different transcripts were sequenced. Comparison of gene expression profile with that of resting monocytes revealed the LPS-inducible gene expression profile. Many cytokines and chemokines, including interleukin (IL)-6, IL-1α, IL-1β, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, MIP-2β, MIP-2α, liver and activation-regulated chemokine (LARC), MIP-1α, thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), growth-regulated oncogene (GRO) α, and IL-8, were observed in the highest inducible transcripts. Other genes encoding plasminogen activator inhibitor type 2 (PAI-2), Hc-gp39, apolipoproteins, malate dehydrogenase, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase (COX2) were also highly elevated in LPS-stimulated monocytes. Moreover, up-regulation of Naf1β, IL-7 receptor, adenosine receptor A2a, and many novel genes was newly identified. These results suggest that the LPS-inducible gene products may be involved in cell activation and migration, angiogenesis, tissue remodeling, and metabolism, and thus may orchestrate the inflammatory reactions. On the other hand, the expression of numerous sets of novel genes was discovered to be down-regulated on LPS stimulation. This study represents the first comprehensive analysis of LPS-inducible gene expression in human monocytes and provides tremendous novel information for the function of LPS-activated monocytes and targets for diagnosing, monitoring, and treating sepsis and various human infectious and inflammatory diseases.
- Published
- 2000
29. Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31
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Stephen K. Horrigan, Zarema H. Arbieva, Hong Yan Xie, Jelena Kravarusic, Noreen C. Fulton, Haley Naik, Tiffany T. Le, and Carol A. Westbrook
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hemic and lymphatic diseases ,Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Interstitial deletion or loss of chromosome 5 is frequent in malignant myeloid disorders, including myelodysplasia (MDS) and acute myeloid leukemia (AML), suggesting the presence of a tumor suppressor gene. Loss of heterozygosity (LOH) analysis was used to define a minimal deletion interval for this gene. Polymorphic markers on 5q31 were identified using a high-resolution physical and radiation hybrid breakpoint map and applied to a patient with AML with a subcytogenetic deletion of 5q. By comparing the DNA from leukemic cells to buccal mucosa cells, LOH was detected with markers D5S476 and D5S1372 with retention of flanking markers D5S500 to D5S594. The D5S500–D5S594 interval, which covers approximately 700 kb, thus represents a minimal localization for the tumor suppressor gene. Further refinement of the physical map enabled the specification of 9 transcription units within the encompassing radiation hybrid bins and 7 in flanking bins. The 9 candidates include genes CDC25, HSPA9, EGR1, CTNNA1, and 5 unknown ESTs. Reverse-transcription polymerase chain reaction confirms that all of them are expressed in normal human bone marrow CD34+ cells and in AML cell lines and thus represent likely candidates for the MDS–AML tumor suppressor gene at 5q31.
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- 2000
30. Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31
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Zarema Arbieva, Tiffany Le, Hong Yan Xie, Haley B. Naik, Stephen K. Horrigan, Jelena Kravarusic, Carol A. Westbrook, and Noreen Fulton
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Expressed sequence tag ,Myeloid ,Tumor suppressor gene ,Immunology ,Breakpoint ,CD34 ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,Loss of heterozygosity ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Cancer research ,medicine ,Gene - Abstract
Interstitial deletion or loss of chromosome 5 is frequent in malignant myeloid disorders, including myelodysplasia (MDS) and acute myeloid leukemia (AML), suggesting the presence of a tumor suppressor gene. Loss of heterozygosity (LOH) analysis was used to define a minimal deletion interval for this gene. Polymorphic markers on 5q31 were identified using a high-resolution physical and radiation hybrid breakpoint map and applied to a patient with AML with a subcytogenetic deletion of 5q. By comparing the DNA from leukemic cells to buccal mucosa cells, LOH was detected with markers D5S476 and D5S1372 with retention of flanking markers D5S500 to D5S594. The D5S500–D5S594 interval, which covers approximately 700 kb, thus represents a minimal localization for the tumor suppressor gene. Further refinement of the physical map enabled the specification of 9 transcription units within the encompassing radiation hybrid bins and 7 in flanking bins. The 9 candidates include genes CDC25, HSPA9, EGR1, CTNNA1, and 5 unknown ESTs. Reverse-transcription polymerase chain reaction confirms that all of them are expressed in normal human bone marrow CD34+ cells and in AML cell lines and thus represent likely candidates for the MDS–AML tumor suppressor gene at 5q31.
- Published
- 2000
31. Serial Analysis of Gene Expression in Human Monocyte-Derived Dendritic Cells
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Hong Yan Dong, Kouji Matsushima, Nobuyuki Yamazaki, Shin-ichi Hashimoto, Takuji Suzuki, and Shigenori Nagai
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Chemokine ,Cellular differentiation ,Immunology ,Antigen presentation ,Gene Expression ,Biochemistry ,Monocytes ,medicine ,Humans ,Serial analysis of gene expression ,Cells, Cultured ,Antigen Presentation ,biology ,Follicular dendritic cells ,Tumor Necrosis Factor-alpha ,Monocyte ,Granulocyte-Macrophage Colony-Stimulating Factor ,Cell Differentiation ,Dendritic Cells ,Cell Biology ,Hematology ,Dendritic cell ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Interleukin-4 ,Bone marrow ,Chemokines - Abstract
Dendritic cells (DCs) are professional antigen-presenting cells in the immune system and can be generated in vitro from hematopoietic progenitor cells in the bone marrow, CD34(+) cord blood cells, precursor cells in the peripheral blood, and blood monocytes by culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4, and tumor necrosis factor-alpha. We have performed serial analysis of gene expression (SAGE) in DCs derived from human blood monocytes. A total of 58,540 tag sequences from a DC complementary DNA (cDNA) library represented more than 17,000 different genes, and these data were compared with SAGE analysis of tags from monocytes (Mo) and GM-CSF-induced macrophages (M open diamond). Many of the genes that were differentially expressed in DCs were identified as genes encoding proteins related to cell structure and cell motility. Interestingly, the highly expressed genes in DCs encode chemokines such as TARC, MDC, and MCP-4, which preferentially chemoattract Th2-type lymphocytes. Although DCs have been considered to be very heterogeneous, the identification of specific genes expressed in human Mo-derived DCs should provide candidate genes to define subsets of, the function of, and the maturation stage of DCs and possibly also to diagnose diseases in which DCs play a significant role, such as autoimmune diseases and neoplasms. This study represents the first extensive gene expression analysis in any type of DCs.
- Published
- 1999
32. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene
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Peter E. Manley, Hong Yan Du, Susan J. Bayliss, Monica Bessler, David B. Wilson, Philip J. Mason, Elena Pumbo, and Joshua J. Field
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Adult ,Male ,Proband ,Telomerase ,Clinical Trials and Observations ,Immunology ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Biochemistry ,Dyskeratosis Congenita ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Child ,Aged, 80 and over ,Genetics ,Mutation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Molecular biology ,Pedigree ,Telomere ,Complementation ,Female ,Dyskeratosis congenita - Abstract
Heterozygous mutations in the telomerase components TERT, the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.
- Published
- 2008
33. Detection and Monitoring of BRAF and NRAS Mutant Clones in Myeloma Patients By Digital PCR of Circulating DNA
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Rustad, Even Holth, primary, Dai, Hong Yan, additional, Coward, Eivind, additional, Misund, Kristine, additional, Sundan, Anders, additional, and Waage, Anders, additional
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- 2015
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34. Impact of Chemotherapy Delay on Overall Survival for AML with I DH1/2 Mutations: A Study in Adult Chinese Patients
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Wang, Jing Han, primary, Guo, Qi, additional, Ma, Zhi Xin, additional, Ma, Qiu Ling, additional, Yu, Meng Xia, additional, Yin, Xiu Feng, additional, Lu, Sha Sha, additional, Xie, Qiong Hong, additional, Jiang, Yue Hong, additional, Shen, Dan, additional, Ma, li Ya, additional, Shi, Hui, additional, Yu, Wen Juan, additional, Lou, Ye Jiang, additional, Li, Ying, additional, Yang, Min, additional, Xu, Gai Xiang, additional, Mao, Li Ping, additional, Li, Jian Hu, additional, Wang, Fan Ping, additional, Wang, Dong Mei, additional, Wei, Ju Ying, additional, Tong, Hong Yan, additional, Huang, Jian, additional, and Jin, Jie, additional
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- 2015
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35. Impact of Chemotherapy Delay on Overall Survival for AML with I DH1/2 Mutations: A Study in Adult Chinese Patients
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Wen Juan Yu, Ying Li, Meng Xia Yu, Hui Shi, Li Ping Mao, Xiu Feng Yin, Dongmei Wang, Fan Ping Wang, Sha Sha Lu, Hong Yan Tong, Jie Jin, Qiong Hong Xie, Ye Jiang Lou, Gai Xiang Xu, Qiu Ling Ma, Jing Han Wang, Min Yang, Dan Shen, li Ya Ma, Jian Huang, Yue Hong Jiang, Ju Ying Wei, Qi Guo, Jian Hu Li, and Zhi Xin Ma
- Subjects
Oncology ,medicine.medical_specialty ,NPM1 ,Chemotherapy ,IDH1 ,business.industry ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Context (language use) ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Internal medicine ,CEBPA ,medicine ,Adverse effect ,business - Abstract
The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remain obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3 ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wild type. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
36. Detection and Monitoring of BRAF and NRAS Mutant Clones in Myeloma Patients By Digital PCR of Circulating DNA
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Eivind Coward, Even H Rustad, Hong Yan Dai, Anders Sundan, Kristine Misund, and Anders Waage
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Immunology ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,Targeted Mutation ,Biopsy ,medicine ,Mutation testing ,Plasmacytoma ,Digital polymerase chain reaction ,Bone marrow ,Multiple myeloma - Abstract
Introduction Targeted mutation specific therapy is a promising approach in cancer therapy. However, an obstacle for this approach is the vast heterogeneity of the clonal composition and development. Tumor biopsies represent only a snapshot of the situation. Furthermore, monitoring of the clonal development is difficult because biopsies may not be representative for the whole tumor and availability of repeat biopsies is limited. To meet these difficulties we have established and optimized a method based on Digital PCR (dPCR) for analyses of circulating cell free (cf)DNA from sequential samples of serum and plasma from patients with multiple myeloma. Methods We investigated 19 patients for the BRAF V600E mutation. Nine were previously confirmed as mutation positive in bone marrow biopsies/purfied plasma cells by two independent methods (PCR/immunohistochemistry/whole exome sequencing) whereas 10 were mutation negative (Rustad et al Blood Cancer J 2015). Two patients with NRAS Q61K mutation detected in serial bone marrow samples were also included. In total, 67 serum and 21 EDTA-plasma samples were analyzed. Blood samples were taken, processed and frozen at -800 C within 1,5 hour. The samples were stored for a median of 5 years (range 0-23) before DNA isolation and analysis. Mutation detection by dPCR was performed using a droplet-based system and validated primer/probe-sets (BioRad). In-house validation and optimization of the assay was carried out using cancer cell lines OH2 and HT29 with NRAS Q61 and BRAF V600E mutations respectively. The limit of detection was 1-3 copies of mutated DNA per reaction and no false positives were detected. The threshold of positivity was set to 1 droplet per sample. Experiments were performed in accordance with the Minimum Information for Publication of Digital PCR Experiments (dMIQE) guidelines (Huggett et al Clin Chem 2013). Results BRAF or NRAS mutated cfDNA was detected in all patients with a confirmed mutation in tumor tissue, and in none of the mutation-negative controls (p = 0.000003, Fisher's exact test). When looking only at tumor tissue and blood samples obtained at the same time, mutation positivity was confirmed in the blood of 9/10 patients (p = 0.00012). Furthermore, there was a positive correlation between the percentage of mutated plasma cells in bone marrow biopsies and the concentration of mutated cfDNA (Spearman correlation R = 0.63, p = 0.025). Serial samples were analyzed from 5 patients and provided information about 3 different aspects: 1. Patients 1 (figure), 2 and 3, had large clones (50-100 %) of BRAF or NRAS mutated cells in diagnostic and relapse bone marrow samples. Mutated cfDNA correlated closely to M-protein levels in these patients as demonstrated in the figure. A corollary of the figure is that the BRAF mutated clone produces M protein and is sensitive to MP. 2. Patient 4 developed a pelvic extra medullary plasmacytoma with 75-100% BRAF mutation positive cells (immunohistochemistry), however, time-matched serum samples showed only a modest peak with 23 mutated copies/ml. 3. Patient 5 had a moderately sized BRAF V600E mutated clone of 50-75 % at diagnosis, which, according to serum levels, persisted through the disease course. However, two months prior to death, the patient rapidly deteriorated and became refractory to treatment. BM aspirate showed 95 % plasma cells with plasmablastic morphology. A serum sample contained > 600 ng/ml of cfDNA, 10-100 fold more than any other sample in our study, and was highly positive for BRAF V600E mutation (59 000 copies/ml). The patient clearly had expansion of an aggressive BRAF mutated clone that could easily be detected by serum analysis. Conclusions This study demonstrates that mutations such as BRAF V600E and NRAS Q61K can be reliably detected and monitored in sequential serum or plasma samples from myeloma patients. Quantitative mutation analysis compared to M protein in sequential samples provided significant information with clinical relevance. The great advantage of this approach is the easy access to blood samples compared to bone marrow aspirate/biopsy. This will facilitate studies of clonal development during treatment and detection of druggable mutations. Figure 1. Co-variation of M-protein and circulating BRAF V600E mutated DNA in patient 1. Figure 1. Co-variation of M-protein and circulating BRAF V600E mutated DNA in patient 1. Disclosures Waage: Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding.
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- 2015
37. Clinical and Biological Implications of BRAF V600E Mutation in Multiple Myeloma
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Rustad, Even Holth, primary, Dai, Hong Yan, additional, Hov, Haakon, additional, Coward, Eivind, additional, Beisvag, Vidar, additional, Myklebost, Ola, additional, Hovig, Eivind, additional, Nakken, Sigve, additional, Vodák, Daniel, additional, Meza-Zepeda, Leonardo A, additional, Sandvik, Arne K, additional, Wader, Karin Fahl, additional, Misund, Kristine, additional, Sundan, Anders, additional, Aarset, Harald, additional, and Waage, Anders, additional
- Published
- 2014
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38. TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements
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Jeffrey M. Lipton, Akiko Shimamura, Frederick D. Goldman, Jennifer Ivanovich, Monica Bessler, Philip J. Mason, Deborah Chirnomas, Ping An, Hong Yan Du, Elena Pumbo, Adrianna Vlachos, Richard T. Maziarz, David B. Wilson, Ulrike M. Reiss, and Rakesh K. Goyal
- Subjects
Adult ,Male ,Telomerase ,TERT Gene Mutation ,Hematopoiesis and Stem Cells ,Immunology ,Biology ,TINF2 ,medicine.disease_cause ,Biochemistry ,Dyskeratosis Congenita ,Telomerase RNA component ,Young Adult ,medicine ,Humans ,Child ,Bone Marrow Diseases ,Mutation ,Bone marrow failure ,Infant ,Cell Biology ,Hematology ,Middle Aged ,Telomere ,medicine.disease ,Child, Preschool ,Cancer research ,RNA ,Female ,Dyskeratosis congenita - Abstract
Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (≪ 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.
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- 2008
39. Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells
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Unn-Merete Fagerli, Harald Aarset, Magne Børset, Toril Holien, Hong Yan Dai, Anders Sundan, Bart Barlogie, Randi Utne Holt, Fenghuang Zhan, Thea Kristin Vaatsveen, Kjartan Egeberg, Anders Waage, and John D. Shaughnessy
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Male ,Immunology ,Plasma Cells ,Biology ,Biochemistry ,Cell Movement ,Cell Line, Tumor ,Gene expression ,medicine ,Gene silencing ,Humans ,Gene Silencing ,RNA, Messenger ,RNA, Neoplasm ,Neoplasm Metastasis ,Multiple myeloma ,Randomized Controlled Trials as Topic ,Regulation of gene expression ,Neoplasia ,Cell Cycle ,Cell Biology ,Hematology ,Cell cycle ,medicine.disease ,Molecular biology ,Neoplasm Proteins ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cancer research ,Cytokines ,Female ,Bone marrow ,Protein Tyrosine Phosphatases ,Multiple Myeloma ,Monoclonal gammopathy of undetermined significance - Abstract
Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM). Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3, a metastasis-associated tyrosine phosphatase, was induced by several mitogenic cytokines. Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels. There was significantly higher expression of the PRL-3 gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and myeloma than in PCs from healthy persons. Among 7 MM subgroups identified by unsupervised hierarchical cluster analysis, PRL-3 gene expression was significantly higher in the 3 groups denoted as “proliferation,” “low bone disease,” and “MMSET/FGFR3.” PRL-3 protein was detected in 18 of 20 BM biopsies from patients with MM. Silencing of the PRL-3 gene by siRNA reduced cell migration in the MM cell line INA-6, but had no detectable effect on proliferation and cell-cycle phase distribution of the cells. In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells.
- Published
- 2007
40. Clinical and Biological Implications of BRAF V600E Mutation in Multiple Myeloma
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Eivind Hovig, Harald Aarset, Anders Sundan, Leonardo A. Meza-Zepeda, Eivind Coward, Hong Yan Dai, Vidar Beisvag, Haakon Hov, Sigve Nakken, Arne K. Sandvik, Daniel Vodak, Kristine Misund, Ola Myklebost, Anders Waage, Karin Fahl Wader, and Even H Rustad
- Subjects
Neuroblastoma RAS viral oncogene homolog ,business.industry ,Immunology ,Clone (cell biology) ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Lymphoma ,medicine ,Cancer research ,KRAS ,business ,Multiple myeloma ,Exome sequencing ,V600E - Abstract
In a retrospective cohort, seven patients with multiple myeloma carrying the BRAF V600E mutation had significantly shorter overall survival and higher prevalence of extramedullary disease than 251 BRAF wild type (wt) controls (Andrulis et al Cancer Discov 2013). Three case reports are in concordance with this view (Bohn et al and Sharman et al, Clin Lymphoma Myeloma Leuk, 2014). We conducted this study to further investigate the clinical and biological implications of this mutation in multiple myeloma. We used mutation-specific quantitative real-time PCR (qPCR) to screen biopsies from 209 myeloma patients, of which 185 were taken prior to first relapse. The BRAF V600E mutation was detected in 13 (6.2 %) of the patients. 10 of them also expressed the corresponding protein as evaluated by immunohistochemistry (IHC) using the BRAF V600E specific VE1 antibody, and 2 patients had simultaneous mutations in BRAF and NRAS/KRAS. RAS mutations are of particular interest because in vitro studies indicate that their presence may imply a paradoxical effect of BRAF inhibitors (Lohr et al Cancer Cell 2014). Whole exome sequencing (WES) was carried out in three BRAF V600E positive patients from whom we had stored purified myeloma cells. Among the top 11 recurrently mutated genes listed in Lohr et al (Cancer Cell 2014), we found mutations only in BRAF, NRAS, and KRAS. Clonal fraction of BRAF V600E mutated plasma cells as evaluated by IHC and WES varied from 4 to 100 %. There was agreement between detection methods in the patient with a dominating V600E mutated clone, but less so in the patients with small clones. Estimates of BRAF V600E clone size and RAS mutation analysis in 13 patients positive for BRAF V600E by qPCR | IHC (clone size, %) | WES (clone size, %) | Sanger sequencing | NRAS / KRAS mutation | | --------------------------- | --------------------------- | ------------------------- | ------------------------------------------ | | 75-100 | 86 | + | negative | | 75-100 | | negative | negative | | 75-100 | | + | negative | | 50-75 | | + | negative | | 50-75 | | + | negative | | 25-50 | | negative | negative | | 25-50 | | negative | negative | | 75 % of tumour cells, and all had indolent disease. One of them died after seven years, whereas the remaining two responded with long lasting CR to broad acting therapy (MP, MPT) and are still in remission after five and seven years. The Regional Ethics Committee approved the study (REK 2165-2012). ![Figure 1][1] Figure 1 Overall Survival from symptomatic disease In conclusion, we found no evidence supporting a prognostic role or association with a particular clinical phenotype for the BRAF V600E mutation in early multiple myeloma, which is in contrast to earlier reports. Furthermore, the three patients with a high fraction of mutated cells had a relatively benign disease responsive to conventional treatment. This study demonstrates that the role of mutation V600E is more diverse than previously assumed. Presence, and particularly high fraction of BRAF V600E mutated cells as well as translation to protein, are prerequisites for specific inhibitory treatment. However, these characteristics are alone not sufficient to predict outcome or to choose the right treatment. Disclosures Hovig: PubGene Inc.: Equity Ownership; GeneSeque AS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vodak: PubGene AS: Research Funding. [1]: pending:yes
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- 2014
41. Gene expression profile in human leukocytes
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Shigenori Nagai, Taku J. Sato, Takuji Suzuki, Tomoyuki Nagahata, Hong Yan Dong, Jun Sese, Ken Ichi Shizuno, Koji Matsushima, Makoto Kurachi, Shinichi Morishita, Shin-ichi Hashimoto, Aya Obata, and Nobuaki Toyoda
- Subjects
Databases, Factual ,Immunology ,CCR4 ,Inflammation ,Biology ,Lymphocyte Activation ,Biochemistry ,Monocytes ,Interleukin 21 ,Immune system ,medicine ,Leukocytes ,Humans ,Myeloid Cells ,Serial analysis of gene expression ,Lymphocytes ,Gene Library ,Expressed Sequence Tags ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Macrophages ,Cell Biology ,Hematology ,Dendritic Cells ,Molecular biology ,Lymphocyte Subsets ,Gene expression profiling ,Granulocyte macrophage colony-stimulating factor ,Gene Expression Regulation ,Interleukin 12 ,medicine.symptom ,Immunologic Memory ,medicine.drug - Abstract
Leukocytes are classified as myelocytic or lymphocytic, and each class of leukocytes consists of several types of cells that have different phenotypes and different roles. To define the gene expression in these cells, we have performed serial analysis of gene expression (SAGE) using human leukocytes and have provided the gene database for these cells not only at the resting stage but also at the activated stage. A total of 709 990 tags from 17 libraries were analyzed for the manifestation of gene expression profiles in various types of human leukocytes. Types of leukocytes analyzed were as follows: peripheral blood monocytes, colony-stimulating factor–induced macrophages, monocyte-derived immature dendritic cells, mature/activated dendritic cells, granulocytes, natural killer (NK) cells, resting B cells, activated B cells, naive T cells, CCR4− memory T cells (resting TH1 cells), CCR4+ memory T cells (resting TH2 cells), activated TH1 cells, and activated TH2 cells. Among 38 961 distinct tags that appeared more than once in the combined total libraries, 27 323 tags were found to represent unique genes in certain type(s) of leukocytes. Using probability (P) and hierarchical clustering analysis, we identified the genes selectively expressed in each type of leukocytes. Identification of the genes specifically expressed in different types of leukocytes provides not only a novel molecular signature to define different subsets of resting and activated cells but also contributes to further understanding of the biologic function of leukocytes in the host defense system.
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- 2003
42. Serial analysis of gene expression in human monocytes and macrophages
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Hong-Yan Dong, Shin-ichi Hashimoto, Takuji Suzuki, Kouji Matsushima, and Nobuyuki Yamazaki
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Macrophage colony-stimulating factor ,Chemokine ,Immunology ,Monoblast ,Biochemistry ,Monocytes ,medicine ,Macrophage ,Humans ,Serial analysis of gene expression ,Cells, Cultured ,biology ,U937 cell ,Monocyte ,Macrophage Colony-Stimulating Factor ,Macrophages ,Granulocyte-Macrophage Colony-Stimulating Factor ,Cell Biology ,Hematology ,Macrophage Activation ,Cell biology ,Granulocyte macrophage colony-stimulating factor ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,medicine.drug - Abstract
Monocytes/macrophages serve as sentinels involved in chronic inflammation and the eradication of various pathogens. To define molecularly the differentiation of blood monocytes into macrophages, we conducted serial analysis of gene expression (SAGE) in human blood monocytes/macrophages induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) or M-CSF. SAGE analysis of 57,560, 57,463, and 55,856 tags from monocytes, GM-CSF–, and M-CSF–induced macrophages, respectively, allowed identification of 35,037 different transcripts. Interestingly, the genes with the highest expression during differentiation from monocytes into macrophages were genes involved in lipid metabolism. Both CSF-induced macrophages expressed similar sets of genes except for several genes such as monocyte-derived chemokine (MDC), legumain, prostaglandin D synthetase, and lysosomal sialoglycoprotein. The identification of specific gene expression in human monocytes, GM-CSF–, or M-CSF–induced macrophages provides novel methods to define macrophage subsets and the maturation and activation stage of cells of macrophage lineage and, possibly, to diagnose diseases in which macrophages play a major role. This study represents the first extensive serial analysis of gene expression for any type of human hematopoietic cells.
- Published
- 1999
43. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene
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Du, Hong-Yan, Pumbo, Elena, Manley, Peter, Field, Joshua J., Bayliss, Susan J., Wilson, David B., Mason, Philip J., and Bessler, Monica
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- 2008
- Full Text
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44. P53 is Activated without RPL11 Upregulation in Diamond-Blackfan Anemia,
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Du, Hong-Yan, primary, Elghetany, M. Tarek, additional, Alter, Blanche P, additional, and Shimamura, Akiko, additional
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- 2011
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45. P53 is Activated without RPL11 Upregulation in Diamond-Blackfan Anemia
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Hong-Yan Du, M. Tarek Elghetany, Akiko Shimamura, and Blanche P. Alter
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Messenger RNA ,Gene knockdown ,biology ,Immunology ,Cell Biology ,Hematology ,Ribosomal RNA ,medicine.disease ,Biochemistry ,Molecular biology ,Ubiquitin ligase ,Downregulation and upregulation ,Ribosomal protein ,Polysome ,biology.protein ,medicine ,Diamond–Blackfan anemia - Abstract
Abstract 3432 Diamond-Blackfan anemia (DBA) is an autosomal dominantly inherited bone marrow failure syndrome characterized by red cell aplasia, physical anomalies, and cancer predisposition. DBA is caused by mutations resulting in haploinsufficiency of genes encoding ribosomal proteins. p53 is activated in the erythroid lineage following reduction of ribosomal protein expression; however the mechanism whereby ribosomal stress results in p53 activation in DBA remains unclear. RPL11 has been proposed to play a central role in p53 activation following ribosomal stress. Reduced expression of individual small ribosomal subunit proteins in a tumor cell line resulted in increased translation of RPL11. Excess free RPL11 can bind and inactivate HDM2, an E3 ubiquitin ligase targeting p53 for degradation. The recent demonstration that cellular responses to ribosomal perturbations vary widely between different tissues raised the question of whether RPL11 upregulation contributes to p53 activation following ribosomal stress in hematopoietic progenitors. To address this question, we modeled DBA in human CD34+ cells. Since RPS19 is the most commonly mutated gene in DBA, we used lentiviral vectors expressing short hairpin RNAs to knock down RPS19 expression in primary human CD34+ cells. RPS19 protein levels were reduced to about 50% of control levels in a manner reflecting the haploinsufficient state in DBA. RPS19 depletion resulted in elevated p53 protein levels and increased mRNA levels of p21, a transcriptional target of p53. Total p53 mRNA levels and p53 mRNA translational activity remained unchanged consistent with a post-transcriptional mechanism for p53 activation. Although total RPL11 mRNA levels were not diminished following RPS19 depletion, RPL11 protein levels were significantly decreased consistent with post-transcriptional downregulation. Depletion of RPS19 in human CD34+ cells did not affect polysome loading of RPL11 mRNA. Reduction of additional ribosomal proteins also accompanied RPS19 knockdown consistent with coordinate regulation of multiple ribosomal protein levels. Corticosteroids, which improve anemia in the majority of DBA patients, did not prevent p53 activation, nor did this improve RPS19 or RPL11 protein levels. Expression of p53 was also assessed in bone marrow biopsy slides from 26 DBA patients with the following genotypes: RPS19 (18), RPS24 (2), RPS26 (2), RPS10 (1), RPS17 (1), RPS7 (1), and RPL11 (1). p53 was over-expressed in all but one patient (RPS26), and was clearly over-expressed in the DBA patient harboring the RPL11 mutation. In summary, we find that p53 activation in DBA does not require upregulation of RPL11 translation or elevated RPL11 protein levels. p53 activation persists in DBA caused by RPL11 deficiency. Corticosteroids do not improve ribosomal protein levels nor do they prevent p53 activation. Disclosures: No relevant conflicts of interest to declare.
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- 2011
46. Comparison of the Effects on Reversal of Multi-Drug Resistance of 5-Bromotetrandrine and Tetrandrine in K562/A02 Cell Line in Vivo and in Vitro
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Chen, Bao-An, primary, Wang, Jue-qiong, primary, Cheng, Jian, primary, Gao, Feng, primary, Xu, Wen-lin, primary, Shen, Hui-lin, primary, Ding, Jia-hua, primary, Gao, Chong, primary, Sun, Yun-Yu, primary, Wang, Jun, primary, Zhao, Gang, primary, Song, Hui-hui, primary, Bao, Wen, primary, Sun, Xin-chen, primary, Cheng, Hong-yan, primary, Deng, Yu-xia, primary, Li, Guo-hong, primary, Liu, Li-jie, primary, Chen, Wen-ji, primary, Chen, Ning-na, primary, and Wang, Xue-mei, primary
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- 2008
- Full Text
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47. Magnetic Nanoparticle of Fe3O4 Loaded with Daunorubicin Reverse Leukemia Multidrug Resistance in Vivo
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Chen, Bao-An, primary, Lai, Bin-bin, primary, Cheng, Jian, primary, Gao, Feng, primary, Xu, Wen-lin, primary, Shen, Hui-lin, primary, Ding, Jia-hua, primary, Gao, Chong, primary, Sun, Yun-yu, primary, Wang, Jun, primary, Zhao, Gang, primary, Song, Hui-hui, primary, Bao, Wen, primary, Sun, Xin-chen, primary, Cheng, Hong-yan, primary, Deng, Yu-xia, primary, Li, Guo-hong, primary, Liu, Li-jie, primary, Chen, Wen-ji, primary, Shao, Ze-ye, primary, Xia, Guo-hua, primary, Wang, Jue-qiong, primary, Yuan, Peng, primary, Pei, Xiao-ping, primary, Chen, Ning-na, primary, Li, Qin-ning, primary, and Wang, Xue-mei, primary
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- 2008
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48. Mechanism Research of Reversal of Multidrug Resistance by the Application of 5-Bromotetrandrine and Magnetic Nanoparticle of Fe3O4 Combined with Daunorubicin in a Human-Nude Mice Xenograft Model
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Chen, Bao-An, primary, Wu, Ya-nan, primary, Cheng, Jian, primary, Gao, Feng, primary, Xu, Wen-lin, primary, Shen, Hui-lin, primary, Ding, Jia-hua, primary, Gao, Chong, primary, Sun, Yun-Yu, primary, Wang, Jun, primary, Zhao, Gang, primary, Song, Hui-hui, primary, Bao, Wen, primary, Sun, Xin-chen, primary, Cheng, Hong-yan, primary, Deng, Yu-xia, primary, Li, Guo-hong, primary, Liu, Li-jie, primary, Chen, Wen-ji, primary, Wang, Jue-qiong, primary, Yuan, Peng, primary, Pei, Xiao-ping, primary, Chen, Ning-na, primary, and Wang, Xue-mei, primary
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- 2008
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49. OH-2, a Hyperdiploid Myeloma Cell Line without An IGH Translocation, Has a Complex Translocation Juxtaposing MYC near MAFB and the IGK Locus
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Våtsveen, Thea Kristin, primary, Tian, Erming, primary, Kresse, Stine H, primary, Meza-zepeda, Leonardo A, primary, Gabrea, Ana, primary, Dai, Hong Yan, primary, Kuehl, Michael, primary, Sundan, Anders, primary, and Borset, Magne, primary
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- 2008
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50. Molecular Biological Mechanisms of Cyclosporine a, Tetrandrine and Their Combination on the Reversion of Multidrug Resistance in Leukemia Cell Line
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Chen, Bao-An, primary, Guo, Jing-jing, primary, Cheng, Jian, primary, Gao, Feng, primary, Xu, Wen-lin, primary, Shen, Hui-lin, primary, Ding, Jia-hua, primary, Gao, Chong, primary, Sun, Yun-Yu, primary, Wang, Jun, primary, Zhao, Gang, primary, Song, Hui-hui, primary, Bao, Wen, primary, Sun, Xin-chen, primary, Cheng, Hong-yan, primary, Deng, Yu-xia, primary, Li, Guo-hong, primary, Liu, Li-jie, primary, Chen, Wen-ji, primary, Wang, Jue-qiong, primary, Yuan, Peng, primary, Pei, Xiao-ping, primary, Chen, Ning-na, primary, and Wang, Xue-mei, primary
- Published
- 2008
- Full Text
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