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Weijie Cao,
Haowen Xiao,
Xiaoyu Lai,
Yi Luo,
Jimin Shi,
Yamin Tan,
Weiyan Zheng,
Jingsong He,
Wanzhuo Xie,
Li Li,
Xiujin Ye,
Xiaohong Yu,
Maofang Lin,
Zhen Cai,
He Huang
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ABSTRACT: Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme of mycophenolate mofetil (MMF). Single nucleotide polymorphisms (SNPs) in the IMPDH1 gene are reportedly relevant to acute rejection in renal transplant patients receiving MMF. The objective of this study was to identify the impact of IMPDH1 gene polymorphisms on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Four IMPDH1 gene SNPs (IVS7 +125 G>A, IVS8-106 G>A, exon15 1572 G>A, and 5' flanking intron-exon region C>T) were analyzed in 240 consecutive pairs of transplant recipients and their donors. The presence of the IMPDH1 IVS8-106 G/G genotype in recipients was associated with a significantly higher incidence of acute graft-versus-host disease (aGVHD) than other genotypes, in both unrelated and sibling transplantation cohorts (unrelated cohort: 83.3% vs 63.9%, P = .048; sibling cohort: 47.6% vs 17.3%, P = .008). Multivariate analysis confirmed that recipients with the IVS8-106 G/G genotype were at significantly higher risk of developing aGVHD (relative risk [RR] = 2.018, 95% confidence interval [CI]: 1.354-3.009, P = .001) and grades II-IV aGVHD (RR = 2.232, 95% CI: 1.352-3.685, P = .002). There was no association among IVS7 +125, exon15 1572, and 5' flanking intron-exon region genotypes and the risk of aGVHD. These results represent the first report of an association between IMPDH1 gene polymorphisms and the risk of aGVHD in allo-HSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(2):273-9. · 3.15 Impact Factor
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Lizhen Liu,
Qin Yu,
Jie Lin,
Xiaoyu Lai, Weijie Cao,
Kaili Du,
Yingjia Wang,
Kangni Wu,
Yongxian Hu,
Lifei Zhang,
Haowen Xiao,
Yanping Duan,
He Huang
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ABSTRACT: Mobilization of mesenchymal stem cells (MSCs) is a promising strategy for tissue repair and regenerative medicine. The establishment of an appropriate animal model and clarification of the underlying mechanisms are beneficial to develop the mobilization regimens for therapeutic use. In this study, we therefore established a rat MSC mobilization model and investigated the related mechanisms, using continuous hypoxia as the mobilizing stimulus. We found that MSCs could be mobilized into peripheral blood of rats exposed to short-term hypoxia (2 days) and the mobilization efficiency increased in a time-dependent manner (2-14 days). Hypoxia-inducible factor-1α (HIF-1α) was upregulated during hypoxic exposure and was expressed continuously in bone marrow. Inhibition of HIF-1α expression by YC-1 remarkably reduced the number of mobilized MSCs, suggesting that HIF-1α is essential for hypoxia-induced MSC mobilization. Further, we investigated the potential role of HIF-1α target genes, vascular endothelial growth factor (VEGF), and stromal cell-derived factor-1α (SDF-1α). VEGF expression was elevated from day 2 to day 7 of hypoxia, stimulating an increase in bone marrow sinusoidal vessels and possibly facilitating the egress of MSCs. SDF-1α protein levels were increased in the peripheral blood of rats during MSC mobilization and promoted the migration of MSCs under hypoxic conditions in vitro. These results suggest that HIF-1α plays a pivotal role in hypoxia-induced MSC mobilization, possibly acting via its downstream genes VEGF and SDF-1α. These data provide a novel insight into the mechanisms responsible for MSC mobilization and may help in the development of clinically useful therapeutic agents.
Stem cells and development 01/2011; 20(11):1961-71. · 4.15 Impact Factor
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Haowen Xiao, Weijie Cao,
Xiaoyu Lai,
Yi Luo,
Jimin Shi,
Yamin Tan,
Jingsong He,
Wanzhuo Xie,
Xiaojian Meng,
Weiyan Zheng,
Gaofeng Zheng,
Xiaoyan Han,
Lai Jin,
Lifei Zhang,
Yingjia Wang,
Xiaohong Yu,
Zhen Cai,
Maofang Lin,
Xiujin Ye,
He Huang
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ABSTRACT: Cytokine gene polymorphisms can affect the outcome of allogeneic hematopoietic stem cell transplantation. We analyzed 6 single nucleotide polymorphisms in 3 immunosuppressive cytokine genes, TGFβ1-509(C>T), +869(T>C), TGFβ1 receptor II (TGFβ1RII) +1167(C>T, codon389 AAC/AAT), and IL-10-1082(A>G), -819(T>C), -592(A>C), in a cohort of 138 pairs of recipients and their unrelated donors and a second cohort of 102 pairs of recipients and their HLA-identical sibling donors. TGFβ1-509 T/T genotype in the donors or T allele-positivity in the recipients was associated with a significant protective effect against acute graft-versus-host disease (aGVHD) and grades II-IV aGVHD in the unrelated transplantation cohort. In the combined cohort, multivariate analysis confirmed that donors with the TGFβ1-509 T/T genotype also conferred protection against the risk of aGVHD and grades II-IV aGVHD. In both the unrelated transplantation cohort and the sibling transplantation cohort, the IL-10-819 C/C and -592 C/C genotypes in either recipients or donors were significantly associated with a higher incidence of aGVHD. In the combined cohort, the IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 influenced the occurrence of aGVHD and death in remission. Recipients without the A-T-A haplotype or those transplanted from donors without the A-T-A haplotype had a higher incidence of aGVHD than those who were A-T-A homozygotes or heterozygotes. Estimates for death in remission showed a clear advantage for recipients transplanted from donors with the A-T-A haplotype. In multivariate analysis, recipients without the A-T-A IL-10 haplotype had a higher risk of aGVHD (relative risk [RR] = 0.764; 95% confidence interval [CI]: 0.460-1.269; P = .096) and grades II-IV aGVHD (RR = 0.413; 95% CI: 0.245-0.697; P = .001). These results provide the first report of an association between TGFβ1, TGFβ1RII, and IL-10 polymorphic features and outcome of allo-HSCT in a Chinese population, and suggest an interaction between TGFβ1-509 genotypes and IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 and the risk of aGVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2010; 17(4):542-9. · 3.15 Impact Factor
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Yanmin Zhao,
Lizhen Liu,
Yingjia Wang,
Gongqiang Wu,
Xiaoyu Lai, Weijie Cao,
Yi Luo,
Yamin Tan,
Jimin Shi,
Wanzhuo Xie,
Xiujin Ye,
Zhen Cai,
Maofang Lin,
He Huang
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ABSTRACT: There is limited data from developing countries on the current status of imatinib treatment for chronic myeloid leukemia (CML), thus we retrospectively analyzed 116 Chinese CML patients who received imatinib between 2003 and 2008. The response rates for 102 patients in chronic phase were: complete hematologic, 94.1%; complete cytogenetic, 69.6%; and complete molecular response, 54.9%. For 14 patients in the accelerated phase, the respective response rates were 85.7, 35.7 and 28.6%. The 3-year progression-free survival and 5-year overall survival were 73.3 and 74.8%. Although skin hypopigmentation occurs as the most common side effect (77.6%), imatinib is still well tolerated. In addition to the known pretreatment characteristics of spleen size, leukocyte and platelet counts, disease phase and Sokal scores, we found that delayed therapy, variant Philadelphia chromosome translocations and IM-related grade 3/4 leucopenia were associated with an inferior cytogenetic response. Four factors emerged as predictors of disease progression: molecular response, cytogenetic response, disease phase and disease duration prior to imatinib treatment, but only the latter three remained significant after multivariate analysis. The results indicate that the suboptimal outcome in Chinese patients is associated with delayed imatinib therapy, so the importance of the optimal treatment opportunity for CML should be emphasized.
International journal of hematology 05/2009; 89(4):445-51. · 1.17 Impact Factor
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Leukemia research 03/2009; 33(7):e85-7. · 2.36 Impact Factor
