76 results on '"Ting Niu"'
Search Results
2. Phase 2, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-BCMA CAR-T Cell Therapy, in Chinese Patients with Relapsed/Refractory Multiple Myeloma (CARTIFAN-1): 26-Month Median Follow-up
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Jian-Qing Mi, Wanhong Zhao, Hongmei Jing, Weijun Fu, Jianda Hu, Lijuan Chen, Yiwen Zhang, Dan Yao, Hui Li, Jordan M Schecter, Fan Yang, Huabin Sun, Sen Hong Zhuang, Da Xu, Tracy Luo, Xiaohu Fan, Ting Niu, Jie Jin, and Sai-Juan Chen
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Sustained Remission and Decreased Severity of CAR T-Cell Related Adverse Events: A Pivotal Study Report of CNCT19 (inaticabtagene autoleucel) Treatment in Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-Cell ALL) in China
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Ying Wang, Xudong Wei, Dongmei Yan, Cheng Zhang, Hongsheng Zhou, Chunrong Tong, Heng Mei, Jie Jin, Ting Niu, Aibin Liang, Jienan Ren, Yiping Deng, Wei Jin, Yi Feng, Lin Shi, Yongzeng Wang, Changting Haudenschild, Lulu Lv, and Jianxiang Wang
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Switching from Eltrombopag to Hetrombopag in Patients with Primary Immune Thrombocytopenia (ITP): Post-Hoc Analysis of a Multicenter, Randomized Phase III Trial
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Yu Hu, Renchi Yang, Ting Niu, Heng Mei, Liu Xiaofan, Yan Li, Hu Zhou, Ying Feng, Guangxun Gao, Peng Cheng, Ruibin Huang, Linhua Yang, Jianda Hu, Ming Hou, Yazhou Yao, Li Liu, Yi Wang, De-Pei Wu, Xuliang Shen, Jie Jin, Jianmin Luo, Zeng Yun, Xin Zhou, Ruixiang Xiang, Zhongxing Jiang, Yuansong Bai, Junye Xiong, Runzi Li, and Jianjun Zou
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. Oligosecretory Waldenström Macroglobulinemia Patients Exhibit Excellent Treatment Response and Outcomes
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Ying Yu, Wenjie Xiong, Zanzan Wang, Yuting Yan, Jiawen Chen, Yanshan Huang, Xinxin Cao, Zhongxing Jiang, Huihan Wang, Zhen Cai, Juan Du, Chunyan Sun, Ting Niu, Guangzhong Yang, Hua Xue, Bingzong Li, Honghui Huang, Zhenling Li, Qinhua Liu, Fei Li, Ou Bai, Min Mao, Rong Fu, Ling Wang, Chunrui Li, Xiaoxia Chu, Lihong Liu, Yujun Dong, Luqun Wang, Jun Luo, Yongqiang Wei, Lugui Qiu, Jian Li, and ShuHua Yi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. Flonoltinib, a Novel JAK2/FLT3 Inhibitor, Potently Treats Hemophagocytic Lymphohistiocytosis and Increases Sensitivity to Dexamethasone
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Ailin Zhao, Xin Wang, Mengshi Hu, Lijuan Chen, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Phase 1 Safety and Dose Escalation of Purinostat Mesylate, a Uniquely Potent and Selective Inhibitor of HDAC I and IIb in Relapsed or Refractory Lymphoma and Multiple Myeloma
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Jie Wang, He Li, Linyu Yang, Ailin Zhao, Peng Zhao, Jishi Wang, Jin Xiang, Jia Miao, Li Zheng, Yongsheng Wang, Lijuan Chen, and Ting Niu
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
8. The Efficacy and Safety of Modified Melphalan and Busulfan-Based Conditioning Regimen for Allogeneic-HSCT in Refractory/Relapsed or Persistent MRD Positive AML Patients
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Shulian Chen, Xiaoyu Zhang, Weihua Zhai, Yi He, Sizhou Feng, Mingzhe Han, Ting Niu, Yajing Xu, Guangxun Gao, Shengjin Fan, Zeping Zhou, Fang Zhou, Xi Rui, Li Liu, Wei Yang, Qifa Liu, Xi Zhang, and Erlie Jiang
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
9. KMT2D Deficiency Promotes Myeloid Leukemias through Regulating Ribosome Biogenesis
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Jing Xu, Ailing Zhong, Chong Chen, Yu Liu, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. A Population-Based Study Reveals the Unique Clinical Characteristics and Long-Term Survival of Patients with Gray Zone Lymphoma
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Xin Wang and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. ISG20L2 Suppresses Bortezomib Anti-Myeloma Activity By Attenuating Bortezomib Binding to PSMB5
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Yan Yang, Yuhan Gao, Jingcao Huang, Ting Niu, and Yuhuan Zheng
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Phase I Study of a Novel Oral Proteasome Inhibitor TQB3602 in Relapsed/Refractory Multiple Myeloma
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Wenjiao Tang, Yan Li, Qiushi Liang, Ying Qu, Li Zhang, Yuzhang Liu, Baijun Fang, Zeng Yun, Xiaobo Du, Yaming Xi, Ting Wang, Xin Li, Jie Huang, Wenbin Qian, Zhen Cai, Qingwei Zhao, Yue Lv, and Ting Niu
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Establishment of Mortality Risk Prediction Model for Bloodstream Infections in Patients with Hematological Diseases
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Jinjin Wang, Hui Zhou, Mengyao Wang, Ailin Zhao, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
14. An Emerging Prognosis Prediction Model for Multiple Myeloma: Hypoxia-Immune Related Microenvironmental Gene Signature
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Zhengyu Yu, Linfeng Li, Jin Xu, Hui Zhou, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Study of Fabrication of Two Novel Methotrexate-Loaded Micelles and Their Anti-Lymphoma Effects
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Mengyao Wang, Danrong Hu, Ying Qu, Zhiyong Qian, and Ting Niu
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Selinexor-Loaded Polymeric Micelles for Multiple Myeloma Therapy
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Peipei Yang, Ying Qu, Mengyao Wang, Bingyang Chu, Wen Chen, Yuhuan Zheng, Zhiyong Qian, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. Hematopoietic Stem Cell Transplantation Activity in China 2020–2021 During the SARS-CoV-2 Pandemic: A Report From the Chinese Blood and Marrow Transplantation Registry Group
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Lan-Ping Xu, Dao-Pei Lu, De-Pei Wu, Er-Lie Jiang, Dai-Hong Liu, He Huang, Zi-Min Sun, Nai-Nong Li, Qi-Fa Liu, Xi Zhang, Yong-Rong Lai, Yong-Ping Song, Xian-Min Song, Si-Xi Liu, Yi-Cheng Zhang, Cheng-Juan Luo, Ling-Hui Xia, Ting Niu, Yu Yu, Xiao-Hui Zhang, Xiao-Wen Tang, Yi Luo, and Xiao-Jun Huang
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Abstract
Between 2020 and 2021, 31,525 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group throughout mainland China. In this report, we describe the activity and current trends for HSCT in China during the SARS-CoV-2 pandemic. In 2020, a total of 13,415 cases of HSCT were reported from 166 transplantation teams, and 75% (10,042 cases) were allogeneic HSCTs. In 2021, a total of 18,110 cases of HSCT were reported from 174 transplantation teams, and 70% (12,744 cases) were allogeneic HSCTs. Haploidentical donor (HID) transplantation accounted for 63% (7977 cases) of allogeneic HSCTs in 2021. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (37%) and acute lymphoblastic leukemia (23%), and the largest proportion of nonmalignant disease comprised aplastic anemia (13%). The peripheral blood stem cell source accounted for 41% of HIDs and 75% of matched sibling donors. The BuCy-based regimen (57%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu-based regimen (28%) and total body irradiation-based regimen (11%). This survey provides comprehensive information about the current activities and might benefit clinical physicians' decision planning for HSCT.
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- 2023
18. Daratumumab, Bortezomib, Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory (RR) Multiple Myeloma (MM): Pooled Subgroup Analysis of Lepus and Castor
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Ting Niu, Steven Sun, Ming Qi, Yafei Wang, Weijun Fu, Jin Lu, Gang An, Xi-Nan Cen, Lijuan Chen, Maria-Victoria Mateos, Ajay K. Nooka, Jianda Hu, Jie Jin, Weiping Liu, Andrew Spencer, Xiao-Jun Huang, Wei Li, Xue Gai, Chengcheng Fu, Zhen Cai, Xue Yang, Katja Weisel, and Zheng Ge
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medicine.medical_specialty ,business.industry ,Immunology ,Daratumumab ,Subgroup analysis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Median follow-up ,Baseline characteristics ,Internal medicine ,Medicine ,Median body ,business ,Multiple myeloma ,Complete response ,Bortezomib/dexamethasone - Abstract
Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In phase 3 clinical studies, the addition of daratumumab to standard-of-care regimens consistently demonstrated a significant progression-free survival (PFS) benefit and improved depth of response, including minimal residual disease-negativity, in patients (pts) with newly diagnosed MM or RRMM. In the primary analysis of the phase 3 CASTOR study (median follow-up: 7.4 mo), D-Vd reduced the risk of disease progression or death by 61% (median PFS, not reached [NR] vs 7.2 mo; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28-0.53; P Methods: Eligible pts in LEPUS and CASTOR received ≥1 prior line of therapy and were randomized 2:1 in LEPUS and 1:1 in CASTOR to 8, 21-day cycles of V (1.3 mg/m2 SC) on Days 1, 4, 8, and 11, and d (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± D (16 mg/kg IV) given QW for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. The primary endpoint for both studies was PFS. Results: A total of 211 (D-Vd, n=141; Vd, n=70) pts in LEPUS and 498 (D-Vd, n=251; Vd, n=247) pts in CASTOR were randomized. The median (range) age was 61 (28-82) years for Chinese and 64 (30-88) years for global pts. In general, baseline characteristics were similar between Chinese and global pts and balanced between treatment arms, with the exception of median body weight (LEPUS: 67 kg; CASTOR: 76 kg). Chinese and global pts both received a median of 2 prior lines of therapy; 79% and 66% received prior V, 27% and 28% were refractory to lenalidomide, and 64% and 32% were refractory to their last prior line of therapy, respectively. After a median follow up of 8.2 months in LEPUS and 7.4 months in CASTOR, a consistent PFS benefit of D-Vd vs Vd was demonstrated in the pooled analysis set across age (60 mL/min) subgroups (Table 1). Median time to progression was also consistently prolonged with D-Vd vs Vd across pooled pt subgroups. Among response evaluable pts, D-Vd improved overall response rate, rate of very good partial response or better, and rate of complete response or better (Table 2) and prolonged median duration of response vs Vd in all pt subgroups. Additional data, including PFS2, from the pooled subgroups analysis will be presented at the meeting. The safety profile of D-Vd was generally consistent across pts in LEPUS and CASTOR. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Vd/Vd) occurring at a ≥5% frequency with D-Vd vs Vd in both Chinese and global pts included thrombocytopenia (51%/37%; 45%/33%), lymphopenia (44%/29%; 10%/3%), neutropenia (16%/6%; 13%/4%), and hypertension (12%/3%; 7%/1%). 49%/38% of Chinese and 42%/34% of global pts had ≥1 serious TEAEs. TEAEs leading to treatment discontinuation occurred in 4%/3% of Chinese and 7%/9% of global pts, and TEAEs leading to death occurred in 4%/10% of Chinese and 5%/6% of global pts. Rates of infusion-related reactions (IRRs) were similar for D-Vd across studies (LEPUS: 38%; CASTOR: 45%); most occurred during the first infusion and the majority were grade 1/2. Conclusions: D-Vd demonstrated a clinical benefit, including significantly improved PFS, in pooled Chinese and global pts with RRMM who received ≥1 prior line of therapy, regardless of age, cytogenetic risk status, or renal function. The safety profile of D-Vd was consistent across all pts, and no new safety concerns were identified. These results support the use of D-Vd in Chinese pts with RRMM. Disclosures Jin: The First Affiliated Hospital of Zhejiang University: Current Employment. Spencer:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cilag GmbH: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weisel:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Honoraria. Mateos:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka:Adaptive Technologies: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Gai:Janssen: Current Employment, Current equity holder in publicly-traded company. Liu:Janssen: Current Employment, Current equity holder in publicly-traded company. Yang:Janssen: Current Employment, Current equity holder in publicly-traded company.
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- 2020
19. ALCAM regulates multiple myeloma chemoresistant side population
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Fangfang Wang, Zhang Dan, Hongmei Luo, Jingcao Huang, Yushan Cui, Hong Ding, Juan Xu, Zhimei Lin, Yuhan Gao, Xinyu Zhai, Yan Yang, Ying Qu, Li Zhang, Fengjiao Chen, Qiang Wang, Xin Wang, Yu Feng, Ting Liu, Qing Yi, Ting Niu, and Yuhuan Zheng
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Fetal Proteins ,Cancer Research ,QH573-671 ,Epidermal Growth Factor ,Cell Adhesion Molecules, Neuronal ,Immunology ,Cell Biology ,ErbB Receptors ,Mice ,Cellular and Molecular Neuroscience ,Antigens, CD ,Activated-Leukocyte Cell Adhesion Molecule ,Cell Line, Tumor ,Animals ,Humans ,Hedgehog Proteins ,Cytology ,Multiple Myeloma - Abstract
Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.
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- 2022
20. Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36-inflammatory monocyte axis
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Shan-He Yu, Xiang-Qin Weng, Wu Zhang, Li-Ting Niu, Jun Shi, Wan-Ting Qiang, Yi Zhang, Yuanyuan Tian, Shao-Yan Hu, Jiang Zhu, Meng-Meng Huang, Zi-Hua Guo, Hui Yang, Juan Chen, and He-Zhou Guo
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Chemotherapy ,Multidisciplinary ,business.industry ,medicine.medical_treatment ,Cell ,food and beverages ,Myeloid leukemia ,SciAdv r-articles ,Endogeny ,Immunosuppression ,Cell Biology ,Immunosurveillance ,Immune system ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Cancer research ,Medicine ,Biomedicine and Life Sciences ,Progenitor cell ,business ,Research Article ,Cancer - Abstract
Description, A stimulated proinflammatory feature of leukemic progenitors facilitates their survival and immune evasion after chemotherapy., Chemotherapy can effectively reduce the leukemic burden and restore immune cell production in most acute myeloid leukemia (AML) cases. Nevertheless, endogenous immunosurveillance usually fails to recover after chemotherapy, permitting relapse. The underlying mechanisms of this therapeutic failure have remained poorly understood. Here, we show that abnormal IL-36 production activated by NF-κB is an essential feature of mouse and human leukemic progenitor cells (LPs). Mechanistically, IL-36 directly activates inflammatory monocytes (IMs) in bone marrow, which then precludes clearance of leukemia mediated by CD8+ T cells and facilitates LP growth. While sparing IMs, common chemotherapeutic agents stimulate IL-36 production from residual LPs via caspase-1 activation, thereby enabling the persistence of this immunosuppressive IL-36–IM axis after chemotherapy. Furthermore, IM depletion by trabectedin, with chemotherapy and PD-1 blockade, can synergistically restrict AML progression and relapse. Collectively, these results suggest inhibition of the IL-36–IM axis as a potential strategy for improving AML treatment.
- Published
- 2021
21. Clinical Characteristics of Hemophagocytic Lymphohistiocytosis in Adults with Central Nervous System Involvement
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Meng Li, Ai-lin Zhao, Lin-feng Li, Xin-ai Gan, Jin-rong Yang, Jie Wang, He Li, Kai Shen, Yun-fan Yang, and Ting Niu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. BMI1 regulates multiple myeloma-associated macrophage’s pro-myeloma functions
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Yuping Gong, Zhigang Liu, Qing Yi, Li Zhang, Yan Yang, Yuhuan Zheng, Danfeng Zhang, Ting Niu, Hongmei Luo, Fangfang Wang, Ling Pan, Yuhan Gao, Ying Qu, Juan Xu, Jingcao Huang, Liping Xie, Yushan Cui, Wenyan Zhang, Yu Wu, Hong Ding, Sha Zhao, and Weiping Liu
- Subjects
Cancer microenvironment ,Cancer Research ,Programmed cell death ,Immunology ,Myeloma ,macromolecular substances ,Article ,Mice ,Cellular and Molecular Neuroscience ,Bone Marrow ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Macrophage ,Sonic hedgehog ,Multiple myeloma ,Polycomb Repressive Complex 1 ,Tumor microenvironment ,QH573-671 ,biology ,Chemistry ,Macrophages ,Cell Biology ,medicine.disease ,Hedgehog signaling pathway ,medicine.anatomical_structure ,BMI1 ,Cancer research ,biology.protein ,Bone marrow ,Cytology ,Multiple Myeloma - Abstract
Multiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.
- Published
- 2021
23. Inhibitory Effect of LPS on the Proliferation of Oligodendrocyte Precursor Cells through the Notch Signaling Pathway in Intrauterine Infection-induced Rats
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Ling Hou, Yan Liang, Sheng-Juan Jin, Yan-Qin Ying, Xiaoping Luo, Xue-Qin Yan, and Wan-Ting Niu
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Lipopolysaccharides ,0301 basic medicine ,Notch signaling pathway ,Biology ,Infections ,Corpus callosum ,Biochemistry ,Corpus Callosum ,White matter ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,Leukoencephalopathies ,Pregnancy ,Genetics ,medicine ,Animals ,Humans ,Cell Lineage ,Myelin Proteolipid Protein ,Cell Proliferation ,Oligodendrocyte Precursor Cells ,Receptors, Notch ,Wnt signaling pathway ,Brain ,Gene Expression Regulation, Developmental ,Myelin Basic Protein ,Embryonic stem cell ,Oligodendrocyte ,Rats ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,nervous system ,Brain Injuries ,Female ,Signal transduction ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Periventricular white matter injury (PWMI) is very common in survivors of premature birth, and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination. How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field. This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms. Lipopolysaccharide (LPS) (300 μg/kg) was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury. Corpus callosum tissues were collected at postnatal day 14 (P14) to quantify the number of oligodendrocytes, the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP). Furthermore, the expression of Wnt and Notch signaling-related proteins was analyzed. The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced, and the expression levels of myelinating proteins were down-regulated. Further analysis showed that the Notch signaling pathway was down-regulated in the LPStreated group. These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Wnt signaling pathway, leading to hypomyelination of white matter.
- Published
- 2018
24. Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults
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Jiazhuo Liu, Ting Liu, Xiao Shuai, Yong Guo, Pengpeng Liu, Xiangyu Pan, Liping Xie, Yu Liu, Yu Wu, Ting Niu, Jian Wang, Xuelan Chen, and Chong Chen
- Subjects
0301 basic medicine ,Adult ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Adolescent ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Biochemistry ,Virus ,Lymphohistiocytosis, Hemophagocytic ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Recurrence ,hemic and lymphatic diseases ,medicine ,Neoplasm ,Cytotoxic T cell ,Humans ,Epstein–Barr virus infection ,Hemophagocytic lymphohistiocytosis ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Epstein–Barr virus ,030104 developmental biology ,Nivolumab ,Treatment Outcome ,Drug Resistance, Neoplasm ,Retreatment ,Female ,business ,030215 immunology - Abstract
Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1–positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.
- Published
- 2019
25. Global expression profiling and pathway analysis of mouse mammary tumor reveals strain and stage specific dysregulated pathways in breast cancer progression
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Ming Ming Yang, Hong Fa Xu, Wen Wen Wei, Fen Lin, Qing Liu, Li Xia Peng, Yan Mei, Ting Niu, Xing Si Peng, Hao Hu, Liang Xu, Chao Nan Qian, Lijing Wang, Dong Fang Meng, Qin Yang, Li Sheng Zheng, Jun Ping Yang, Bi Jun Huang, Yan Hong Lang, Yuan Yuan Qiang, and Chang-Zhi Li
- Subjects
0301 basic medicine ,Genotype ,Breast Neoplasms ,Mammary Neoplasms, Animal ,Mice, Inbred Strains ,Tumor initiation ,Biology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,Report ,medicine ,Animals ,Humans ,Molecular Biology ,Neoplasm Staging ,Principal Component Analysis ,Mammary tumor ,Gene Expression Profiling ,Reproducibility of Results ,Cancer ,Cell Biology ,medicine.disease ,Extracellular Matrix ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,Signal transduction ,Signal Transduction ,Developmental Biology - Abstract
It is believed that the alteration of tissue microenvironment would affect cancer initiation and progression. However, little is known in terms of the underlying molecular mechanisms that would affect the initiation and progression of breast cancer. In the present study, we use two murine mammary tumor models with different speeds of tumor initiation and progression for whole genome expression profiling to reveal the involved genes and signaling pathways. The pathways regulating PI3K-Akt signaling and Ras signaling were activated in Fvb mice and promoted tumor progression. Contrastingly, the pathways regulating apoptosis and cellular senescence were activated in Fvb.B6 mice and suppressed tumor progression. We identified distinct patterns of oncogenic pathways activation at different stages of breast cancer, and uncovered five oncogenic pathways that were activated in both human and mouse breast cancers. The genes and pathways discovered in our study would be useful information for other researchers and drug development.
- Published
- 2018
26. Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency
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Joseph S. Janicki, Lei Qi, Ting Niu, Mitzi Nagarkatti, Xuejun Wang, Huimei Zang, Xing Li Wang, Linmao Lyu, Qingyun Qin, Chen Qu, Prakash S. Nagarkatti, and Taixing Cui
- Subjects
0301 basic medicine ,Aortic arch ,medicine.medical_specialty ,NF-E2-Related Factor 2 ,Biology ,digestive system ,environment and public health ,Article ,Constriction ,Mice ,03 medical and health sciences ,FYN ,Downregulation and upregulation ,medicine.artery ,Autophagy ,Ventricular Pressure ,Internal Medicine ,medicine ,Animals ,Myocytes, Cardiac ,Nuclear export signal ,Mice, Knockout ,Cardioprotection ,Ventricular Remodeling ,Myocardium ,respiratory system ,Pathophysiology ,Up-Regulation ,Cell biology ,Surgery ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Signal Transduction - Abstract
Nuclear factor erythroid-2–related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload–induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction –induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction.
- Published
- 2016
27. PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization
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Fangfang Wang, Ting Liu, Jiazhuo Liu, Yu Wu, Ting Niu, Yuhuan Zheng, Jianjun Li, and Leiwen Peng
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0301 basic medicine ,Cellular differentiation ,Apoptosis ,Cathepsin B ,Antioxidants ,Immunoenzyme Techniques ,Tumor Cells, Cultured ,Medicine ,Enzyme Inhibitors ,Caspase ,bcl-2-Associated X Protein ,Membrane Potential, Mitochondrial ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Nuclear Proteins ,ROS ,Cell Differentiation ,Cell biology ,Leukemia ,chemosensitivity ,Leukemia, Myeloid, Acute ,Oncology ,Caspases ,Drug Therapy, Combination ,Research Paper ,Programmed cell death ,Necroptosis ,Blotting, Western ,Antineoplastic Agents ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Humans ,cathepsin ,RNA, Messenger ,Cell Proliferation ,LMP ,Cell growth ,business.industry ,PIG7 ,Intracellular Membranes ,medicine.disease ,030104 developmental biology ,Drug Resistance, Neoplasm ,Immunology ,biology.protein ,business ,Lysosomes ,Reactive Oxygen Species ,Transcription Factors - Abstract
PIG7 localizes to lysosomal membrane in leukemia cells. Our previous work has shown that transduction of pig7 into a series of leukemia cell lines did not result in either apoptosis or differentiation of most tested cell lines. Interestingly, it did significantly sensitize these cell lines to chemotherapeutic drugs. Here, we further investigated the mechanism underlying pig7-induced improved sensitivity of acute leukemia cells to chemotherapy. Our results demonstrated that the sensitization effect driven by exogenous pig7 was more effective in drug-resistant leukemia cell lines which had lower endogenous pig7 expression. Overexpression of pig7 did not directly activate the caspase apoptotic pathway, but decreased the lysosomal stability. The expression of pig7 resulted in lysosomal membrane permeabilization (LMP) and lysosomal protease (e.g. cathepsin B, D, L) release. Moreover, we also observed increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) induced by pig7. Some autophagy markers such as LC3I/II, ATG5 and Beclin-1, and necroptosis maker MLKL were also stimulated. However, intrinsic antagonism such as serine/cysteine protease inhibitors Spi2A and Cystatin C prevented downstream effectors from triggering leukemia cells, which were only on the "verge of apoptosis". When combined with chemotherapy, LMP increased and more proteases were released. Once this process was beyond the limit of intrinsic antagonism, it induced programmed cell death cooperatively via caspase-independent and caspase-dependent pathways.
- Published
- 2015
28. Efficacy Analysis of Ruxolitinib in Treatment of 72 Patients with Myelofibrosis in a Chinese Institution
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Jie Ji, Yongqian Jia, Ting Niu, Ting Liu, Huanling Zhu, Zhongqing Zou, Ling Pan, Hong Chang, Yu Wu, Yuping Gong, Jian Li, and Yunfan Yang
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medicine.medical_specialty ,Ruxolitinib ,Univariate analysis ,Multivariate analysis ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Logistic regression ,Biochemistry ,Clinical trial ,medicine.anatomical_structure ,Fibrosis ,Internal medicine ,medicine ,Bone marrow ,Myelofibrosis ,business ,medicine.drug - Abstract
Background: Ruxolitinib, a potent JAK1/JAK2 inhibitor, has been proved to improved splenomegaly and debilitating myelofibrosis-related symptoms in several clinical trials. However, not much is known about the efficacy of ruxolitinib, especially low-dose ruxolitinib, in real world patients in China. Here we assess the efficacy of ruxolitinib in treatment of patients with myeloproliferative neoplasms associated myelofibrosis (MPN-MF) in real world and to analyze factors affect the treatment efficacy. Methods and Results: From July 2017 to June 2019, data of MPN-MF patients treated with ruxolitinib in West China hospital, Sichuan University, China, were retrospectively collected and analyzed. Logistic regression was used for univariate and multivariate analysis of binary variables. Simple linear regression was used in univariate analysis of continuous variables, and multiple linear regression was used in multivariate analysis of continuous variables. Dose of ruxolitinib were decided according to platelet count and financial condition of patients. Of 72 MPN-MF patients, 1 patient was treated with ruxolitinib in an initial dose of 5mg qd, 37 patients with 5mg bid, 15 patients with 10mg bid, 2 patients with 25mg bid. At week 12, 89.3% of patients achieved reduction from baseline in palpable spleen length, of which 44.6% patients achieved ≥50% reduction (Figure 1) ; 95.6% patients achieved reduction from baseline in Total Symptom Score (TSS), of which 44.6% patients achieved ≥50% reduction(Figure 2). At week 48, all 25 patients with bone marrow biopsies achieved improved or stable bone marrow fibrosis grading from baseline, of which 44.0% improved (Figure 3). Both univariate analysis and multivariate analyses showed higher dose of ruxolitinib (>5mg bid VS ≤5mg bid and>10mg bid VS ≤10mg bid) was the major factor associated with better spleen response(P10mg VS ≤10mg) was the only factor associated with better TSS improvement(P Conclusion These data indicated that ruxolitinib treatment provided reduction in spleen, improvement in symptoms and stable or improve bone marrow fibrosis in Chinese MPN-MF patients. Although some MPN-MF patients derived benefit at low-dose ruxolitinib, higher dose were associated with better spleen and symptom responses. Legends to figures Figure 1: Percent change from baseline in palpable spleen length at week 12 for individual patients. Only patients with palpable spleen length measurements at baseline and week 12 (n=56) were included. qd: once daily, bid: twice daily Figure 2: Percent change from baseline in TSS at week 12 for individual patients. Only patients with TSS measurements at baseline and week 12 (n=68) were included. qd: once daily, bid: twice daily Figure 3: Change in marrow histomorphologic features in 25 patients at week 48. Green: fibrosis improved, Yellow: fibrosis stable, Red: fibrosis progress Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
29. A Novel Hybrid Transplantation with Autologous Hematopoietic Stem Cells and Matched Unrelated Cord Blood Stem Cells Is Effecttive and Safe for Relapsed or Refractory Lymphoma: A Pilot Study
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Jian Li, Yingli Wang, Ting Niu, Tian Dong, Ting Liu, Yongqian Jia, Zhigang Liu, Jianchun Lu, Qiuhui Wu, Jie Ji, Zhong-Ping Lu, Xinchuan Chen, Guochao Xu, Huan Tao, Xu Xu, Chen Qiang, Fan Liu, Jianjun Li, Rong Tian, Yamei Leng, Fang Liu, Pu Kuang, Li Zhang, and Sha Zhao
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Microchimerism ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Lymphoma ,Transplantation ,Haematopoiesis ,Internal medicine ,Cord blood ,medicine ,Stem cell ,business ,Diffuse large B-cell lymphoma - Abstract
Backgroud: Autologous hematopoietic stem cell transplantation (ASCT) is widely recommended for relapsed or refractory lymphoma as an important second-line salvage therapy. Post-transplant relapse is a main issue due to its lacking of the graft versus tumor effects with routine ASCT. Hereby we present a novel hybrid transplantation with autologous stem cells and matched unrelated cord blood cells for relapsed or refractory lymphoma. Method A total of 37 patients with relapsed or refractory lymphoma were enrolled from July 2013 to May 30, 2019 in the West China Hospital of Sichuan University. The autologous peripheral blood stem cells were collected and freezed. HLA matched cord blood cells were searched and provided by the Sichuan Cord Blood Bank. Autologous peripheral blood stem cell transplantation (APBSCT) were infused at day 0 and the selected cord blood cells were infused at day+1 with standard BEAM conditioning regimen. Result The gender distribution was 51.4% female and 48.6% male.The Median age was 37 years old (16-65 years old). The disease characteristics: relapsed or refractory HL 14 cases, relapsed or refractory DLBCL 9 cases, relapsed Burkitt lymphoma 1 case, HGBL with DHL 1 case, DEL 4 cases, Nos 2 cases, DLBCL with high IPI 3 cases. Advanced nasal NK/T cell lymphoma 2 cases, relapdsed EBV-LPD 1 case. The median number of CD34*106/kg for ASCT was 2.35 (1.32-4.58). The median number of total nucleated cord blood cells was 10.2*108 (6.13-17.9) and the CD34+ cord blood cells was 2.72*106 (1.08-5.2). HLA-identical related donor (6/6) was 10.81%, one-antigen-mismatched (5/6) was 72.98%, two-antigen-mismatched (4/6) was 16.21%. All patients were transplanted succesfully with neutrophil recovery of 11days (8-29) and platelet recovery of 14 days (10-120). An early transplanted syndrom with rash or fever were observed in 7 pts (18.9%), while a delayed neutropenia were observed in 5 pts (13.5%). All symptoms were relieved with prednisone therapy. 2 out of 10 pts examined showed sign of microchimerism at 1 month post transplant. With a median 28 months of follow-up (2-73 months), our hybrid transplantation for R/R lymphoma showed that the relapse-free surviaval (RFS) is 90.4% ,and the overall survival (OS) is 86.4%, which is improved remarkablly. The overall OS and RFS were significant different between complete remission (CR) and Non-CR before transplantation (p= 0.002 for OS; p= 0.015 for RFS), but there was no significant difference in the subgroups of HL and NHL. Conclusion This preliminary pilot study suggested that the hybrid stem cell transplantation with autologous stem cells and matched cord blood stem cells is effective and safe for the treatment of high risk lymphoma with limited controlable immuno reactions. Disclosures Zhang: the National Natural Science Foundation of China: Research Funding.
- Published
- 2019
30. SLC2A5 Overexpression in Childhood Philadelphia Chromosome Positive Acute Lymphoblastic Leukaemia
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Pan Zhao, Ting Niu, and Yuhuan Zheng
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Philadelphia Chromosome Positive ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Philadelphia chromosome ,Biochemistry ,Dasatinib ,Imatinib mesylate ,hemic and lymphatic diseases ,Acute lymphocytic leukemia ,Cancer research ,Medicine ,Lymphoblastic leukaemia ,business ,Burkitt's lymphoma ,medicine.drug ,Protein overexpression - Abstract
To study glycolysis/glycogenesis-related genes expression in childhood B cell acute lymphoblastic leukaemia (B-ALL), we performed a microarray-based analysis using published gene expression profiles. We found that gene SLC2A5, which encoded fructose transporter GLUT5 that facilitated cell fructose uptake, was up-regulated in Philadelphia chromosome positive ALL (Ph+ALL). Microarray-based analyses also suggested that SLC2A5 expression was significantly down-regulated in childhood B-ALL with t(1;19) or 11q23 mutation. High SLC2A5 expression was found in the patients who had recurrence within 3 years, early relapse, shortened complete remission duration, and positive minimal residue disease (MRD) status after treatment. The overexpression of SLC2A5 at both mRNA level and protein level in Ph+ALL was confirmed in a validation cohort of childhood B-ALL. We also validated the correlation of SLC2A5 expression and MRD status. In a mechanistic study using a human Ph+ALL cell line, we found that BCR-ABL kinase might regulate GLUT5 expression via c-myc. The tyrosine kinase inhibitors imatinib and dasatinib repressed GLUT5 expression and the cell uptake of fructose. Fructose protected the tumour cells from nutrition deficiency and drug-induced cell death. Overall, our findings showed that SLC2A5 was up-regulated in childhood Ph+ALL. The expression of SLC2A5 correlated with childhood B-ALL clinical factors, such as MRD status. Since TKI was able to inhibit GLUT5 expression, repression of fructose utility after TKI treatment contributes to TKI-induced Ph+ALL cytotoxicity. Targeting GLUT5 might be promising in B-ALL treatment, especially for Ph+ALL patients with high expression of SLC2A5. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
31. Chidamide-Containing Conditioning Allogenic Hematopoietic Stem Cell Transplantation Improves Prognosis of Acute Lymphoblastic Leukemia with Pre-Transplant Response Less Than Complete Remission
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Zhigang Liu, Jie Ji, Jiazhuo Liu, Tian Dong, Li Zhang, Ting Liu, Ting Niu, and Pu Kuang
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Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Fludarabine ,Transplantation ,chemistry.chemical_compound ,Graft-versus-host disease ,chemistry ,Acute lymphocytic leukemia ,Chidamide ,Internal medicine ,Medicine ,business ,Busulfan ,medicine.drug - Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option currently offered to patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). However, active disease or minimal residual disease (MRD) prior to HSCT is associated with early relapse and poor prognosis with long-term survival less than 30%. We have confirmed that chidamide, a selective histone deacetylase inhibitor (HDACi), work synergistically with cytotoxic agents such as combination of cladribine, gemcitabine and busulfan as conditioning therapy against lymphocytic malignancies. Here, we conducted a clinical trial to evaluate the efficacy of chidamide containing conditioning allo-HSCT in patients with these high-risk ALLs. Methods: Patients with active ALL or MRD received a myeloablative conditioning consisting of chidamide, fludarabine, cytarabine and busulfan (ChiFAB), followed by infusion of peripheral blood hematopoietic stem cells from related or unrelated donors. The ChiFAB was administered as following: chidamide was given orally at 20 mg twice weekly started from D-7 for 3 weeks; fludarabine was given intravenously at 30 mg/m2 D-6 to D-2; cytarabine was given 4 hours after the finish of fludarabine at 1 g/m2 D-6 to D-2; and busulfan was given intravenously once daily at 3.2 mg/kg D-6 to -3. Prophylaxis of acute graft-versus-host-disease were posttransplant cyclophosphamide plus cyclosporine for matched donor transplants, and additional post-transplant anti-thymocyte globulin and mycophenolate mofetil for haplo-HSCT. Donor lymphocyte infusion was not routinely administered in this trial. Results: Twenty-four patients were enrolled with median age of 24.5 (16-61 years). Male to female ratio was 3:1. Six (25%) had a diagnosis of Philadelphia positive acute B cell lymphoblastic leukemia (Ph+B-ALL), 8 (33.3%) had Ph-B-ALL, and 10 (41.7%) had T-ALL. Nineteen (79.2%) patients were MRD positive (blast cells Conclusions: Chidamide-containing conditioning allo-HSCT may improve the prognosis of ALL with MRD. Figure 1. Figure 1. Disclosures Liu: West China Hospital of Sichuan University: Employment.
- Published
- 2018
32. KMT2D Is a Haploinsufficient Tumor Suppressor in Acute Leukemia
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Yu Liu, Chong Chen, Ting Niu, and Jing Xu
- Subjects
Acute leukemia ,Myeloid ,Tumor suppressor gene ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,medicine ,Cancer research ,Bone marrow ,Lymphoid leukemia - Abstract
Introduction: Epigenetic dysregulation plays a critical role in hematologic tumorigenesis and cancer progression. Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 (mixed-lineage leukemia 4), belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases, which is amongst the most frequently mutated epigenetic genes in human cancers. It was reported that deletion of KMT2D inhibits MLL1-fusion-induced acute myeloid leukemia (Santos et al. 2014). However, in human cancers, the vast majority of the mutations in KMT2D is heterozygous deletion. Recent studies have revealed the role of KMT2D in lymphomagenesis, but the potential tumor suppressor function of KMT2D in leukemogenesis remains largely unclear. In addition, KMT2D was found to exist within a macromolecular complex named COMPASS (complex of proteins associated with Set1). KMT2C is another component of the complex, and was validated as another haploinsufficient tumor suppressor gene in acute myeloid leukemia (Chen et al. 2014). Mutations in KMT2D and KMT2C frequently co-occur in hematologic malignancies. Thus, we sought to first examine the role and molecular mechanism of KMT2D in acute leukemia, and then investigate whether co-mutated gene KMT2D and KMT2C have cooperative function in malignancies initiation and progression. Methods: Here we utilized RNAi approach to knockdown the expression of Kmt2d, and an approximate 50% reduction in gene dosage was validated by quantitative RT-PCR. We introduced two independent short-hairpin RNAs (shRNAs) targeting Kmt2d and a shRNA targeting Nf1 into p53 null hematopoietic stem and progenitor cells (hereafter referred to as shKmt2d;shNf1;p53-/- cells), and transplanted them into sublethally irradiated mice to model the impact of haploinsufficient tumor suppressors. The recipient mice were then monitored for the emergence of diseases by complete blood count as well as overall survival. Bone marrow was harvested and analyzed by flow cytometry after sacrifice. Histological analyses of blood smear, liver, spleen and bone marrow were conducted to accurately diagnose the disease. Besides, we established Kmt2d heterozygous and homozygous conditional knockout mouse models (Kmt2d fl/+; Mx1-Cre, Kmt2d fl/fl; Mx1-Cre) to further investigate the respective role of haploinsufficiency and deletion of KMT2D in acute leukemia. To study the cooperative function of KMT2D and KMT2C in leukemogenesis, two genes were co-suppressed by shRNAs in the same aforementioned genetic background (shNf1; p53-/-). Transplantation-based mouse modeling approach was used and the recipient mice were monitored for evidence of hematologic diseases. Results: A significant increase in peripheral white blood cell counts, anemia and thrombocytopenia were noticed in recipients of shKmt2d;shNf1;p53-/- cells over the same period after 4 weeks post-transplantation. Massive hepatomegaly and splenomegaly were displayed in those mice and a dramatic reduction in survival was observed (shKmt2d-1: median survival = 47 days, p = 0.0004 versus shRen; and shKmt2d-2: median survival = 74 days, p = 0.0127 versus shRen). Flow cytometry of cells from bone marrow of sacrificed mice showed a substantial enrichment of doule-positve cells (shRNAs targeting Kmt2d were linked to GFP and those targeting Nf1 were linked to mCherry) as compared to pre-injected, which were filled with leukemic cells that expressed myeloid/lymphoid lineage markers. Pathological analyses demonstrated the onset of acute myeloid/lymphoid leukemia. In Kmt2d and Kmt2c double-knockdown animal assay, the onset of acute myeloid leukemia was promoted compared with single-knockdown groups. (shKmt2d;shKmt2c: median survival = 48.5 days, p < 0.0001 versus shKmt2d; p = 0.0013 versus shKmt2c). Conclusions: KMT2D is a haploinsufficient tumor suppressor in acute leukemia. KMT2D deficiency cooperates with KMT2C to promote the development and progress of acute leukemia. Further understandings of the molecular mechanism of KMT2D as a haploinsufficient tumor suppressor in acute leukemia and the cooperative function of KMT2D and KMT2C in leukemogenesis are demanded, which can provide insights into developing novel therapeutic targets. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
33. Methotrexate-Loaded Biodegradable Polymeric Micelles for Lymphoma Therapy in Mouse Model
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Ting Niu, Zhiyong Qian, Ying Qu, and Mengyao Wang
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Polymeric micelles ,Chemistry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Micelle ,Lymphoma ,Folic acid ,medicine ,Cancer research ,Inhibitory concentration 50 ,Methotrexate ,Tumor growth ,Burkitt's lymphoma ,medicine.drug - Abstract
Purpose: Methotrexate (MTX), a folate antimetabolite, competitively inhibits dihydrofolate reductase, the intracellular enzyme responsible for converting folic acid to folate cofactor, thus blocking the synthesis of thymine and purine, causing impairment of tumor growth and induction of cell death. High dose MTX (HD-MTX) is infused in doses of 3-5g/m2 and over a period of 6-24h to maintain the serum MTX at high levels, which shows benefit in the treatment of childhood leukemia and certain adult NHL, particularly the Burkitt type. However, the clinical implication of MTX is hampered for some reasons. On the one hand, the adverse effects of HD- MTX are severe, including bone marrow suppression, mucositis, hepatotoxicity, nephrotoxicity and neurological symptoms. On the other hand, leucovorin rescue, adequate hydration, urinary alkalization and monitoring of MTX concentration is required to avoid life-threating side effects of HD-MTX, which makes the administration rather complicated. In addition, the poor water solubility also impedes the application of MTX. To overcome these obstacles, a new drug delivery system is required to reduce the side effects of HD-MTX as well as to increase the solubility of the drug. So we designed a self-assembled micellar system to load MTX to overcome water solubility and to enhance therapeutic efficacy while reduce toxicity. Materials and Methods: Monomethyl poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) our group previously synthesized was employed to load MTX through a one-step solid dispersion method. The preparation was done without any surfactants, organic solvents, or vigorous stirring. Results: MTX loaded micelles had a small particle size of 25.64±0.99nm and polydisperse index (PDI) of 0.176±0.05. Drug loading and encapsulation efficiency of MTX loaded micelle were 5.57±0.14% and 92.46±2.38%, respectively. Compared with free MTX, MTX loaded micelles demonstrated a much slower and sustained release behavior in vitro. MTT assay and cell apoptosis study suggested that MTX loaded micelles were more effective in inhibiting proliferation (IC50 value 137.8ug/ml vs 86.5ug/ml, p0.05). Furthermore, immunofluorescent and immunohistochemical studies showed that tumors of MPEG-PCL-MTX treated mice had more apoptotic cells (p Conclusions: In this work, MPEG-PCL-MTX micelle was fabricated with a thin-film hydration method to improve the water solubility of MTX and to meet the requirements of intravenous administration, which was stable, safe, effective, easy to produce and scale up, and showed potential clinical application. The enhanced therapeutic efficiency of MPEG-PCL-MTX micelle might be attributed to enhanced permeability and retention (EPR) effect, which increased drug accumulation in the tumor site. Besides, compared with MTX injection with highest concentration in our experiment, MPEG-PCL-MTX micelle with lowest concentration achieved similar or better therapeutic outcome, which indicated the amount of drug could be reduced to achieve the same therapeutic efficiency and alleviate adverse effects towards normal tissues and organs. Moreover, MPEG-PCL-MTX micelle of high dose (7mg/ml) achieved great therapeutic advantage without obvious toxicity, which makes micelle an effective and safe choice when HD-MTX is clinically employed. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
34. Alox15b Gene Contributes to Lymphoma Tumorigenesis Via PI3K/AKT/mTOR Pathway Activation and Has a Synergistic Effect with Alox5 Gene
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Yu Liu, Ting Liu, Pengpeng Liu, Chong Chen, and Ting Niu
- Subjects
Phosphoinositide 3-kinase ,biology ,Chemistry ,ALOX15B ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Lymphoma ,Cell culture ,medicine ,Cancer research ,biology.protein ,Carcinogenesis ,Protein kinase B ,Gene ,PI3K/AKT/mTOR pathway - Abstract
Deletion of the short arm of chromosome 17(del17p) is associated with resistance to standard treatment and the very poor clinical outcome in lymphocytic malignancy. Alongside with TP53 gene, ALOX15B gene is also lost in del(17p) patients. In our pervious study, partially knockdown of Alox15b in mice could accelerate lymphoma tumorigenesis with or without TP53 loss. Accumulation of arachidonic acid (AA) and reduction of apoptosis was observed. But how Alox15b gene and AA effect lymphoma tumorigenesis is not fully understood. Here we show that PI3K/AKT/mTOR pathway is activated in Alox15b-knockdown lymphocytes and contributes to the drug resistance. Besides, we also find that Alox15bgene and Alox5gene play a synergistic role lymphoma tumorigenesis in mice model. Experiments were performed using murine preB cell line, baf3 cell. We introduced shRNAs targeting Alox15b at 2 different loci (shAlox15b.1252 and shAlox15b.2865) to create 2 separated Alox15b-deficient cell lines. Intracellular AA level was tested by liquid chromatograph-mass spectrometer(LC-MS). And Alox15b-deficient lymphocytes showed an accumulation of intracellular AA. Then the activation status of PI3K/AKT/mTOR pathway was detected by examining the phosohor-S6 (pS6) protein level using Western Blot assay in wild-type baf3 cells with exogenous-added AA and Alox15b-deficient baf3 cell lines respectively. The results showed that exogenous-added AA activated PI3K/AKT/mTOR pathway in a dose-dependent manner in wild-type baf3 cells. Also, Alox15b-dificient baf3 cell lines showed an increase in pS6 protein level than control, suggesting that in Alox15b-deficient lymphocytes, PI3K/AKT/mTOR pathways is activated via accumulation of AA In addition, the cell viability test was involved to test how Alox15b gene knockdown affected lymphocyte's reaction to rapamycin(RAPA), a mTOR inhibitor. The results showed Alox15b-dificient baf3 cells are more resistant to RAPA, which indicated that mTOR inhibitors may not be a suitable choice in del17p patients. At Last, we collected primary murine lymphoma cells induced by shAlox15b-shTP53/shREN-shTP53 and blood sample from del17p/non-del17p CLL patients to verify our assumption. In mice samples, as AA accumulation was already observed in previous study, we only test pS6 level. And one sample from each experimental group (shAlox15b-shTP53) showed an increase in pS6 level. In human samples, we can see a slightly increase in AA in del17p patient. But due to individual variation, the result isn't statistical significant. Besides, we constructed a plasmid, namely eMLM-shAlox15b-shAlox5, with 2 shRNA targeting Alox5 and Alox15b gene at the same time, introduced the plasmid into primary murine preB cells and transplanted back to recipient mice. After verified by flow cytometry and pathological staining, survival analysis revealed the fact that silencing Alox5 and Alox15b gene at the same time can accelerate lymphoma formation, suggesting that Alox5 and Alox15b gene have a synergistic effect in lymphoma tumorigenesis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
35. The impact of ALOX cluster loss in chromosome 17p deletions on cancer
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Ting Niu, Yu Liu, Zhengmin Xu, Scott W. Lowe, and Chong Chen
- Subjects
Genetics ,lcsh:R5-920 ,lcsh:QH426-470 ,Cancer ,Cell Biology ,Biology ,medicine.disease ,Disease cluster ,Biochemistry ,lcsh:Genetics ,Chromosome (genetic algorithm) ,medicine ,lcsh:Medicine (General) ,Molecular Biology ,Genetics (clinical) - Published
- 2017
36. Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction
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Xing Li Wang, Bin Li, Joseph S. Janicki, Hui Wang, Ting Niu, Taixing Cui, Lei Shao, Yimu Lai, Siying Li, Huanjie Li, Dongqi Tang, and Wenjuan Wang
- Subjects
Male ,Aging ,medicine.medical_specialty ,Necrosis ,Article Subject ,NF-E2-Related Factor 2 ,ATG5 ,Biology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,environment and public health ,Autophagy-Related Protein 5 ,Mice ,Internal medicine ,medicine ,polycyclic compounds ,Autophagy ,Myocyte ,Animals ,Doxorubicin ,Myocytes, Cardiac ,lcsh:QH573-671 ,Cells, Cultured ,Mice, Knockout ,Cardiotoxicity ,Gene knockdown ,lcsh:Cytology ,Myocardium ,Heart ,Cell Biology ,General Medicine ,respiratory system ,carbohydrates (lipids) ,Mice, Inbred C57BL ,Oxidative Stress ,Endocrinology ,medicine.symptom ,Cardiomyopathies ,Microtubule-Associated Proteins ,Oxidative stress ,medicine.drug ,Research Article - Abstract
The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
- Published
- 2014
37. Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation
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Wenjuan Wang, Dongqi Tang, Weiwei Wu, Qingyun Qin, Huanjie Li, Ting Niu, Fang Wang, Linlin Guo, Xiaoming Zhang, Lei Shao, Taixing Cui, Xing Li Wang, and Linmao Lv
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Male ,Cardiac fibrosis ,medicine.medical_treatment ,Becaplermin ,Gene Expression ,lcsh:Medicine ,Blood Pressure ,Vascular Medicine ,Deubiquitinating enzyme ,chemistry.chemical_compound ,Mice ,MG132 ,Medicine and Health Sciences ,Phosphorylation ,STAT3 ,lcsh:Science ,Aorta ,Platelet-Derived Growth Factor ,Lymphokines ,Multidisciplinary ,biology ,Ventricular Remodeling ,Proto-Oncogene Proteins c-sis ,Animal Models ,Flow Cytometry ,Cell biology ,Up-Regulation ,Cardiovascular Diseases ,Research Design ,Hypertension ,Cardiomyopathies ,Ubiquitin Thiolesterase ,Signal Transduction ,Research Article ,Cyclin-Dependent Kinase Inhibitor p21 ,STAT3 Transcription Factor ,Clinical Research Design ,Cardiology ,Mouse Models ,Research and Analysis Methods ,Sincalide ,Molecular Genetics ,Model Organisms ,Downregulation and upregulation ,medicine ,Autophagy ,Genetics ,Animals ,Gene Regulation ,Animal Models of Disease ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Heart Failure ,Growth factor ,Myocardium ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Fibroblasts ,medicine.disease ,Protein Structure, Tertiary ,Rats ,Mice, Inbred C57BL ,chemistry ,Animals, Newborn ,biology.protein ,lcsh:Q - Abstract
Aims Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction. Methods and Results Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts. Conclusion UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction.
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- 2014
38. A Potent Small Molecule Compound Might Overcome High Level Drug Resistant Mutations of Bcr-Abl1
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Feng-Juan Wang and Ting Niu
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Chemistry ,Immunology ,Ponatinib ,Cancer ,Cell Biology ,Hematology ,Drug resistance ,medicine.disease ,Biochemistry ,Small molecule ,Dasatinib ,Bcr abl1 ,chemistry.chemical_compound ,Imatinib mesylate ,hemic and lymphatic diseases ,Mutation (genetic algorithm) ,medicine ,Cancer research ,medicine.drug - Abstract
Objective: The third-generation tyrosine kinase inhibitor (TKI) ponatinib can overcome many kinds of single mutations including T315I of Bcr-Abl1. Unfortunately, recent clinical studies have identified some new point mutations resistant to ponatinib and the other marketed TKIs. These mutations include compound mutations or T315M single mutation, which we called high level drug resistant mutations in this study. Therefore, it is an urgent task to find a potent small molecule inhibitors, which can overcome these high level drug resistant mutations. Methods: To screen for compounds that can overcome the high level drug resistant mutations of Bcr-Abl1, we firstly established genetic engineering cell models using the Ba/F3 cell line, including: (1) Ba/F3-Bcr-Abl1T315M; (2) Ba/F3-Bcr-Abl1T315I/E255V; (3) Ba/F3-Bcr-Abl1E255V/Y253H. The established cell lines were also carefully verified .Then we used these established cell models and others we have already obtained, including Ba/F3-Bcr-Abl1WT, Ba/F3-Bcr-Abl1T315I, and Ba/F3-Bcr- Abl1E255V, to screen an in-house chemical library. The most potent compound SKLB-518 was finally chosen to perform further studies both in vitro (cell and protein level) and in vivo (allograft subcutaneous cancer mice model). Results: In vitro assays, three marketed TKIs, namely imatinib, dasatinib, and ponatinib, were chosen as the references. The IC50 value of SKLB-518 to inhibit Ba/F3-Bcr-Abl1E255V/Y254H cells was 0.033 μM, which was more active by >100 times and 6.14 times than that of imatinib (IC50: >10 μM) and ponatinib (IC50:0.201μM), respectively, and comparable with dasatinib (IC50:0.028 μM). The IC50 of SKLB-518 to inhibit Ba/F3- Bcr-Abl1T315I/E255V cells was 0.094 μM, which was more potent by >100 times, 30~100 times, and 8.69 times than that of imatinib (IC50: >10 μM), dasatinib (IC50: 3~10 μM), and ponatinib (IC50: 0.817 μM), respectively. In vivo, thedata indicated that SKLB-518 could significantly inhibit tumor proliferation at the doses of 30 mg/kg/d and 45 mg/kg/d (%T/C was 62.1 and 72.5, respectively; both groups p Conclusion:Independently developed small molecule SKLB- 518 might overcome the high level drug resistant mutations of Bcr-Abl1. Disclosures No relevant conflicts of interest to declare.
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- 2016
39. Retrospective Treatment Analysis of a Series of 104 Patients with Adult Onset Hemophagocytic Lymphohistiocytosis in a Single Institution of China
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Bing Xiang, Chuan He, Ting Liu, Jie Huang, Yongqian Jia, Xu-Shu Zhong, Wenjiao Tang, Liping Xie, Zhigang Liu, Yu Wu, Jianjun Li, Xiao Shuai, Yuping Gong, Jie Ji, Yan Li, Xinchuan Chen, Ling Pan, Hong Chang, Hongbing Ma, Xu Cui, Juan Xu, Ting Niu, Yang Dai, and Huanling Zhu
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Univariate analysis ,Hemophagocytic lymphohistiocytosis ,Pediatrics ,medicine.medical_specialty ,business.industry ,Immunology ,Therapeutic effect ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Etiology ,030212 general & internal medicine ,Prospective cohort study ,business ,Survival rate ,Etoposide ,medicine.drug - Abstract
Objective. Hemophagocytic lymphohistiocytosis (HLH), also known as Hemophagocytic Syndrome (HPS), is an increasingly recognized clinical syndrome that is characterized by extreme immune activation. HLH was first described as an inherited immune disorder in pediatrics, but it may also arise in adults as the result of persistent antigen stimulation due to infections, autoimmune disorders or malignancies. Early recognition of HLH and appropriate treatment are critically important. For the pediatric patients, the Histiocyte Society Study Group for HLH has developed the HLH-94 and HLH-2004 treatment protocols, but there is no such guideline or consensus for adult HLH. Although there were increasing amount of clinical studies in adult HLH, the majority of them just described the etiologies and clinical profiles, and failed to analyze the treatment effects on outcomes. Therefore, there is an urgent need for more clinical data focusing on treatment in adult HLH patients, in order to clarify optimal therapeutic regimens. Our study retrospectively analyzed the causes, treatment strategies, and relevant outcomes in 104 adult HLH patients in our institution, and with the goal of identifying more appropriate therapeutic strategies for adult HLH patients. Methods. After the approval of our protocol by local institutional Ethics Committee, the medical records of 104 consecutive patients with adult onset HLH in West China Hospital from June 2008 to February 2016 were reviewed. The diagnosis was re-confirmed according to HLH-04 criteria, and demographic data, clinical profiles, treatments and outcomes were collected and analyzed. The latest follow-up visit occurred on 1st July 2016. The different therapeutic effects on prognosis were discussed based on the endpoints which were defined as short-term (30 days) and long-term (last follow-up date) survival rates. Statistical analysis was performed on SAS 9.4 software, and was involved in Log-rank test in univariate analysis and Cox proportional hazard regression model in multivariate analysis. All p values were two-sided and p Results. All of 104 consecutive patients with adult HLH were enrolled in this study. The male/female ratio was 1.6:1 with the median age of 35 (range 16-77). In etiological classification, 75 cases were lymphoma-associated HLH, 13 cases were infection-associated HLH, 2 cases were with autoimmune disorders, and for the remaining 14 cases, the underlying diseases could not be identified. In treatment analysis, corticosteroids were used in 91 cases (87.5%), the median initiation time was 0 day (range 0-26 days) after HLH diagnosis, the median four-week accumulating dosage was 236.57mg dexamethasone. Etoposide was employed in 55 cases (52.9%), the median initiation time was 3.5 days (range 0-62 days), the median four-week accumulating dosage was 590.00mg. Cyclosporine A (CSA) was used in 42 cases (40.4%), the median initiation time was 2 days (range 0-51 days), the median four-week accumulating dosage was 7100.00mg. The median survival time for all patients was 46 days (1-2529 days). On the 30th day after admission, 27 patients (26.0%) had died, and 77 patients (74.0%) had survived. At the last follow-up visit, 74 patients (71.2%) had died, 17 patients (16.2%) were still alive, and 13 patients had been lost to follow-up. Statistical analysis indicated that patients in etoposide-treated group was associated with superior short-term survival rate, compared with non-etoposide-treated group (p=0.0471), but there was no difference in long-term survival rate between the two groups. CSA-treated group was associated with inferior long-term survival rate (p=0.0214), compared with non-CSA-treated group. In patients with lymphoma-associated HLH, those who received antineoplastic chemotherapy had a higher long-term survival rate than those who did not receive it (HAZARD=0.07, p Conclusion. The major underlying diseases of adult onset HLH are malignant lymphomas. Etoposide might only improve the short-term survival, but fail to change the long-term survival. Immunosuppressor CSA seems to be associated with negative effects on long-term survival rate. For patients with lymphoma-associated HLH, antineoplastic chemotherapy might improve the long-term outcome. More clinical prospective studies should be initiated for adult acquired HLH. Disclosures No relevant conflicts of interest to declare.
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- 2016
40. Chimeric Antigen Receptor 4SCAR19-Modified T Cells in Acute Lymphoid Leukemia: a Phase II Multi-Center Clinical Trial in China
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Rong Liu, Lujia Dong, Heng-Xiang Wang, Zhi-Yong Gao, Tong-Hua Yang, Lung-Ji Chang, Ting Liu, Huyong Zheng, Le-Ping Zhang, Yu-Hong Chen, Xun Lai, Jing-Bo Wang, Jian-Ping Zhang, Ting Niu, He Huang, Li Gao, and Dao-Pei Lu
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medicine.medical_specialty ,Acute leukemia ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Transplantation ,Leukemia ,Aldesleukin ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,business ,medicine.drug - Abstract
Background: Relapsed/refractory leukaemia is associated with poor prognosis. T cells genetically modified to express CD19-specific chimeric antigen receptor (CD19CAR) in patients (pts) with chronic lymphoblastic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have shown a remarkable ant-cancer activity. However, many questions remain related to the predictive indicators of long-term response and the management of cytokine release syndrome (CRS) after CAR-T cell infusion. In this phase II multi-center clinical trial, we evaluated the safety and efficacy of a fourth generation, safety-improved CD19-CAR (4SCAR19) in B-ALL pts. Patients and Methods: Fifty evaluable B-ALL patients (pts), with demonstrated persistent disease following salvage chemotherapy from 14 hospitals in China between July 2013 and June 2015 have been enrolled. The mean age is 14 (from 3 to 65) including 26 children and 24 adults. Leukemic genotypes include 16 Bcr-Abl (13 pT315I), 11 WT-1, 3 MLL-AF4, 3 E2A-PBX-1, 1 TEL/AML1, 1 IKZF1, 1 K-ras and the remaining 14 pts have undetectable genotype. Their disease characteristics include: 4 hypercritical acute leukemia, 10 extramedullary leukemia (7 CNSL, 3 multiple sites), with associated co-morbidity: 12 Aspergillus pneumonia, 4 cGVHD, 2 pleura/pericardial cavity effusion, 2 hepatitis B, 2 diabetes mellitus, 1 gastrointestinal hemorrhage, and 1 liver/spleen abscess. Twenty-one (42%) pts received allo-HSCT including 15 haplo-identical, 5 matched related donor (MRD) and 1 unrelated cord blood (URD-CB). These pts who relapsed after transplantation have received chemotherapy (chemo), combined with Tyrosine Kinase Inhibitors (TKIs, 10), donor leukocyte infusion (DLI, 19), or dendritic cells-cytokine induced killer cell (DC-CIK)/NK cell infusions (7). CAR-T cells were prepared from autologous (37), transplant donor (12) or non-transplant donor mother (1). T cells. Peripheral lymphocytes were collected from leukapheresis, and T cells were transduced with a 4th generation, safety-engineered, CD19scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR-19) lentivector. Pre-CAR-T lymphodepleting chemotherapy includes individualized chemo in 17 pts, and the others received Fludarabine (Flu) + Cyclophosphamide (Cy)(FC), or either Flu or Cy regimen: (1) FC: Cy 250mg/m2/d x3d and Flu 30mg/m2/d x3d ,or (2) either Flu x3 days, or (3) Cy x3 days, followed by CAR-T infusions at a dose of 2.13 (range from 0.42 - 5.9) x106 CAR-T cells per kg body weight per infusion. Results: For statistical analysis, 50 patients were divided into 2 cohorts: Cohort 1: B-ALL with morphological blast Toxicities: CRS occurred in most pts within the first 10 days of CAR-T cell infusion. 47/50 (94%) pts developed fever with elevated IL-2, IL-6, IL-10, and interferon gamma. Eight (16%) pts required either 12.5 mg Etanercept or 8 mg/kg tocilizumab, and three pts were treated with both drugs. Four pts developed hypotension and fully recovered after receiving dopamine. Four pts were treated once by methylprednisolone (1 mg/kg/day). The median follow-up was 4 months (range from 3~24 month), with 16 pts followed up for more than 6 months. Clinical outcomes: 1. LFS: The 120 days LFS for pts in cohort 1 and cohort 2 were 86% (CI,80%~93%) and 44.4% (CI, 31%~58%, P=0.0030), respectively. 2. OS (10 month) probabilities for patients in cohort 1 and cohort 2 were 82% (73%~91%) and 36% (19%~52%) (P= 0.0029), respectively. Conclusion: Our results indicate the potential of rapid leukemia eradication kinetics of 4SCAR19 therapy in treating chemo-resistant B-ALL. This therapy dramatically improves the prognosis of B-ALL pts by either providing a bridging approach to allo-HSCT or a better remission induction with longer period of CR than the routine treatment. Moreover, pts with morphological blasts Disclosures Dong: America Yuva Biotech: Consultancy, Other: clinical consultation.
- Published
- 2015
41. Rescue of a Terminally Ill Patient with Chemo-Refractory Acute Lymphoblastic Leukemia Carrying Bcr/Abl and TP53 Mutations Based on a 4th Generation CD19 Chimeric Antigen Receptor-Engineered T (CAR-T) Therapy
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Ting Liu, Wei Wang, Ting Niu, Yu-Chen Liu, Jin-Rong Yang, Lung-Ji Chang, and Lujia Dong
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medicine.medical_specialty ,Chemotherapy ,Gastrointestinal bleeding ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Gastroenterology ,Surgery ,Leukemia ,Imatinib mesylate ,Acute lymphocytic leukemia ,Internal medicine ,Medicine ,Chills ,medicine.symptom ,business ,medicine.drug - Abstract
Background: Chemo-refractory, advanced acute lymphoblastic leukemia (ALL) with ultra high-risk factors such as Bcr/Abl,TP53 mutation are difficult to treat and often fatal. Recent studies have shown that CD19 chimeric antigen receptor-engineered T (CAR-T) cells can effectively treat late-stage B-ALL. Here we report an extreme case of successful rescue of a critically ill patient with refractory B-ALL carrying Bcr/Abl, TP53 mutations by repeated infusions of CD19 CAR-T cells. Patient and Methods: A 15-year-old girl was diagnosed with Bcr/Abl positive, Pro-B-ALL, with 97% bone marrow (BM) blasts. Induction therapy containing Imatinib, vindesine, and dexamethasone failed to control the symptoms. She withdrew Imatinib for allergic reason and Idarubicin was added, but the leukemia progressed. Chemotherapy was then suspended due to her aggravated pneumonia and the condition worsened 2 days later with melena ~200ml/day; DIC was suspected and treated accordingly, but failed. Fifty days after admission, her BM showed 98% blasts, positive for CD34, CD19, partially positive for CD13, CD33, with complicated cytogenetic aberrationsF56~57,XX,+X,+13,+14,-16,der(17:20)(q10Fp10),+22/der(19:22)(p10Fq10),+mar1×2{cp2}, and TP53 C275Y mutation. The patient was heavily dependent on blood transfusion, and her gastrointestinal bleeding aggravated with bloody stools 300-350ml daily, and lymph nodes, liver and spleen continued to increase in size. The therapeutic options were extremely scarce and we obtained consent from the patient's parents for a pilot CD19 CAR-T cell therapy. Under intensive supportive transfusion, peripheral blood mononuclear cells were collected by apheresis with >75% CD19+ B-ALL blasts. The CD3+ T cells were magnetically selected and lentivirally transduced with a 4th generation, apoptosis-inducible, safety-engineered CAR: CD19-scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR19). The patient received lympho-depleting conditioning of cyclophosphamide 1000 mg d1, 3, 5, vindesine 4 mg d2, methylprednisolone 40mg d1-5, followed by CAR-T infusion at 3.5×106 cells/kg with 7% gene marking efficiency. After 3 days, the patient developed chills and high fever over 39.5o C, with C-reactive protein 87.3 mg/L and IL-6 166.5 pg/ml. Indomethacin and etanercept were applied to control the cytokine release syndrome (CRS). The fever above 39o C lasted for 3-14 days post infusion,which was managed with antipyretic drug. Her vital sign turned normal, and gastrointestinal bleeding relieved gradually with decreased lymph node size. Then the patient developed a serious intermittent abdominal pain with suspected gastrointestinal infection, tigecycline was administered, and the symptom was relived. Later on the patient developed an epileptic seizure 15 days after CAR-T infusion with symptoms of unconsciousness, staring eyes, lockjaw, stiff upper limbs, and urinary incontinence. The seizure repeated hours later with reduced heart rate, which lasted for 30 min before returning to consciousness, the ECG showed an escaped rhythm of 60 beats/min. The patient gradually recovered with relief of gastrointestinal bleeding, reduced lymph node, liver and spleen size. Thirty-four days after CAR-T cell infusion, there was no ALL blast detectable in the circulation and the BM revealed complete remission (CR), with a minimal residual disease (MRD) of 1%. She was discharged from the hospital, however relapsed with 47% BM blasts 79 days later. Additional CAR-T infusions of 3×106/kg and 2×106/kg 4SCAR19-T cells with 27% gene marking efficiency were given. The patient did not show any sign of CRS this time and achieved CR 17 days later with negative MRD. This patient has been followed up for 6 months, still in the good medical condition up to date. Conclusions: Ultra high-risk, chemo-resistent B-ALL with complicated cytogenetic and molecular aberrations (Bcr/Abl, TP53 mutations), and refractory to existing treatments can be rescued by repeated CD19 CAR-T cell therapy. Patients in such condition have no chance of survival under traditional chemotherapy and targeted therapy, and salvage allogeneic-transplantation is not applicable. Our study indicates that CAR-T-related adverse reactions even under extreme conditions are manageable. In addition, repeated CAR-T infusions with optimal gene marking efficiencies maybe necessary for patients with serious complications. Disclosures Liu: America Yuva Biomed: Employment.
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- 2015
42. A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts
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H. Yang, Roy B. Jones, Simon N. Robinson, Jingjing Ng, John McMannis, S. Li, M. de Lima, Dongxia Xing, M. S. Lee, Borje S. Andersson, Ting Niu, Xin Yao, Allen C. Eaves, William K. Decker, Elizabeth J. Shpall, Richard E. Champlin, and Connie J. Eaves
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Cell Survival ,medicine.medical_treatment ,Immunology ,CD34 ,Stem cell factor ,Antigens, CD34 ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Cell Separation ,Biochemistry ,Transplantation, Autologous ,Piperazines ,chemistry.chemical_compound ,Mafosfamide ,Antigens, CD ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Autologous transplantation ,Humans ,Progenitor cell ,neoplasms ,Cyclophosphamide ,Transplantation ,business.industry ,Bone Marrow Purging ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Flow Cytometry ,Neoplastic Cells, Circulating ,Granulocyte colony-stimulating factor ,Leukemia ,Imatinib mesylate ,Pyrimidines ,chemistry ,Benzamides ,Cancer research ,Imatinib Mesylate ,Stem cell ,business ,K562 Cells ,medicine.drug ,Allotransplantation ,Chronic myelogenous leukemia ,Stem Cell Transplantation - Abstract
Allogeneic hematopoietic progenitor cell transplantation (HPCT) remains an established curative approach for selected patients with chronic myelogenous leukemia (CML). Patients for whom an allogeneic donor cannot be found or who are unable to tolerate allotransplantation require post-Gleevec alternatives. Autologous HPCT causes less morbidity/mortality than allotransplantation but CML cells in the autograft pose a potential risk for post-transplant relapse. An effective purging method for eliminating leukemic cells without compromising normal reconstituting activity would make autotransplantation a more attractive strategy for selected CML patients. In previous studies, we and others have shown that primitive CML cells are selectively killed after brief treatments in vitro with Mafosfamide (Maf) or Gleevec. Additionally, cultured primitive CML cells differentiate much more rapidly than their normal counterparts resulting in a selective depletion of CML stem cells after 1–2 weeks. Here we report the development of a novel autograft purging strategy that combines the use of a brief exposure of CML cells to Gleevec plus Maf followed by extended culture without cytotoxic agents but with added recombinant cytokines that favor the maintenance of normal stem cells. Methods: CD34+ cells were isolated from the peripheral blood progenitor cell (PBPC) products of CML patients and normal donors, treated for 72 hrs with graded concentrations of Gleevec (0.5–1.0 uM) followed by 0, 30, 60 or 90 ug/ml of Maf for 30 min. Cells were then washed and cultured for 14 days in medium containing 10% FBS and 100 ng/ml each of stem cell factor (SCF), granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO). Following treatment, cells from each group were evaluated for total viable cells, BCR-ABL message by real time polymerase chain reaction (RT-PCR) assays and colony-forming unit-granulocyte macrophage (CFU-GM) content in methylcellulose assays. Results: BCR-ABL+ cells were eliminated in the CML PBPC products from patients in chronic phase (n=3), but not blast crisis (n=1) when treated with Gleevec (0.75 uM) and Maf (60 ug/ml) followed by 2 weeks in vitro with SCF+G-CSF+TPO. Residual Ph positive cells by RT PCR Patient/Disease stage Culture alone Drugs alone (Gleevec 0.75 or 1uM + Maf 60ug/ml) Culture + Drugs 1-chronic phase/Gleevec refractory Positive Positive Negative 2-chronic phase/Gleevec refractory Positive Positive Negative 3-chronic phase/Gleevec naïve Positive Negative Negative 4-blastic phase/Gleevec naïve Positive Positive Positive Treatment of CD34+ PBPCs from normal donors with 0.75 uM Gleevec + 60 ug/ml Maf reduced CFU-GMs to 15% of input controls immediately post drug-exposure but these recovered to 320% of input after the additional 2 weeks in culture. Conclusion: Triple purging of CML cells with Gleevec, Maf and 2 weeks of culture appears to eradicate chronic phase BCR-ABL+ cells while retaining most of the normal progenitor activity as assessed by in vitro clonogenic assays. This approach may be useful as a strategy for purging CML autografts for Gleevec-refractory patients and, pending confirmatory results from in vivo xenograft assays, will be tested in a clinical autotransplant trial.
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- 2006
43. Effect of Eltrombopag on Platelet Response and Safety Results in Chinese Adults with Chronic ITP-Primary Result of a Phase III Study
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Jie Jin, Ting Niu, Ming Hou, Junmin Li, Ziqiang Yu, Meijuan Huang, Xin Du, Xiaojun Xu, Jianmin Wang, Renchi Yang, Hua Lu, Belinda Hsu, Jing Sun, Yongqiang Zhao, Haiyi Guo, Xiaoyan Ke, Jing Liu, and Xiao-Hui Zhang
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Splenectomy ,Cmax ,Eltrombopag ,Cell Biology ,Hematology ,Odds ratio ,Placebo ,Biochemistry ,Gastroenterology ,law.invention ,Surgery ,chemistry.chemical_compound ,Randomized controlled trial ,chemistry ,law ,Concomitant ,Internal medicine ,medicine ,Adverse effect ,business - Abstract
INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline) is a non peptide, oral thrombopoietin receptor agonist which promotes the differentiation and proliferation of megakaryocytes and increases platelet counts. In previous studies, East Asians ITP subjects had an approximately 1.85 fold higher plasma eltrombopag AUC (0-τ) and 1.6 fold higher plasma eltrombopag Cmax than non-East Asian ITP subjects who were predominantly Caucasian. An initial dose of 25mg once daily has not been studied in a randomized fashion in East Asian subjects with ITP. METHODS: This is a randomized study comprising a double-blind (DB), placebo (PBO)-controlled phase, followed by an open-label (OL) phase in previously treated Chinese patients with chronic ITP who had failed ≥1 previous treatment. Subjects were stratified at baseline by use of ITP medication, splenectomy status and platelet count ≤15×109/L. In the DB phase, Chinese Adults with Chronic ITP and platelet counts 50×109/L) was not achieved. The primary efficacy endpoint was the proportion of patients achieving a platelet count of ≥50×109/L and ≤250×109/L after the first 6 weeks of study treatment using a logistic regression model adjusted for stratification factors . All subjects completing the DB phase entered the OL phase where they initiated (if they were on placebo) or continued (if they were on eltrombopag) to receive eltrombopag (25, 50 or 75 mg/day) based on individual platelet counts. RESULTS: 155 subjects were randomized to receive 6 weeks of once daily eltrombopag (n=104) or matching placebo (n=51) in 2:1 ratio. Of 155 subjects randomized, 81 subjects (52.3%) were receiving concomitant ITP medication at baseline, 25 subjects (16.1%) had prior splenectomy, and 82 subjects (52.9%) had baseline platelet count ≤15×109/L. A total of 53/104 (51%) subjects on eltrombopag were receiving concomitant ITP medication at baseline vs 28/51 (54.9%) subjects on placebo. A total of 18/104 (17.3%) subjects on eltrombopag had prior splenectomy vs 7/51 (13.7%) subjects on placebo. A total of 54/104 (51.9%) subjects on eltrombopag had baseline platelet counts ≤15×109/L vs 28/51 (54.9%) subjects on placebo. The primary efficacy analysis showed that eltrombopag statistically significantly increased platelet counts in patients with chronic ITP: 57.7% (60/104) of subjects in eltrombopag group, and 6% (3/50) of subjects in placebo group achieved a platelet count of ≥50×109/L after the first 6 weeks of study treatment. (Odds ratio= 26.08, 95% CI [7.29, 93.26]; p CONCLUSION: This is the first study to evaluate eltrombopag at an initial dose of 25mg once daily in a randomized fashion in East Asian patients with previously treated chronic ITP. Eltrombopag statistically significantly increased platelet counts in Chinese adults with chronic ITP when compared to placebo. Eltrombopag was well-tolerated and these results are consistent with the known clinical benefit: risk profile of eltrombopag in patients with chronic ITP. Eltrombopag may be a new treatment option for Chinese patients with chronic ITP. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
44. Clinical Research on Burkitt Lymphoma—a Single-Center Report in China
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Meng Jiang and Ting Niu
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Univariate analysis ,medicine.medical_specialty ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,CHOP ,Single Center ,Biochemistry ,Gastroenterology ,Surgery ,Regimen ,B symptoms ,Internal medicine ,Statistical significance ,Cohort ,medicine ,medicine.symptom ,business - Abstract
Objectives To analysis the clinical characteristics and discuss the factors that influence the treatment efficacy and prognosis of the patients with Burkitt lymphoma (BL). Patients and Methods A retrospective study was performed to collect the clinical characteristics and follow-up data of the patients with BL from January 2004 to December 2014 in West China Hospital. Results A total of 42 patients with BL included 32 male patients and 10 female ones,with a median age at diagnosis of 45 yr (range: 13 to 74 yr) old. In the whole cohort, 66.67% of the patients had an Ann Arbor stage III`W. Patients with B symptoms accounted for 50.00%. Gastrointestinal discomfort and axillary, jugular and mandibular mass were the main complaints. Twenty patients received Hyper-CVAD/HD-MTX-Ara-C regimen (Hyper regimen), while the other 22 patients received non-Hyper regimen, which included CHOP/CHOP-like, CODOX-M/IVAC regimen and others. The 42 cases showed an overall response of 59.52%, with a complete response (CR) rate of 57.14% (24/42). With univariate analysis: the CR rates of the patients received Hyper regimen and non-Hyper regimen were 75.00% and 40.91%, respectively, indicating a statistical significance between the two groups (P=0.027); the CR rate of the patients with elevated LDH was higher than the patients with normal LDH; the CR rate of patients with ECOG PS of 0`2 was higher than the patients with PS 3`4; the CR rate of the patients with IPI of 0`2 was higher than the patients with IPI of 3`5; for the patients whose LDH increased, the CR rate of the patients received Hyper regimen was higher than the patients with non-Hyper regimen. The OS of the patients who received Hyper regimen was better; the OS of the patients with ECOG of 0`2 was superior to that with ECOG of 3`4; the OS of the patients with IPI of 0`2 is better than that of 3`5; the OS of the patients with Ann Arbor stage of ±`II was higher than that of III`W; the OS of the patients who acquired CR was better than that did not; the OS of the patients without bone marrow involvement was superior to that with it. In multivariate analysis: treatment regimen was of significance in predicting the probability of CR, whereas treatment regimen and IPI score were confirmed as being highly predictive for OS. The main side reactions of the 20 cases who accepted Hyper regimen were hematologic toxicity of III`W degree, gastrointestinal discomforts and infections, and there was no treatment-related mortality occurred. Conclusions: Hyper regimen could improve the CR rate and prolong the survival of BL patients, and the adverse reactions could well be tolerated. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
45. Clinical Research on Hematological Malignancies Complicated with dic-a Single Center Report in China
- Author
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Qing Wei and Ting Niu
- Subjects
Disseminated intravascular coagulation ,Gastrointestinal bleeding ,medicine.medical_specialty ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Single Center ,Biochemistry ,Clinical research ,Refractory ,Heart failure ,Internal medicine ,Medicine ,business ,Adverse effect ,Intensive care medicine - Abstract
Objective This study aimed to explore the most appropriate way of diagnosis and treatment among the patients with hematological malignancies complicated with disseminated intravascular coagulation (DIC) by evaluating the risk factors which would affect the prognosis and the efficiency of therapies. Methods The data of 162 definitely-diagnosed patients in West China Hospital between 2009 and 2013 has been collected and analyzed in our retrospective study. We have summarized the information on clinical features, laboratory indicators and interventions, which has been statistically analyzed to evaluate the effect on mortality. Results Elderly patients, AML patients accompanied with hyperleukocytosis, APL patients accompanied with differentiation syndrome combined deteriorated DIC symptoms, patients accompanied with infections, refractory/relapsed patients, patients with any of the following clinical symptoms such as gastrointestinal bleeding, intracranial hemorrhage, more than three sites of bleeding, acute renal dysfunction,acute respiratory dysfunction, acute left heart failure, MOF or shock, presented higher mortality (P6 had poorer prognosis. In our study, we tried to classify Fig < 1 g/L or > 4 g/L as a Fig abnormal group, the rest of the patients classified as a Fig normal group, then we found the abnormal Fig group had an increased mortality (P < 0.05). In addition, it had been found that patients who received standard chemotherapy had lower mortality (P < 0.05). With respect to non-APL patients, ones who took anti-fibrinolysis agents had similar mortality compared with the patients who didn't (P>0.05). Conclusions Among the patients of hematological malignancies complicated with DIC, the patients with any of above clinical risk factors or abnormal laboratory indicators would have poorer prognosis. Moreover, the cut-off value of PLT should be dropped when we diagnose or evaluate this kind of patients’ prognosis. We put forward a new cut-off value of Fig as described above and it is valuable to evaluate the prognosis. The treatment of underlying diseases and substitute therapy act as basis of these patients, however, the adverse effects should be pay attention to as well as infections and acute heart failure. No benefit has been shown in the non-APL patients treated with anti-fibrinolytic agents. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
46. Construction of the Lentiviral and Electric Transfection Vectors Encoding Anti-Human CD30 or CD33 Chimeric Antigen Receptor (CAR) Gene and Respective Expression Injurkat Leukemia Cell Line
- Author
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Ting Niu and Ke Zeng
- Subjects
Expression vector ,medicine.medical_treatment ,Immunology ,Nucleofection ,Cell Biology ,Hematology ,Immunotherapy ,Transfection ,Biology ,Biochemistry ,Molecular biology ,Jurkat cells ,Chimeric antigen receptor ,Viral vector ,medicine ,Cytotoxic T cell - Abstract
Adoptive cellular therapy (ACT), as a kind of biological treatment, has played an important role in immunotherapy for malignancies, by which an individual passively acquires the specific immunological rejection to tumor molecular target through cellular infusion, resulting in the suppression or destruction of malignancies. In the early clinical studies, immunotherapies based on tumor-infiltrating lymphocytes (TILs) have demonstrated definitively therapeutic effect on a variety of tumors, especially on melanoma, which underlined feasibility and necessity of ACT in anti-tumor therapies. However, the difficulties on cellular material acquisition, relatively complex cellular constitute, undefined anti-tumor target and unstable efficacy, all of which affected and limited the clinical practice with TILs, in addition to the immune tolerance-inducing behaviors of the tumor itself, such as the immune escape, suppression of the immune effects via peri-tumor microenvironment, down-regulation of MHC to minimize antigen exposure, et al. Chimeric antigen receptor (CAR) has effectively integrated the specific recognition of Ab-Ag and signal transfer function of TCR to form a transmembrane molecule with different functional domains. The expression fragment of CAR could be formed by aligning single chain antibody fragment (scFv) cDNA and costimulatory domain in tandem, which is subsequently transferred via lentiviral vectors to modify autologous T lymphocytes. After gene expression and translation, the CAR has an MHC-independent specific recognition to tumor-associated antigen (TAA), resulting in T cell activation, anti-tumor cytotoxic effort and memory cell differentiation. CAR-modified lymphocytes (CART) are effective ACT tools cells with anti-tumor specificity through gene transfection. Currently, CD19-targeted CART therapy has yielded promising therapeutic effect. Our study selected a lineage-specific CD33 and another tumor-specific CD30 as CAR-associated targets, with which we designed and constructed a series of third generation CAR containing CD28 activation domain and 4-1BB costimulatory domain. The CAR-containing expression vectors were transfected into the Jurkat cell line via lentiviral system and nucleofector electroporation system, respectively.The target gene fragments, anti-CD30-scFv, anti-CD33-scFv, and CD28-4-1BB-CD3ζ sequence encoding T cell activation plus costimulatory signals were amplified from pUC57-CD30-scFv, pUC57-CD33-scFv and pUC57-CD2841BBZ via PCR. The separated scFv and signal sequence were linked into a continuous fragment, CAR-CD30 and CAR-CD33 cDNA, by overlapping PCR, which were subsequently subcloned into a lentiviral expression vector, pCDH-CMV-MCS-EF1-Puro, to construct recombinant lentiviral vector pCDH-CAR30 and pCDH-CAR33; the electric transfection vector pmax-CAR30 and pmax-CAR33 were constructed as well.With virus packaging, the corresponding CARs/GFP/Blank-containing virus were added into Jurkat cell medium, which were immediately centrifuged to facilitate infection; puromycin was used to screen Jurkat strains highly expressing CAR, CAR-modified Jurkat strains were thus harvested one week from antibiotic screening, named as: Jurkat-pCDH-Blank, Jurkat-pCDH-GFP, Jurkat-pCDH-CAR30 and Jurkat-pCDH-CAR33, whose protein samples were then extracted for CAR detection. The Jurkat cells could also be effectively transfected by applying an electrical pulse to momentarily create small pores in cell membranes, with the aid of pmax-CAR30 or pmax-CAR33, moreover, different discharge mode was designed to yield higher cell viability, and otherwise higher transfection efficiency. The fluorescent signal could be observed 24h from electric pulse and protein samples could be extracted at the same time. After one-week screening with puromycin, fluorescence from Jurkat cells infected with GFP-containing virus were detected. Electroporation was used as an alternative procedure to produce CAR-modified Jurkat cell line, and the transfection efficiency was higher than lentiviral system did, approximately 90%, by GFP observation. The expression of CAR-CD30 and CAR-CD33 were also successfully detected by western blot in Jurkat cells, indicating a preliminary and technical basis ahead of in-depth study on ACT and CART agent preparation. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
47. Ex vivo expansion of umbilical cord blood
- Author
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Sean L. O'Connor, Richard E. Champlin, M. de Angel, P. Fu, Tara Sadeghi, M. de Lima, S. Karandish, Elizabeth J. Shpall, John McMannis, Ting Niu, H. Yang, Simon N. Robinson, and Jingjing Ng
- Subjects
Cancer Research ,Immunology ,Population ,CD34 ,Cell Culture Techniques ,Immunology and Allergy ,Medicine ,Humans ,Progenitor cell ,education ,Genetics (clinical) ,Cells, Cultured ,Transplantation ,education.field_of_study ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Fetal Blood ,Coculture Techniques ,Haematopoiesis ,Oncology ,Cord blood ,Cancer research ,Cord Blood Stem Cell Transplantation ,Stromal Cells ,business ,Ex vivo - Abstract
The efficacy of cord blood (CB) transplantation is limited by the low cell dose available. Low cell doses at transplant are correlated with delayed engraftment, prolonged neutropenia and thrombocytopenia and elevated risk of graft failure. To potentially improve the efficacy of CB transplantation, approaches have been taken to increase the cell dose available. One approach is the transplantation of multiple cord units, another the use of ex vivo expansion. Evidence for a functional and phenotypic heterogeneity exists within the HSC population and one concern associated with ex vivo expansion is that the expansion of lower 'quality' hematopoietic progenitor cells (HPC) occurs at the expense of higher 'quality' HPC, thereby impacting the reserve of the graft. There is evidence that this is a valid concern while other evidence suggests that higher quality HPC are preserved and not exhausted. Currently, ex vivo expansion processes include: (1) liquid expansion: CD34+ or CD133+ cells are selected and cultured in medium containing factors targeting the proliferation and self-renewal of primitive hematopoietic progenitors; (2) co-culture expansion: unmanipulated CB cells are cultured with stromal components of the hematopoietic microenvironment, specifically mesenchymal stem cells (MSC), in medium containing growth factors; and (3) continuous perfusion: CB HPC are cultured with growth factors in 'bioreactors' rather than in static cultures. These approaches are discussed. Ultimately, the goal of ex vivo expansion is to increase the available dose of the CB cells responsible for successful engraftment, thereby reducing the time to engraftment and reducing the risk of graft failure.
- Published
- 2005
48. Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2
- Author
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Jing Mei Su, Yong Qiu Mao, Yu Jiang, Yan Jun Wen, Bing Kan, Ling Tian, Fen Liu, Yan Yan Lou, Ji Yan Liu, Ting Niu, Qiu Ming He, Li Yang, Feng Luo, Yang Wu, Jian Mei Hou, Yu Quan Wei, Feng Peng, Xia Zhao, Bing Hu, and Jin Liang Yang
- Subjects
Adoptive cell transfer ,Lung Neoplasms ,Lymphoma ,Angiogenesis ,medicine.medical_treatment ,Fibrosarcoma ,Immunology ,Biology ,Biochemistry ,Cancer Vaccines ,Quail ,chemistry.chemical_compound ,Carcinoma, Lewis Lung ,Mice ,Growth factor receptor ,Immunity ,T-Lymphocyte Subsets ,Antigens, Heterophile ,medicine ,Animals ,Autoantibodies ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,ELISPOT ,Cell Biology ,Hematology ,Immunotherapy ,Vascular Endothelial Growth Factor Receptor-2 ,Vascular endothelial growth factor ,Mice, Inbred C57BL ,Vascular endothelial growth factor A ,chemistry ,Colonic Neoplasms ,Cancer research ,Neoplasm Transplantation ,Plasmacytoma - Abstract
The breaking of immune tolerance of “self-antigens” associated with angiogenesis is an attractive approach to cancer therapy by active immunity. We used vascular endothelial growth factor receptor-2 (VEGFR-2) as a model antigen to explore the feasibility of the immunotherapy with a vaccine based on a xenogeneic homologous protein. To test this concept, we prepared a quail homologous VEGFR-2 protein vaccine (qVEGFR) based on quail VEGFR-2. At the same time, a protein vaccine based on the corresponding ligand-binding domain of mouse self-VEGFR-2 (mVEGFR) was also prepared and used as a control. We found that immunotherapy with qVEGFR was effective at protective and therapeutic antitumor immunity in several solid and hematopoietic tumor models in mice. Autoantibodies against mouse VEGFR-2 (Flk-1) were identified by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Anti-VEGFR antibody-producing B cells were detectable by ELISPOT. Endothelial deposition of immunoglobulins developed within tumor. VEGF-mediated endothelial cell proliferation was inhibited in vitro by immunoglobulins from qVEGFR-immunized mice. Antitumor activity was caused by the adoptive transfer of the purified immunoglobulins. Antitumor activity and production of autoantibodies against Flk-1 could be abrogated by the depletion of CD4+ T lymphocytes. Angiogenesis was apparently inhibited within the tumors, and the vascularization of alginate beads was also reduced. No marked toxicity was found in the immunized mice. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factor receptor associated with angiogenesis in a cross-reaction with single xenogeneic homologous protein.
- Published
- 2003
49. Clinical Research On Hematological Malignancies Complicated With Active Tuberculosis:A Single Center Experience In China
- Author
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Ting Liu, Jun Li, Meng Jiang, Yi-ming Yang, and Ting Niu
- Subjects
medicine.medical_specialty ,education.field_of_study ,Tuberculosis ,Pleural effusion ,business.industry ,Incidence (epidemiology) ,Immunology ,Population ,Retrospective cohort study ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Surgery ,Internal medicine ,medicine ,Risk factor ,education ,business - Abstract
Objectives Large sample clinical retrospective studies about infection caused by Mycobacterium tuberculosis (TB) among the patients with hematological malignancies(HM) have rarely been investigated. The aim of this study was to analyze the clinical features and treatment of the HM patients complicated with active TB. Methods HM patients complicated with active TB in our single center between January 2006 and December 2012 were retrospectively studied. Results Up to 4712 HM patients have been diagnosed and treated, sixty-six patients of which were confirmed with active TB, as a result, the prevalence of active TB in HM patients was 1.40%(pulmonary TB 1.10%, extra-pulmonary TB 0.30%). The prevalence of various subgroups of HM patients were as following: AML 2.02%、ALL 1.22%、CML and CLL 1.38%、MDS 1.85%、Lymphoma 0.58%、MM 1.15%、SAA 1.66%. In addition, the patients with AML had a significantly higher incidence of TB disease than other subtypes of HM (2.02% vs 1.13%, P=0.017). Most of the patients were male patients, with a male:female ratio of 2.67:1, median age 41 years old (range 14 to 78). Among them, the median age of extra-pulmonary TB group was younger than the pulmonary TB group (38 vs 44.5 years), so did the neutropenia group when compared with the non-neutropenic group (38 vs 48years). Fifty-two cases(80.3%)were pulmonary TB, 14 cases were(21.2%)extra-pulmonary TB and other 8 cases(12.1%)presented as both pulmonary and extra-pulmonary TB. In addition, atypical clinical manifestations, such as high fever, cough, malnutrition, pleural effusion were the main clinical manifestations in our patients. Twenty-nine patients(43.9%) were diagnosed with definitely etiological evidence while other 37 patients(56.1%)were diagnosed clinically. The extra-pulmonary TB group had a higher PPD test positive rate than that of the pulmonary TB group(85.7% vs 46.2%,P=0.014); The main characteristics of chest CT were as follows:mediastinal or hilar lymphadenopathy, nodules, fibrous cord shadow, pleural effusion. The specificity and sensitivity of T-SPOT.TB test were 100% and 83.3% when 14 patients were checked by this test, which was a helpful tool for diagnosis. In addition, finding more ways to put the lesions under pathological examination was beneficial to the diagnosis of extra-pulmonary TB. The efficacy of first-line anti-tuberculosis chemotherapy was 87.3%, but the extra-pulmonary TB group presented a lower response rate than the pulmonary one (64.3% vs 90.4%, P=0.01).Patients with fever needed a median 8–day(3~26 days)anti-tuberculosis chemotherapy before their temperature dropped to normal range ,meanwhile the patients who had suffered from lymphnode TB needed 12 days(7~28 days)to get their enlarged lymphnode shrink. The total course in order to cure TB was around 12 months. Six cases were dead due to TB with a 9.1% attributable mortality, moreover, the rate was especially higher in the extra-pulmonary TB group(28.6% vs 3.8%,P=0.016). Our study demonstrated that the potential risk factors of HM patients complicated with active TB were as follows: age less than 50 years old, male patients, three months within the diagnosis of HM, intravenous use of immunosuppressive drugs. In addition, age less than 50 years old was the only risk factor of extra-pulmonary TB. Conclusions The prevalence of HM patients complicated with active tuberculosis is higher than the general population. Definitely etiological evidence was not easy to collect, which made it difficult for the diagnosis and differential diagnosis of TB. A few characteristics such as age less than 50 years old, male patients, three months within the diagnosis of HM, intravenous use of immunosuppressive drugs were the potential risk factors of HM patients with TB. It was clearly showed that these patients demonstrated good overall responses to the first-line anti-tuberculosis chemotherapy, with relatively lower attributable mortality and good outcome. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
50. Decitabine Combined With Chemotherapy For The Treatment Of Refractory Acute Myeloid Leukemia: a Pilot Phase 1 Clinical Study
- Author
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Ling Pan, Hong Chang, Yuping Gong, Ting Liu, Xu Cui, Yongqian Jia, Jianjun Li, Xinchuan Chen, Hongbing Ma, Meng Chen, and Ting Niu
- Subjects
Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Decitabine ,Epley maneuver ,Subgroup analysis ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Surgery ,Granulocyte colony-stimulating factor ,Regimen ,Refractory ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background The demethylating agent decitabine (DCA) had been employed in the treatment of acute myeloid leukemia (AML) as epigenetic therapy. A phase 3 trial for older patients (pts) with newly diagnosed AML had clearly demonstrated that DAC alone was more effective than ‘treatment choice’. However, outcomes are poorer in refractory AML with DAC alone or chemotherapy alone. Since combine index of DAC and Ara-C had been reported in preclinical study, the efficacy and safety of DAC combined with chemotherapy for pts with refractory AML were investigated in this pilot phase 1 clinical study. Patients A total of 23 pts (8 female and 15 male) with AML were enrolled from Jan 4 2012 to June 30 2013. According to World Health Organization (WHO) classification criteria, 2 pts were diagnosed as AML-M1, 6 were AML-M2, 4 were AML-M4, 7 were AML-M5 and 4 were AML-M6, among whom 6 pts were with overt myelodysplastic syndrome (MDS) history. Median age was 61 years (range, 36-78). The Eastern Cooperative Oncology Group (ECOG) score was 1 in 5 pts, 2 in 13 pts and 3 in 5 pts. Median courses of disease was 9 months (range, 3 months to over 4 years). Cytogenetics at diagnosis according to National Comprehensive Cancer Network (NCCN) guideline was poor-risk in 7 pts, not poor-risk in 12 pts and without examination of cytogenetic abnormality in 4 pts. 19 pts had received at least 2 standard courses of chemotherapy and failed to achieve complete remission (CR), 4 pts could not tolerate standard chemotherapy. Methods At the beginning, 4 pts were given DAC 15 mg/m2/day intravenous (IV) over 90 minutes from days 1 to 5, and chemotherapy was given 48 hours after the first dose of DAC. Two pts were enrolled into DAC with standard DA regimen, and another two into DAC with AA (aclacinomycin 10 mg/d IV days 3 to 6 and Ara-C 10mg/m2 ih bid days 3 to 9). As DAC with DA regimen was poorly tolerated, then the other 19 pts were enrolled into 2 schedules of DAC plus AA. Schedule 1(12Pts) was DAC 15 mg/m2/day IV 90 minutes qd, days 1 to 5; schedule 2(7Pts) was DAC 15 mg/m2 IV 90 minutes bid, days 1 to 3(According to a special situation in China, 50mg DCA was divided into two equal amount, from which the needed amount was used separately in a interval of 4 hours) The therapy were given at least 2 courses, and continued until pts achieved CR. During treatment with DAC and chemotherapy, pts were given best available support care including blood component transfusion, preventing infection and granulocyte colony-stimulating factor (G-CSF) subcutaneous injection. Results Among the 23 pts, 11 (47.8%) achieved CR or bone marrow remission without platelet recovered(CRp), 3 achieved partial remission (PR). The overall response rate (ORR) was 60.9%. Up to now, 16 pts were still alive, 6 were dead, and one lost follow-up. For the 6 death, 4 were caused by disease progression, one by severe infection, and one in CR condition died from food obstruction in the laryngeal which was a very rare situation. The half-year overall survival rate (OS) was 64.7%. For pts who achieved CR/CRp, the half-year OS was 88.9%. 10 pts (43.5%) were with 3 to 4 grade of myelosuppression; 16 pts (69.6%) developed infection. There was no statistically significant difference in efficacy (62.5% VS 60%) and safety between the two schedules of DAC, and also no statistically significant difference in subgroups, in terms of WHO classification, age (distinguished by age of 60), pre-treatment courses, ECOG and NCCN cytogenetics. Conclusion DAC combined with AA (aclacinomycin and Ara-C) was efficient and tolerable for refractory AML pts, and the advantage of the 2 DAC schedules should be evaluated by further study. Results of subgroup analysis indicated that DAC combined with AA could overcome poor prognosis factors such as WHO classification, elder age, pre-treatment courses, ECOG score and poor-risk cytogenetic abnormalities. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
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