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Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

Science China(Life Sciences) 2023年第3期66卷 528-544页

作者： Qi Wen Zheng-Li Xu Yu Wang Meng Lv Yang Song Zhong-Shi Lyv Tong Xing Lan-Ping Xu Xiao-Hui Zhang Xiao-Jun Huang Yuan Kong Peking University People's Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationCollaborative Innovation Center of HematologyPeking UniversityBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China

Although glucorticosteroids(GCs)are the standard first-line therapy for acute graft-versus-host disease(a Gv HD),nearly 50%of a Gv HD patients have no response to *** role of T cell metabolism in murine a Gv HD was recently ***,whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate a Gv HD remains to be *** glycolysis,characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3),and higher rates of glucose consumption and lactate production were found in Tcells from a Gv HD *** upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory *** a humanized mouse model,PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented a Gv HD,***,our integrated data from patient samples in vitro,in a humanized xenogeneic murine model of a Gv HD and graft-versus-leukaemia(GVL)demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate a Gv HD without loss of GVL ***,the current study indicated that glycolysis is critical for T cell activation and induction of human a Gv ***,the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for a Gv HD *** combined with glycolysis inhibitors promises to be a novel first-line combination therapy for a Gv HD patients.

关键词： allogeneic haematopoietic stem cell transplantation graft versus host disease human T cells glycolysis

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Recovery from Bell’s palsy after treatment using uncultured umbilical cord-derived mesenchymal stem cells:A case report

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World Journal of Clinical Cases 2023年第12期11卷 2817-2824页

作者： Hyunjun Ahn Won-Ju Jung Sang Yeon Lee Kye-Ho Lee stem cell Treatment and Research Institute bio Beauty and Health CompanySeoul 04420South Korea stem cell Treatment 97.7 Beauty and Health ClinicSeoul 04420South Korea

BACKGROUND Bell’s palsy is an idiopathic facial palsy with an unknown cause,and 75%of patients heal ***,the other 25%of patients continue experiencing mild or severe disabilities,resulting in a reduced quality of ***,various treatment methods have been developed to treat this ***,there is controversy regarding their effectiveness,and new alternative treatments are *** SUMMARY The patient suffered from left-sided facial paralysis due to Bell’s palsy for 7 *** patient received an uncultured umbilical cord-derived mesenchymal stem cell transplant eight times for *** follow-up for 32 mo,the paralysis was cured,and there was no *** Uncultured umbilical cord-derived mesenchymal stem cell transplantation may be a potential treatment for patients with Bell’s palsy who do not spontaneously recover.

关键词： Bell’s palsy Facial palsy Umbilical cord-mesenchymal stem cells Allogenic Case report

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Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia

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Science China(Life Sciences) 2023年第11期66卷 2553-2570页

作者： Shu-Qian Tang Tong Xing Zhong-Shi Lyu Li-Ping Guo Mi Liang Chen-Yuan Li Yuan-Yuan Zhang Yu Wang Lan-Ping Xu Xiao-Hui Zhang Xiao-Jun Huang Yuan Kong Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationCollaborative Innovation Center of HematologyPeking UniversityBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China

Aplastic anemia(AA)is a life-threatening disease characterized by bone marrow(BM)failure and *** an important component of the BM microenvironment,endothelial cells(ECs)play a crucial role in supporting hematopoiesis and regulating ***,whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain *** this study,a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of ***-L-cysteine(NAC,a reactive oxygen species scavenger)or exogenous EC infusion was administered to AA ***,the frequency and functions of BM ECs from AA patients and healthy donors were *** ECs from AA patients were treated with NAC in vitro,and then the functions of BM ECs were *** found that BM ECs were significantly decreased and damaged in AA *** failure and immune imbalance became more severe when the function of BM ECs was antagonized,whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA ***,BM ECs in AA patients were decreased and ***,dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes,which could be repaired by NAC in *** reactive oxygen species pathway was activated,and hematopoiesis-and immune-related signaling pathways were enriched in BM ECs of AA *** conclusion,our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA,suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.

关键词： aplastic anemia endothelial cell N-acetyl-L-cysteine hematopoietic stem cell T cell

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Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation

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cellular & Molecular Immunology 2022年第4期19卷 482-491页

作者： Xu-Ying Pei Xue-Fei Liu Xiang-Yu Zhao Meng Lv Xiao-Dong Mo Ying-Jun Chang Qian-Nan Shang Yu-Qian Sun Yu-Hong Chen Lan-Ping Xu Yu Wang Xiao-Hui Zhang Kai-Yan Liu Xiao-Jun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing100044China Peking-Tsinghua Center for Life Sciences Beijing100871China

Adoptive transfer of cytomegalovirus(CMV)-specific cytotoxic T lymphocytes(CMV-CTLs)from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation(allo-SCT),but the antiviral activity of CMV-CTL types has not been *** determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs,we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models,compared the in vivo recovery of CMV-specific immunity,and analyzed the underlying mechanisms driving sustained antiviral *** results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days *** in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups.A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both *** clinical study,which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection,further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related *** observed strong expansion of CD8+tetramer+T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion,which were associated with a reduced or cleared viral *** data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

关键词： Allogeneic stem cell transplantation CMV-specific cytotoxic T lymphocytes transplant donor Third party donor Immunotherapy

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Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

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Frontiers of Medicine 2019年第3期13卷 354-364页

作者： Xiaodong Mo Xiaohui Zhang Lanping Xu Yu Wang Chenhua Yan Huan Chen Yuhong Chen Wei Han Fengrong Wang Jingzhi Wang Kaiyan Liu Xiaojun Huang Peking University People's Hospital Peking University Institute of HematologyBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Peking-Tsinghua Centerfor Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China

The efficacy of minimal residual disease (MRD)-directed immunotherapy,including interferon-α (IFN-α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI),was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT).High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of hematology and were MRD-positive after ailo-HSCT were studied (n =47).The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms' tumor gene 1 expression is present in a single bone marrow *** cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P=0.377)and 9.1% and 0.0% (P=0.985) for patients in the IFN-α and chemo-DLI groups,*** probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P =0.891) and 84.3% and 84.6% (P=0.972) for patients in the IFN-α and chemo-DLI groups,*** MRD after immunotherapy was associated with poor ***,the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after alIo-HSCT,and the efficacy was comparable between chemo-DLI and IFN-α treatment.

关键词： donor leukocyte infusion hematopoietic stem cell transplantation interferon-α minimal residual disease myelodysplastic syndrome

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Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation

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Frontiers of Medicine 2019年第2期13卷 238-249页

作者： Xiaodong Mo Xiaohui Zhang Lanping Xu Yu Wang Chenhua Yan Huan Chen Yuhong Chen Wei Han Fengrong Wang Jingzhi Wang Kaiyan Liu Xiaojun Huang Peking University People’s Hospital Peking University Institute of HematologyBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China

The efficacy of salvage interferon-α(IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI)(n=24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2–3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and>2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

关键词： interferon-α hematopoietic stem cell transplantation minimal residual disease donor lymphocyte infusion

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Comparison of clinical outcomes between unrelated single umbilical cord blood and"ex-vivo"T-cell depleted haploidentical transplantation in children with hematological malignancies

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World Journal of Pediatrics 2021年第6期17卷 609-618页

作者： Carmen Gomez-Santos Marta Gonzalez-Vicent Blanca Molina Natalia Deltoro Blanca Herrero Julia Ruiz Antonio Perez-Martinez Miguel A Diaz Department of Pediatrics Hematopoietic Stem Cell Transplantation UnitHospital Infantil Universitario"Nino Jesus"Menedez Pelayo 6528009 MadridSpain Hospital Infantil Universitario"La Pa"Madrid MadridSpain

Background Over the last two decades,umbilical cord blood(UCB)and haploidentical transplantation(HaploHSCT)have emerged as alternative sources of hematopoietic stem cell for allogeneic *** are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric *** We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood(UCB)(n=42)or an"tex-vivo"T-cell depleted transplant from a haploi-dentical-related donor(HaploHSCT)(n=92)between 1996 and *** recovery was faster after HaploHSCT than the UCB transplant group(median times to neutrophil and platelet recovery:13 vs.16 days,10 vs.57 days,respectively)(Pcells compared with the UCB ***,after the first year *** had a lower number of CD4+ T and B lymphocytes compared with the UCB transplant *** cumulative incidence of TRM was 29±8%in the HaploHSCT group versus 40±5%in the UCB *** incidence was 21±7%in the HaploHSCT group and 19±8%in the UCB *** of DFS was 58±8%in the HaploHSCT group versus 40±9%in the UCB group(P=0.051).Conclusions TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution *** haploidentical transplant was associated with lower incidence of infectious and non-infectious complications,especially in the early phases of the transplant compared with UCB transplant ***,there are no advantages in transplant outcomes compared with UCB transplant.

关键词： Children Cord blood transplant Hematologic malignancies Immune reconstitution TCD haploidentical transplant

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Effects of telomere length on leukemogenesis

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Science China(Life Sciences) 2020年第2期63卷 308-311页

作者： Shihui Ma Guohuan Sun Shangda Yang Zhenyu Ju Tao Cheng Hui Cheng State Key Laboratory of Experimental hematology Institute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Center for stem cell Medicine Chinese Academy of Medical SciencesTianjin 300020China Department of stem cell and Regenerative Medicine Peking Union Medical CollegeTianjin 300020China Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou 510632China

Dear Editor,Most cancer cells maintain the length of their telomeres via telomerase(Günes and Rudolph,2013;Kim et al.,1994).However,in some cancers,telomeres are maintained not by telomerase but by alternative lengthening of telomeres(Bryan et al.,1997).Telomerase activity appears to be reduced in some bone marrow(BM)diseases,including chronic myeloid leukemia,acute myeloid leukemia(AML),and myeloproliferative neoplasms(MPN),leading to shortened telomeres that correlate with leukemogenesis(Bouillon et al.,2018;Engelhardt et al.,2000;Shay et al.,1996).Our current study aimed to determine the definitive roles of telomeres and telomerase in leukemogenesis.

关键词： al. neoplasms acute

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Arsenic trioxide alleviates acute graft-versus-host disease by modulating macrophage polarization

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Science China(Life Sciences) 2020年第11期63卷 1744-1754页

作者： Xiao Liu Yan Su Xueyan Sun Haixia Fu Qiusha Huang Qi Chen Xiaodong Mo Meng Lv Yuan Kong Lanping Xu Xiaojun Huang Xiaohui Zhang Peking University People’s Hospital Beijing 100044China Peking University Institute of hematology Beijing 100044China National Clinical Research Center for Hematologic Disease Beijing 100044China Beijing Key Laboratory of Hematopoietic stem cell transplantation Beijing 100044China

This study aimed to explore macrophage polarization in acute graft-versus-host disease after hematopoietic stem cell transplantation, and investigated if arsenic trioxide(ATO) could correct this imbalance. In the colon of GVHD mice, we found that the number of F4/80+iNOS+ cells as well as the expression intensity of TNF-α and IL-1β was greater in the GVHD group than in the BM group, whereas the number of F4/80+CD206+ cells and the expression intensity of IL-10 and TGF-β was greater in the BM group than in the GVHD group. We investigated the effect of ATO on GVHD mice, and found that ATO treatment clearly improved the survival of the mice and reduced the severity of GVHD. In addition, ATO reduced the number of F4/80+iNOS+ cells, and increased the number of F4/80+CD206+ cells in the colon of GVHD mice. Furthermore, ATO sharply decreased CD86 and CD80 expression, and increased CD163 and CD206 expression in macrophages induced from aGVHD patients. Therefore,ATO can modulate the M1 and M2 phenotype in GVHD mice or in macrophages from aGVHD patients. Our data suggest that macrophage polarization is involved in the pathogenesis of aGVHD, and ATO treatment modulates macrophage polarization toward an M2 phenotype.

关键词： ATO macrophage polarization acute graft-versus-host disease

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simplifyEnrichment:A Bioconductor Package for Clustering and Visualizing Functional Enrichment Results

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Genomics, Proteomics & Bioinformatics 2023年第1期21卷 190-202页

作者： Zuguang Gu Daniel Hübschmann Molecular Precision Oncology Program National Center for Tumor Diseases(NCT)HeidelbergD-69120 HeidelbergGermany Heidelberg Institute of stem cell Technology and Experimental Medicine(HI-stem) D-69120 HeidelbergGermany German Cancer Consortium(DKTK) D-69120 HeidelbergGermany Department of Pediatric Immunology Hematology and OncologyUniversity Hospital HeidelbergD-69120 HeidelbergGermany

Functional enrichment analysis or gene set enrichment analysis is a basic bioinformatics method that evaluates the biological importance of a list of genes of ***,it may produce a long list of significant terms with highly redundant information that is difficult to *** tools to simplify enrichment results by clustering them into groups either still produce redundancy between clusters or do not retain consistent term similarities within *** propose a new method named binary cut for clustering similarity matrices of functional *** comprehensive benchmarks on both simulated and real-world datasets,we demonstrated that binary cut could efficiently cluster functional terms into groups where terms showed consistent similarities within groups and were mutually exclusive between *** compared binary cut clustering on the similarity matrices obtained from different similarity measures and found that semantic similarity worked well with binary cut,while similarity matrices based on gene overlap showed less consistent *** implemented the binary cut algorithm in the R package simplifyEnrichment,which additionally provides functionalities for visualizing,summarizing,and comparing the *** simplifyEnrichment package and the documentation are available at https://***/packages/simplifyEnrichment/.

关键词： Functional enrichment Simplify enrichment Clustering R/Bioconductor Software Visualization

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