Background Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances （including water） into brain tissue, few studies of brain antigens leaking into the blood and t...Background Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances （including water） into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury.Methods In part one, methylene blue was injected into the rabbits’ cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor （TNF）-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 （IL-1）, IL-10, interferon （IFN）-γ, transforming growth factor （TGF）-β, anti-brain antibodies （ABAb）, and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H＆E staining. Results In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group （P 〈0.05）. Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid （CSF） injected group were higher than in the control cerebrospinal fluid injected group （P 〈0.05）. In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate （Glu）, neuronal degeneration and number of peripheral blood leukocytes were lower in the group wit展开更多
Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used ...Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.展开更多
To compare the efficacy of HLA6/6-matched haploidentical hematopoietic stem cell transplant(haplo-HSCT) with that of HLA3/6-matched HSCT in T-cell-replete transplants, we recruited 27 consecutive recipients from multi...To compare the efficacy of HLA6/6-matched haploidentical hematopoietic stem cell transplant(haplo-HSCT) with that of HLA3/6-matched HSCT in T-cell-replete transplants, we recruited 27 consecutive recipients from multiple centers who received HLA6/6-matched haplo-HSCT from a parent or child donor between February 2010 and May 2016. A matched-pair analysis was designed. For each recipient from the study cohort, two recipients were randomly selected from the control cohort and matched(according to patient age, patient sex, disease type, disease status, donor age, donor sex, and recipient-donor relationship). No significant differences were found in hematopoietic recovery. The incidence of grade II–IV and III–IV acute graft versus host disease was similar(18.5% vs. 31.5%, P=0.216; 11.1% vs. 9.3%, P=0.792) in the HLA6/6 and HLA3/6 groups, respectively. The3-year cumulative incidence of relapse was 14.8% and 17.0%(P=0.800). The 3-year cumulative incidence of nonrelapse mortality was 12.1% and 17.6%(P=0.751). The estimated 3-year disease-free survival was 73.1% and 65.5%(P=0.489). The estimated 3-year overall survival was 74.7% and 74.0%(P=0.946). The data suggested the efficacy and safety of the HLA6/6-and the HLA3/6-matched haplo-HSCT between parents and children are comparable. That HLA-mismatch disparity is not correlated with T-cell-replete haplo-HSCT outcome was substantiated.展开更多
BACKGROUND:Emerging evidence suggests that pancreatic adenocarcinoma is hierarchically organized and sustained by pancreatic cancer stem cells.Furthermore,elimination of these cells is possible and therapeutically rel...BACKGROUND:Emerging evidence suggests that pancreatic adenocarcinoma is hierarchically organized and sustained by pancreatic cancer stem cells.Furthermore,elimination of these cells is possible and therapeutically relevant.This study aimed to investigate the expression patterns of pancreatic cancer stem cell surface markers CD44,CD24 and ESA in pancreatic adenocarcinoma cell lines and explore the influence of their local microenvironment.METHODS:Flow cytometry was used to analyze the expression patterns of CD44,CD24 and ESA in five pancreatic adenocarcinoma cell lines (PANC-1,PC-2,MIA-Paca-2,AsPC-1 and BxPC-3).In addition,the capacity for sphereformation in serum-free medium of four cell lines (PANC-1,PC-2,MIA-Paca-2 and BxPC-3) was assessed.Then,the same assays were performed when tumor cell spheres were developed.The role of sonic hedgehog (SHH) in cell spheres from PANC-1 and MIA-Paca-2 were also assessed by RT-PCR.RESULTS:CD44 and CD24 were detected in PANC-1.Only CD44 expression was detected in PC-2,MIA-Paca-2 and AsPC-1.CD44,CD24 and ESA were all detected in BxPC-3.Tumor cell spheres developed in PANC-1 and MIA-Paca-2 in serumfree medium.This was accompanied by an increase in CD24 expression and a decrease in CD44 expression in PANC-1.Interestingly,the expression of CD44 and CD24 returned to initial levels once the medium was changed back from serumfree to serum-containing medium.No significant change in the expression of CD44 was detected in MIA-Paca-2.Furthermore,the relative quantification of SHH mRNA in PANC-1 cell spheres was significantly higher than that in cells cultured in the serum-containing medium.CONCLUSION:The expression patterns of the pancreatic cancer stem cell surface markers CD44,CD24 and ESA were diverse in different pancreatic adenocarcinoma cell lines and changed with their local microenvironment.展开更多
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the standard of care for adult acute lymphoblastic leukemia (ALL) patients. In recent years, with the continuous development of immunotherapy...Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the standard of care for adult acute lymphoblastic leukemia (ALL) patients. In recent years, with the continuous development of immunotherapy, such as chimeric antigen receptor T cells, blinatumomab, and inotuzumab ozogamicin, a series of vital clinical studies have confirmed its high response rate and favorable outcomes for ALL. Although the emergence of immunotherapy has expanded relapsed or refractory (r/r) ALL patients’’ opportunities to receive allo-HSCT, allo-HSCT is associated with potential challenges. In this review, the role of allo-HSCT in the treatment of adult ALL in the era of immunotherapy will be discussed.展开更多
Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD...Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo?HSCT). Methods: We retrospectively analyzed 145 consecutive AML patients undergoing allo?HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre?HSCT. Results: In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ2 = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ2 = 8.759, P = 0.003) or pre?HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ2 = 5.547, P = 0.019). In haploidentical SCT (haplo?SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre?HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo?SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo?SCT, those without persistent MRD underwent haplo?SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ2 = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200–2.382, P = 0.003), worse leukemia?free survival (HR = 1.812, 95% CI: 1.168–2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528–3.627, P < 0.001). Conclusion: Our results suggest that persistent positive MRD展开更多
Background： Acute graft-versus-host disease （aGVHD） is a common and severe complication of allogeneic hematopoietic stem cell transplantation （allo-HSCT）. Some studies have found that the presence of certain spec...Background： Acute graft-versus-host disease （aGVHD） is a common and severe complication of allogeneic hematopoietic stem cell transplantation （allo-HSCT）. Some studies have found that the presence of certain specific human leukocyte antigen （HLA） loci could affect the occurrence of aGVHD. Meanwhile, the impact of HLA haplotypes on aGVHD has been rarely studied. This study aimed to investigate the effects of HLA loci and haplotypes on intestinal aGVHD. Methods： Totally, 345 consecutive patients undergoing first HLA-matched sibling peripheral blood stem cell transplantation （PBSCT） from February 2004 to June 2013 at Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were enrolled in this study. HLA loci and haplotypes of recipients with frequency over 5% were searched and their effects on intestinal aGVHD were investigated. Other important factors including donor age, recipient age, donor-recipient sex combinations, and conditioning regimens were also evaluated using logistic regression. Pure upper gastrointestinal tract aGVHD without diarrhea was excluded because the histological proof was unavailable. The follow-up end-point was 6 months after HSCT. Results： The cumulative incidence of intestinal aGVH D was 19.4%, with 18.0% of the patients classified as classic aGVH D and 1.4% as persistent, recurrent, or late aGVH D. Multivariate analysis showed that HLA-A31 locus （odds ratio [OR] 2.893, 95% confidence interval [CI] [1.054, 7.935], P = 0.039）, H LA B40-DR 15 （OR 3.133, 95% CI [1.250, 7.857], P = 0.015）, and HLA B46-DR9 haplotypes （OR 2,580, 95% CI l1.070, 6.220], P- 0.035）, fizmale donor for male recipient （OR 2.434, 95% （27 [1.319, 4.493], P = 0.004） were risk factors tbr intestinal aGVHD. Conclusion： The presence of certain HLA loci and haplotypes may influence the occurrence of intestinal aGVHD in PBSCT with HLA-identical sibling donors.展开更多
文摘Background Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances （including water） into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury.Methods In part one, methylene blue was injected into the rabbits’ cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor （TNF）-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 （IL-1）, IL-10, interferon （IFN）-γ, transforming growth factor （TGF）-β, anti-brain antibodies （ABAb）, and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H＆E staining. Results In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group （P 〈0.05）. Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid （CSF） injected group were higher than in the control cerebrospinal fluid injected group （P 〈0.05）. In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate （Glu）, neuronal degeneration and number of peripheral blood leukocytes were lower in the group wit
基金The authors thank all patients who participated and their families, as well as the investigators and staff at this study for their valuable contribution to this study. We＇d like to give a special thanks to Zhiqiang Wu for the construction of plasmids. This study was supported by grants from the National Natural Science Foundation of China （Grant Nos. 81230061, 81402566, 81672319, 81602507, and 81602711）, the Science and Technology Planning Project of Beijing City （No. Z151100003915076） and the key Nursery Project of Chinese PLA General Hospital （16KMZ05） and was partially supported by a grant from the National Basic Science and Development Programme of China （No. 2013BAI01B04）.
文摘Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.
基金supported by National Natural Science Foundation of China (81400143, 81530046, 81621001)National Key Research and Development Plan (2017YFA0104500)
文摘To compare the efficacy of HLA6/6-matched haploidentical hematopoietic stem cell transplant(haplo-HSCT) with that of HLA3/6-matched HSCT in T-cell-replete transplants, we recruited 27 consecutive recipients from multiple centers who received HLA6/6-matched haplo-HSCT from a parent or child donor between February 2010 and May 2016. A matched-pair analysis was designed. For each recipient from the study cohort, two recipients were randomly selected from the control cohort and matched(according to patient age, patient sex, disease type, disease status, donor age, donor sex, and recipient-donor relationship). No significant differences were found in hematopoietic recovery. The incidence of grade II–IV and III–IV acute graft versus host disease was similar(18.5% vs. 31.5%, P=0.216; 11.1% vs. 9.3%, P=0.792) in the HLA6/6 and HLA3/6 groups, respectively. The3-year cumulative incidence of relapse was 14.8% and 17.0%(P=0.800). The 3-year cumulative incidence of nonrelapse mortality was 12.1% and 17.6%(P=0.751). The estimated 3-year disease-free survival was 73.1% and 65.5%(P=0.489). The estimated 3-year overall survival was 74.7% and 74.0%(P=0.946). The data suggested the efficacy and safety of the HLA6/6-and the HLA3/6-matched haplo-HSCT between parents and children are comparable. That HLA-mismatch disparity is not correlated with T-cell-replete haplo-HSCT outcome was substantiated.
基金supported by a grant from the National Natural Science Foundation of China(30801100)
文摘BACKGROUND:Emerging evidence suggests that pancreatic adenocarcinoma is hierarchically organized and sustained by pancreatic cancer stem cells.Furthermore,elimination of these cells is possible and therapeutically relevant.This study aimed to investigate the expression patterns of pancreatic cancer stem cell surface markers CD44,CD24 and ESA in pancreatic adenocarcinoma cell lines and explore the influence of their local microenvironment.METHODS:Flow cytometry was used to analyze the expression patterns of CD44,CD24 and ESA in five pancreatic adenocarcinoma cell lines (PANC-1,PC-2,MIA-Paca-2,AsPC-1 and BxPC-3).In addition,the capacity for sphereformation in serum-free medium of four cell lines (PANC-1,PC-2,MIA-Paca-2 and BxPC-3) was assessed.Then,the same assays were performed when tumor cell spheres were developed.The role of sonic hedgehog (SHH) in cell spheres from PANC-1 and MIA-Paca-2 were also assessed by RT-PCR.RESULTS:CD44 and CD24 were detected in PANC-1.Only CD44 expression was detected in PC-2,MIA-Paca-2 and AsPC-1.CD44,CD24 and ESA were all detected in BxPC-3.Tumor cell spheres developed in PANC-1 and MIA-Paca-2 in serumfree medium.This was accompanied by an increase in CD24 expression and a decrease in CD44 expression in PANC-1.Interestingly,the expression of CD44 and CD24 returned to initial levels once the medium was changed back from serumfree to serum-containing medium.No significant change in the expression of CD44 was detected in MIA-Paca-2.Furthermore,the relative quantification of SHH mRNA in PANC-1 cell spheres was significantly higher than that in cells cultured in the serum-containing medium.CONCLUSION:The expression patterns of the pancreatic cancer stem cell surface markers CD44,CD24 and ESA were diverse in different pancreatic adenocarcinoma cell lines and changed with their local microenvironment.
基金This work was supported by the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No. 81621001) , the Key Program of National Natural Science Foundation of China (No. 81530046) , the National Key Research and Development Program of China (No. 2017YFA0104500) , and the Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (No. BMU2021PYB006) supported by the Fundamental Research Funds for the Central Universities.
文摘Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the standard of care for adult acute lymphoblastic leukemia (ALL) patients. In recent years, with the continuous development of immunotherapy, such as chimeric antigen receptor T cells, blinatumomab, and inotuzumab ozogamicin, a series of vital clinical studies have confirmed its high response rate and favorable outcomes for ALL. Although the emergence of immunotherapy has expanded relapsed or refractory (r/r) ALL patients’’ opportunities to receive allo-HSCT, allo-HSCT is associated with potential challenges. In this review, the role of allo-HSCT in the treatment of adult ALL in the era of immunotherapy will be discussed.
文摘Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo?HSCT). Methods: We retrospectively analyzed 145 consecutive AML patients undergoing allo?HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre?HSCT. Results: In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ2 = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ2 = 8.759, P = 0.003) or pre?HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ2 = 5.547, P = 0.019). In haploidentical SCT (haplo?SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre?HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo?SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo?SCT, those without persistent MRD underwent haplo?SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ2 = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200–2.382, P = 0.003), worse leukemia?free survival (HR = 1.812, 95% CI: 1.168–2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528–3.627, P < 0.001). Conclusion: Our results suggest that persistent positive MRD
文摘Background： Acute graft-versus-host disease （aGVHD） is a common and severe complication of allogeneic hematopoietic stem cell transplantation （allo-HSCT）. Some studies have found that the presence of certain specific human leukocyte antigen （HLA） loci could affect the occurrence of aGVHD. Meanwhile, the impact of HLA haplotypes on aGVHD has been rarely studied. This study aimed to investigate the effects of HLA loci and haplotypes on intestinal aGVHD. Methods： Totally, 345 consecutive patients undergoing first HLA-matched sibling peripheral blood stem cell transplantation （PBSCT） from February 2004 to June 2013 at Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were enrolled in this study. HLA loci and haplotypes of recipients with frequency over 5% were searched and their effects on intestinal aGVHD were investigated. Other important factors including donor age, recipient age, donor-recipient sex combinations, and conditioning regimens were also evaluated using logistic regression. Pure upper gastrointestinal tract aGVHD without diarrhea was excluded because the histological proof was unavailable. The follow-up end-point was 6 months after HSCT. Results： The cumulative incidence of intestinal aGVH D was 19.4%, with 18.0% of the patients classified as classic aGVH D and 1.4% as persistent, recurrent, or late aGVH D. Multivariate analysis showed that HLA-A31 locus （odds ratio [OR] 2.893, 95% confidence interval [CI] [1.054, 7.935], P = 0.039）, H LA B40-DR 15 （OR 3.133, 95% CI [1.250, 7.857], P = 0.015）, and HLA B46-DR9 haplotypes （OR 2,580, 95% CI l1.070, 6.220], P- 0.035）, fizmale donor for male recipient （OR 2.434, 95% （27 [1.319, 4.493], P = 0.004） were risk factors tbr intestinal aGVHD. Conclusion： The presence of certain HLA loci and haplotypes may influence the occurrence of intestinal aGVHD in PBSCT with HLA-identical sibling donors.
