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Objective:To investigate the relationship between telomere length of bone marrow mononuclear cells and prognosis of patients with acute myeloid leukemia (AML) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Telomere length of bone marrow mononuclear cells before transplantation, after transplantation and before donor mobilization as well as information related to follow-up of 33 AML patients who received allo-HSCT in the Affiliated Hospital of Guizhou Medical University between June 2020 and June 2021 were retrospectively analyzed. Telomere length was detected by using telomeric terminal restriction fragment (TRF) method. Telomere length was compared among patients with different prognoses. The recurrence within 1 year was treated as the gold standard and receiver operating characteristic (ROC) curve was used to analyze the effect of telomere length before transplantation or before donor mobilization in the judgement of the recurrence within 1 year after transplantation. The patients were stratified according to the optimal threshold value of telomere length for patients or donors, and Kaplan-Meier method was used to compare the progression-free survival (PFS) of patients with different stratification, and log-rank test was performed.Results:The median age of 33 patients was 34 years (14-61 years), and there were 17 males and 16 females; 31 patients were initially diagnosed with AML, 1 patient transferred from myelodysplastic syndrome (MDS) to AML, and 1 patient transferred from chronic granulocytic leukemia (CML) to AML; 14 received identical sibling transplantation and 19 received haploidentical sibling transplantation. The median age of the donors was 30 years (20-65 years), including 24 males and 9 females. Telomere length of bone marrow mononuclear cells before mobilization in 33 donors was longer than that in patients before transplantation (33 cases) and at +30 d after transplantation (31 cases) [(6.67±0.31) kb, (6.40±0.33) kb, (6.48±0.33) kb, respectively; all P < 0.05], and the difference between patients before and at +30 d after transplantation was not statistically significant ( t = 0.89, P = 0.378), and the telomere length of bone marrow mononuclear cells in 11 patients +180 d after transplantation was (6.66±0.18) kb. The incidence of acute graft-versus-host disease (aGVHD) after transplantation was 45.5% (15/33), the incidence of infection with clear imaging and pathogenic basis was 39.4% (13/33), the mortality rate within 1 year after transplantation was 3.0% (1/33), and the recurrence rate within 1 year after transplantation was 15.2% (5/33). There were no statistically significant differences in telomere length of donor pre-mobilization bone marrow mononuclear cells between the groups with and without aGVHD and between the infected and non-infected groups (all P > 0.05).Compared with patients who had not relapsed within 1 year after transplantation, telomere length of donor pre-mobilization bone marrow mononuclear cells was shorter in patients who relapsed within 1 year after transplantation [(6.39±0.19) kb vs. (6.72±0.30) kb, t = -3.23, P = 0.011], telomere length was longer in patients before transplantation [(6.75±0.16) kb vs. (6.35±0.36) kb, t = 4.17, P = 0.001]. ROC curve analysis showed that the optimal threshold values for telomere length of pre-transplantation and donor pre-mobilization bone marrow mononuclear cells were 6.48 and 6.42 kb, respectively for patients who relapsed within 1 year after transplantation. PFS in patients with pre-transplantation bone marrow mononuclear cells telomere length < 6.48 kb was better than that in patients with telomere length ≥ 6.48 kb ( P = 0.003); PFS in patients with pre-mobilization bone marrow mononuclear cells telomere length>6.42 kb was better than that in patients with telomere length ≤ 6.42 kb ( P < 0.001). Conclusions:In allo-HSCT for AML, patients have an increased risk of relapse within 1 year after transplantation when their pre-transplantation bone marrow mononuclear cells telomere length is long and the donor bone marrow mononuclear cells telomere length is short.
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Objective: To explore the development of a CAR-T cells targeting CLL-1 and verify its function. Methods: The expression levels of CLL-1 targets in cell lines and primary cells were detected by flow cytometry. A CLL-1 CAR vector was constructed, and the corresponding lentivirus was prepared. After infection and activation of T cells, CAR-T cells targeting CLL-1 were produced and their function was verified in vitro and in vivo. Results: CLL-1 was expressed in acute myeloid leukemia (AML) cell lines and primary AML cells. The transduction rate of the prepared CAR T cells was 77.82%. In AML cell lines and AML primary cells, CLL-1-targeting CAR-T cells significantly and specifically killed CLL-1-expressing cells. Compared to untransduced T cells, CAR-T cells killed target cells and secreted inflammatory cytokines, such as interleukin-6 and interferon-γ, at significantly higher levels (P<0.001) . In an in vivo human xenograft mouse model of AML, CLL-1 CAR-T cells also exhibited potent antileukemic activity and induced prolonged mouse survival compared with untransduced T cells [not reached vs 22 days (95%CI 19-24 days) , P=0.002]. Conclusion: CAR-T cells targeting CLL-1 have been successfully produced and have excellent functions.
Subject(s)
Animals , Humans , Mice , Cell Line, Tumor , Cytokines , Immunotherapy, Adoptive , Lectins, C-Type , Leukemia, Myeloid, Acute/metabolism , Receptors, Mitogen , T-LymphocytesABSTRACT
Objective To discuss the changes and significance of interleukin-17 (IL-17) in perioperative period of congenital heart disease patients with pulmonary hypertension. Methods A total of forty patients with congenital heart disease underwent cardiopulmonary bypass (CPB) were included in this study. According to the pulmonary artery systolic pressure (PASP), patients were divided into non-pulmonary hypertension group (group Ⅰ, PASP < 30 mmHg) and pulmonary hypertension group (groupⅡ, PASP≥30 mmHg). Blood samples were taken before anesthesia (T1), start CPB (T2), 30 min after CPB (T3), 6 h (T4), 24 h (T5) and 7 d (T6) after operation. The concentration of IL-17 was detected by ELISA. Arterial oxygen partial pressure [p(O2)] and arterial carbon dioxide partial pressure [p(CO2)] during the first five time points were recorded. Oxygen index (OI) and alveolar arterial oxygen tension difference (AaDO2) were calculated. Results The plasma IL-17 levels in perioperative period were significantly higher in group Ⅱ than those of group Ⅰ (P < 0.05). The highest concentration of IL-17 emerged at T3, then decreased gradually in both groups. At this time point, the OI decreased, and AaDO2 increased significantly in both groups. Compared with groupⅠ, the OI decreased, while AaDO2 increased at T5 in groupⅡ(P<0.05). Conclusion The high level of IL-17 promotes the formation of pulmonary hypertension in congenital heart disease and leads to the lung injury during CPB, which can be used as a clinical monitoring indicator of evaluating severity.
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Objective To discuss the changes and significance of interleukin-17 (IL-17) in perioperative period of congenital heart disease patients with pulmonary hypertension. Methods A total of forty patients with congenital heart disease underwent cardiopulmonary bypass (CPB) were included in this study. According to the pulmonary artery systolic pressure (PASP), patients were divided into non-pulmonary hypertension group (group Ⅰ, PASP < 30 mmHg) and pulmonary hypertension group (groupⅡ, PASP≥30 mmHg). Blood samples were taken before anesthesia (T1), start CPB (T2), 30 min after CPB (T3), 6 h (T4), 24 h (T5) and 7 d (T6) after operation. The concentration of IL-17 was detected by ELISA. Arterial oxygen partial pressure [p(O2)] and arterial carbon dioxide partial pressure [p(CO2)] during the first five time points were recorded. Oxygen index (OI) and alveolar arterial oxygen tension difference (AaDO2) were calculated. Results The plasma IL-17 levels in perioperative period were significantly higher in group Ⅱ than those of group Ⅰ (P < 0.05). The highest concentration of IL-17 emerged at T3, then decreased gradually in both groups. At this time point, the OI decreased, and AaDO2 increased significantly in both groups. Compared with groupⅠ, the OI decreased, while AaDO2 increased at T5 in groupⅡ(P<0.05). Conclusion The high level of IL-17 promotes the formation of pulmonary hypertension in congenital heart disease and leads to the lung injury during CPB, which can be used as a clinical monitoring indicator of evaluating severity.
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<p><b>OBJECTIVE</b>To explore effects of iron overload on hematopoiesis in mice with bone marrow injury and its possible mechanism (s).</p><p><b>METHODS</b>C57BL/6 mice were divided into control, iron, irradiation, irradiation+iron groups. The iron-overloaded model of bone marrow injury was set up after mice were exposed to the dose of 4 Gy total body irradiation and (or) were injected iron dextran intraperitoneally. Iron overload was confirmed by observing iron deposits in mice and bone marrow labile iron pool. Additionally, the number of peripheral blood and bone marrow mononuclear cells and the frequency of erythroid cells and myeloid cells were counted and hematopoietic function was assessed.</p><p><b>RESULTS</b>(1)Iron overload occurred by bone marrow biopsy and flow cytometry analysis. (2)Compared with control group, the number of platelets [(801.9±81.2)×10⁹/L vs (926.0±28.2)×10⁹/L] and BMMNC and the frequency of erythroid cells and myeloid cells decreased. Moreover, hematopoietic colony forming units and single-cell cloning counts decreased significantly in irradiation group (P<0.05). (3)Compared with irradiation group, the number of platelets [(619.0±60.9)×10⁹/L vs (801.9±81.2)×10⁹/L] and the frequency of erythroid cells and myeloid cells decreased; moreover, hematopoietic colony forming units and single-cell cloning counts decreased significantly in irradiation+iron group (P<0.05). (4)Compared with irradiation group, ROS level increased by 1.94 fold in BMMNC, 1.93 fold in erythroid cells and 2.70 fold in myeloid cells, respectively (P<0.05).</p><p><b>CONCLUSION</b>The dose of 4 Gy total body irradiation caused bone marrow damage and iron overload based on this injury model, which could damage bone marrow hematopoietic function aggravatingly. And further study found that iron overload was closely related to increased ROS level in BMMNC. The findings would be helpful to further study the injury mechanism of iron overload on the hematopoiesis of bone marrow.</p>
Subject(s)
Animals , Mice , Bone Marrow , Wounds and Injuries , Bone Marrow Cells , Cell Biology , Hematopoiesis , Iron Overload , Mice, Inbred C57BLABSTRACT
<p><b>OBJECTIVE</b>To establish a mouse model of iron overload by intraperitoneal injection of iron dextran and investigate the impact of iron overload on bone marrow hematopoiesis.</p><p><b>METHODS</b>A total of 40 C57BL/6 mice were divided into control group, low-dose iron group (12.5 mg/ml), middle-dose iron group (25 mg/ml), and high-dose iron group (50 mg/ml). The control group received normal saline (0.2 ml), and the rest were injected with intraperitoneal iron dextran every three days for six weeks. Iron overload was confirmed by observing the bone marrow, hepatic, and splenic iron deposits and the bone marrow labile iron pool. In addition, peripheral blood and bone marrow mononuclear cells were counted and the hematopoietic function was assessed.</p><p><b>RESULTS</b>Iron deposits in bone marrow, liver, and spleen were markedly increased in the mouse models. Bone marrow iron was deposited mostly within the matrix with no significant difference in expression of labile iron pool.Compared with control group, the ability of hematopoietic colony-forming in three interventional groups were decreased significantly (P<0.05). Bone marrow mononuclear cells counts showed no significant difference. The amounts of peripheral blood cells (white blood cells, red blood cells, platelets, and hemoglobin) in different iron groups showed no significant difference among these groups;although the platelets were decreased slightly in low-dose iron group [(780.7±39.60)×10(9)/L], middle dose iron group [(676.2±21.43)×10(9)/L], and high-dose iron group [(587.3±19.67)×10(9)/L] when compared with the control group [(926.0±28.23)×10(9)/L], there was no significant difference(P>0.05).</p><p><b>CONCLUSIONS</b>The iron-overloaded mouse model was successfully established by intraperitoneal administration of iron dextran. Iron overload can damage the hepatic, splenic, and bone marrow hematopoietic function, although no significant difference was observed in peripheral blood count.</p>
Subject(s)
Animals , Male , Mice , Bone Marrow , Disease Models, Animal , Hematopoiesis , Iron Overload , Iron-Dextran Complex , Toxicity , Mice, Inbred C57BL , SpleenABSTRACT
<p><b>OBJECTIVE</b>To investigate the relationship between serotonin (5-HT) and epilepsy and the mechanism of learning-memory in pilocarpine (PILO)-induced epileptic rats after 5,7-dihydroxytryptamine (5,7-DHT) microinjection in median raphe nucleus.</p><p><b>METHODS</b>Adult S D rats were randomly divided into 3 groups: PILO group, PILO+ 5,7-DHT group, vehicle control group; PILO group was divided into two groups by status epilepticus (SE): PILO + SE group and PILO - SE group. The rats' seizures and cortex electroencephalography (EEG) were observed by video EEG. The rats' spatial learning-memory was evaluated by Morris water maze. Finally, serotonergic neuron in raphe nuclei was observed by immunohistochemistry.</p><p><b>RESULTS</b>After treatment of 5,7-DHT (PILO + 5,7-DHT group), the success rate, the mortality and the frequency of chronic spontaneous seizures in pilocarpine-induced epilepsy model were all improved. Compared with the control group, the number of serotonergic neuron in raphe nuclei was decrease in PILO + SE group (P < 0.05). Moreover, it's extremely decrease in PILO + 5,7-DHT group (P < 0.01). Compared with control group, the mean escape latency was prolonged, the times of crossing target was decreased and the retention time in target zone was shortened in PILO + SE group (P < 0.05), but there was no significant difference between PILO + SE group and PILO + 5,7-DHT group.</p><p><b>CONCLUSION</b>Depletion of serotonin may facility the rats' epileptic seizures, but we could not interpret which may cause epileptic rats' cognitive deficit.</p>
Subject(s)
Animals , Male , Rats , 5,7-Dihydroxytryptamine , Toxicity , Epilepsy , Metabolism , Psychology , Maze Learning , Memory , Pilocarpine , Raphe Nuclei , Rats, Sprague-Dawley , Serotonin , MetabolismABSTRACT
Reactive oxygen species (ROS) are bioactive oxygen molecules produced after exposure to exogenous oxidants or endogenously through cellular aerobic metabolism. Hematopoietic stem cells (HSC) are multipotent, self-renewing stem cells residing in hematopoietic tissues. Recent studies show that an abnormal increase in ROS production is associated closely with HSC senescence. Many signaling molecules such as FoxOs, ATM, mTOR, TSC1, Bmi1 and AKT play a significant role in ROS-induced HSC senescence. The roles of p53-p21 and p16-Rb pathways can induce hematopoietic dysfunction and lead to ROS-induced HSC senescence. This review summarizes the recent progress of studies on ROS-induced HSC senescence, and further elaborates the potential signaling molecules and pathways, aiming to provide a new target and thread for clinical treatment.
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Animals , Humans , Cellular Senescence , Hematopoietic Stem Cells , Cell Biology , Metabolism , Reactive Oxygen Species , Metabolism , Signal TransductionABSTRACT
Objective: To evaluate the efficacy and safety of neoadjuvant concurrent chemoradiotherapy combined with TME (total mesorectal excision) for the treatment of locally advanced middle and lower rectal cancer. Methods: Thirty patients with locally advanced middle and lower rectal cancer were recruited between September 2009 and February 2011, 14 of whom had stage II (T 3-4N0M0) and 16 had stage III (T1-4 N1-2M0). All patients received neoadjuvant concurrent chemoradiotherapy [the total dose of preoperative radiotherapy was 45-50 Gy (1.8 Gy/fx), concurrently combined with two cycles of FOLFOX4 regimen]. The surgical operation was performed 4-6 weeks after concurrent chemoradiotherapy, following the principle of TME. Results: All patients completed the neoadjuvant concurrent chemoradiotherapy. Of these thirty patients, 5 received complete response, 18 received partial response, 7 received stable disease, and 23 patients obtained downstaging (76.6%). Except one patient who receiving complete response rejected the surgical operation, 23 patients received low/ultra-low anterior resection (Dixon), and 6 patients received abdominoperineal resection (Miles) 4-6 weeks after chemoradiotherapy. The sphincter preservation rate was 80.0% (24/30). No perioperative death was observed, and the overall incidence of complication was 20.7% (6/29). Conclusion: Neoadjuvant concurrent chemoradiotherapy combined with TME for treatment of locally advanced middle and lower rectal cancer is effective and safe, which can reduce the tumor stage and increase the complete tumor resection and sphincter preservation rates, and can also improve the quality of life. Copyright© 2011 by TUMOR.