Browsing by Author "Cheng, Tao"

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    An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
    (Ferrata Storti Foundation, 2017-06) Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D.; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A.; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D. Wade; Yang, Feng-Chun; Pediatrics, School of Medicine
    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.
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    Interleukin 8/KC enhances G-CSF induced hematopoietic stem/progenitor cell mobilization in Fancg deficient mice
    (AME Publishing Company, 2014) Li, Yan; Xing, Wen; He, Yong-Zheng; Chen, Shi; Rhodes, Steven D.; Yuan, Jin; Zhou, Yuan; Shi, Jun; Bai, Jie; Zhang, Feng-Kui; Yuan, Wei-Ping; Cheng, Tao; Xu, Ming-Jiang; Yang, Feng-Chun; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and acquisition of malignancies. Successful hematopoietic cell transplantation (HCT) for FA patients is challenging due to hypersensitivity to DNA alkylating agents and irradiation of FA patients. Early mobilization of autologous stem cells from the bone marrow has been thought to be ideal prior to the onset of bone marrow failure, which often occurs during childhood. However, the markedly decreased response of FA hematopoietic stem cells to granulocyte colony-stimulating factor (G-CSF) is circumventive of this autologous HCT approach. To-date, the mechanism for defective stem cell mobilization in G-CSF treated FA patients remains unclear. METHODS: Fancg heterozygous (Fancg (+/-)) mice utilized in these studies. Student's t-test and one-way ANOVA were used to evaluate statistical differences between WT and Fancg (-/-) cells. Statistical significance was defined as P values less than 0.05. RESULTS: Fancg deficient (Fancg (-/-)) mesenchymal stem/progenitor cells (MSPCs) produce significant lower levels of KC, an interleukin-8 (IL-8) related chemoattractant protein in rodents, as compared to wild type cells. Combinatorial administration of KC and G-CSF significantly increased the mobilization of hematopoietic stem/progenitor cells (HSPCs) in Fancg (-/-) mice. CONCLUSIONS: In summary, our results suggest that KC/IL-8 could be proved useful in the synergistic mobilization of FA HSPCs in combination with G-CSF.
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    Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors
    (ACS, 2012) Yang, Peng; Myint, Kyaw-Zeyar; Tong, Qin; Feng, Rentian; Cao, Haiping; Almehizia, Abdulrahman A.; Alqarni, Mohammed Hamed; Wang, Lirong; Bartlow, Patrick; Gao, Yingdai; Gertsch, Jürg; Teramachi, Jumpei; Kurihara, Noriyoshi; Roodman, Garson David; Cheng, Tao; Xie, Xiang-Qun; Medicine, School of Medicine
    N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.
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    System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia
    (BMC, 2017-10-03) Li, Rudong; Wang, Yin; Cheng, Hui; Liu, Gang; Cheng, Tao; Liu, Yunlong; Liu, Lei; Medical and Molecular Genetics, School of Medicine
    Background Molecular mechanisms of the functional alteration of hematopoietic stem cells (HSCs) in leukemic environment attract intensive research interests. As known in previous researches, Maff and Egr3 are two important genes having opposite functions on cell cycle; however, they are both highly expressed in HSCs under leukemia. Hence, exploring the molecular mechanisms of how the genes act on cell cycle will help revealing the functional alteration of HSCs. Results We herein utilize the bioinformatic resources to computationally model the acting mechanisms of Maff and Egr3 on cell cycle. Using the data of functional experiments as reference, molecular acting mechanisms are optimally enumerated through model selection. The results are consolidated by evidences from gene sequence analysis, thus having enhanced the confidence of our pilot findings, which suggest that HSCs possibly undergo a “adaptation - suppression” process in response to the malignant environment of leukemia. Conclusion As a pilot research, our results may provide valuable insights for further experimental studies. Meanwhile, our research method combining computational modeling and data from functional experiments can be worthwhile for knowledge discovery; and it can be generalized and extended to other biological/biomedical studies. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0467-4) contains supplementary material, which is available to authorized users.
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    Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients
    (Springer Nature, 2014-05-15) Chang, Lixian; Yuan, Weiping; Zeng, Huimin; Zhou, Quanquan; Wei, Wei; Zhou, Jianfeng; Li, Miaomiao; Wang, Xiaomin; Xu, Mingjiang; Yang, Fengchun; Yang, Yungui; Cheng, Tao; Zhu, Xiaofan; Pediatrics, School of Medicine
    Background: Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients. Methods: We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing. Results: Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients' clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents. Conclusions: Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology.