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Objective: To evaluate the effect of health management service on hypertension patients (HMSFHP) under the framework of the Basic Public Health Service Project by using regression discontinuity design. Methods: The participants were enrolled from an observational cohort survey in 2015 and followed up was conducted in 2019. The participants with SBP 130-150 mmHg and/or DBP 80-100 mmHg in the baseline survey of the cohort in 2015 were included in the present study. Additionally, we obtained the dates of participants receiving HMSFHP and their blood pressure data from follow-up records, physical examination records and telephone interview. The participants were divided into intervention group and control group based on the cutoff points, i.e. SBP ≥140 mmHg and/or DBP ≥90 mmHg. The local linear regression model were used to estimate the effect of HMSFHP on reducing blood pressure of the participants. Results: After adjusting for age, sex and time length of receiving HMSFHP, the results of the model including participants with 80-100 mmHg for DBP in 2015 indicated that, for the participants who received HMSFHP, the DBP decreased by 6.66 mmHg from 2015 to 2019. For the participants with SBP 130-150 mmHg in 2015, the reduction estimate of the model was -6.17 mmHg, the difference was not significant (P=0.178), suggesting that receiving HMSFHP did not cause change in SBP for the participants who received HMSFHP. Conclusion: Receiving HMSFHP had effect to reduce DBP, and HMSFHP had a positive effect on the control of blood pressure in patients with hypertension.
Subject(s)
Humans , Blood Pressure , Health Services , Hypertension , Linear Models , Physical ExaminationABSTRACT
Objective: To determine whether the adenine base editor (ABE7.10) can be used to fix harmful mutations in the human G6PC3 gene. Methods: To investigate the safety of base-edited embryos, off-target analysis by deep sequencing was used to examine the feasibility and editing efficiency of various sgRNA expression vectors. The human HEK293T mutation models and human embryos were also used to test the feasibility and editing efficiency of correction. Results: ①The G6PC3(C295T) mutant cell model was successfully created. ②In the G6PC3(C295T) mutant cell model, three distinct Re-sgRNAs were created and corrected, with base correction efficiency ranging from 8.79% to 19.56% . ③ ABE7.10 could successfully fix mutant bases in the human pathogenic embryo test; however, base editing events had also happened in other locations. ④ With the exception of one noncoding site, which had a high safety rate, deep sequencing analysis revealed that the detection of 32 probable off-target sites was <0.5% . Conclusion: This study proposes a new base correction strategy based on human pathogenic embryos; however, it also produces a certain nontarget site editing, which needs to be further analyzed on the PAM site or editor window.
Subject(s)
Humans , Gene Editing , CRISPR-Cas Systems , Adenine , HEK293 Cells , Mutation , Glucose-6-Phosphatase/metabolismABSTRACT
BACKGROUND@#Zinc finger and BTB domain-containing protein 46 (Zbtb46) is a transcription factor identified in classical dendritic cells, and maintains dendritic cell quiescence in a steady state. Zbtb46 has been reported to be a negative indicator of acute myeloid leukemia (AML). We found that Zbtb46 was expressed at a relatively higher level in hematopoietic stem and progenitor cells (HSPCs) compared to mature cells, and higher in AML cells compared to normal bone marrow (BM) cells. However, the role of Zbtb46 in HSPCs and AML cells remains unclear. Therefore, we sought to elucidate the effect of Zbtb46 in normal hematopoiesis and AML cells.@*METHODS@#We generated Zbtb46 and Zbtb46Mx1-Cre mice. The deletion of Zbtb46 in Zbtb46Mx1-Cre mice was induced by intraperitoneal injection of double-stranded poly (I). poly (C) (poly(I:C)), and referred as Zbtb46 cKO. After confirming the deletion of Zbtb46, the frequency and numbers of HSPCs and mature blood cells were analyzed by flow cytometry. Serial intraperitoneal injection of 5-fluorouracil was administrated to determine the repopulation ability of HSCs from Zbtb46 and Zbtb46 cKO mice. The correlation between Zbtb46 expression and prognosis was analyzed using the data from the Cancer Genome Atlas. To investigate the role of Zbtb46 in AML cells, we knocked down the expression of Zbtb46 in THP-1 cells using lentiviral vectors expressing small hairpin RNAs targeting Zbtb46. Cell proliferation rate was determined by cell count assay. Cell apoptosis and bromodeoxyuridine incorporation were determined by flow cytometry.@*RESULTS@#The percentages and absolute numbers of HSPCs and mature blood cells were comparable in Zbtb46 cKO mice and its Zbtb46 littermates (Zbtb46vs. Zbtb46 cKO, HPC: 801,310 ± 84,282 vs. 907,202 ± 97,403, t = 0.82, P = 0.46; LSK: 86,895 ± 7802 vs. 102,210 ± 5025, t = 1.65, P = 0.17; HSC: 19,753 ± 3116 vs. 17,608 ± 3508, t = 0.46, P = 0.67). The repopulation ability of HSCs from Zbtb46Mx1-Cre mice was similar to those from Zbtb46 control (P = 0.26). Zbtb46 had elevated expression in AML cells compared to total BM cells from normal control. Knockdown of Zbtb46 in THP-1 cells led to a significant increase in cell apoptosis and reduced cell growth and proliferation.@*CONCLUSION@#Collectively, our data indicate that Zbtb46 is essential for survival and proliferation of AML cells, but dispensable for normal hematopoiesis.
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BACKGROUND@#Hematopoietic stem cells (HSCs) have the ability to differentiate into all subsets of blood cells and self-renew. Large tumor suppressor 1 (LATS1) and large tumor suppressor 2 (LATS2) kinases are essential for cell cycle regulation, organism fitness, genome integrity, and cancer prevention. Here, we investigated whether Lats1 and Lats2 are critical for the maintenance of the self-renewal and quiescence capacities of HSCs in mice.@*METHODS@#Quantitative reverse transcription-polymerase chain reaction was used to determine the expression levels of Lats1 and Lats2 in subsets of progenitor cells and mature bone marrow cells. A clustered regularly interspaced short palindromic repeats system was used to generate Lats1 or Lats2 knockout mice. Complete blood cell counts were used to compare the absolute number of white blood cells, lymphocytes, monocytes, neutrophils, and platelets between Lats1 or Lats2 heterozygotes and littermates. Flow cytometry was used to assess the size of hematopoietic progenitor cells (HPCs) and HSC pools in Lats1 or Lats2 heterozygotes and littermates. The comparison between the two groups was analyzed using Student's t test.@*RESULTS@#Lats1 and Lats2 were widely expressed in hematopoietic cells with higher expression levels in primitive hematopoietic cells than in mature cells. Lats1 or Lats2 knockout mice were generated, with the homozygotes showing embryonic lethality. The size of the HPC and HSC pools in Lats1 (HPC: wild-type [WT] vs. heterozygote, 220,426.77 ± 54,384.796 vs. 221,149.4 ± 42,688.29, P = 0.988; HSC: WT vs. heterozygote, 2498.932 ± 347.856 vs. 3249.763 ± 370.412, P = 0.105) or Lats2 (HPC: WT vs. heterozygote, 425,540.52 ± 99,721.86 vs. 467,127.8 ± 89,574.48, P = 0.527; HSC: WT vs. heterozygote, 4760.545 ± 1518.01 vs. 5327.437 ± 873.297, P = 0.502) heterozygotes were not impaired. Moreover, the depletion of Lats1 or Lats2 did not affect the overall survival of the heterozygotes (Lats1: P = 0.654; Lats2: P = 0.152).@*CONCLUSION@#These results indicate that a single allele of Lats1 or Lats2 may be sufficient for normal hematopoiesis.
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Objective: To investigate the effect of brain derived neurotrophic factor (BDNF) on mesenchymal stem cells (MSC) inhibiting follicular helper T cells (Tfh cells). Methods: The contents of indoleamine 2,3-dioxygenase (IDO), IL-10, TGF-β and IL-21 in MSC culture supernatant were detected by ELISA; The peripheral blood of healthy volunteers were collected, and lymphocyte in peripheral blood was separated by human lymphocyte separation solution; Co-cultures of MSC and lymphocyte were performed by Transwell chamber, and the proportion of CD4(+)CXCR5(+) Tfh cells and their subtypes were detected by flow cytometry. Results: ①The concentrations of IL-10, TGF-β, and IDO in the supernatant of BDNF group (BDNF-stimulated MSC) were higher than those of the control ones (adding PBS with the same volume) [IL-10: (42.1±4.4) ng/ml vs (19.3±2.1) ng/ml, t=4.761, P=0.009; TGF-β: (13.9±1.7) ng/ml vs (5.3±0.6) ng/ml, t=5.129, P=0.008; IDO: (441.3±56.9) ng/ml vs (226.7±37.6) ng/ml, t=3.130, P=0.035]; ②The comparisons between BDNF (co-culture of lymphocyte and BDNF-stimulated MSC) and MSC groups (co-culture of lymphocyte and MSC) were detailed as of follows: the proportion of CD4(+) CXCR5(+)Tfh cells were lower [(3.37±0.21)% vs (6.51±0.27)%, t=9.353, P<0.001], the proportion of CD4(+) CXCR5(+)CXCR3(+) CCR6(-) Tfh cells were higher [(41.14±2.04)% vs (26.72±2.57)%, t=4.383, P=0.012], CD4(+)CXCR5(+)CXCR3(-)CCR6(-) Tfh2 cells and CD4(+)CXCR5(+)CXCR3(-)CCR6(+) Tfh17 cells were lower [Tfh2: (30.16±5.38)% vs (43.26±4.11)%, t=4.426, P=0.012; Tfh17: (15.61±1.52)% vs (22.32±0.72)%, t=4.202, P=0.014], the proportion of CD4(+)CXCR5(+)Foxp3(+) Tfr cells were higher [(4.95±0.22)% vs (2.32±0.16)%, t=10.241, P<0.001], the concentration of IL-21 in the lymphocyte supernatant was lower [(0.28±0.03) ng/ml vs (0.85±0.08) ng/ml, t=6.675, P=0.003]. Conclusion: BDNF could enhance the inhibitory effect of MSC on Tfh cells through inhibiting the increasing of Tfh cells and the differentiations of Tfh2 and Tfh17 cells.
Subject(s)
Humans , Brain-Derived Neurotrophic Factor , Cell Differentiation , Flow Cytometry , Mesenchymal Stem Cells , T-Lymphocytes, Helper-InducerABSTRACT
Objective To learn the epidemic characteristics and time trends of drowning-induced mortality among the Ningbo residents aged less than 20 years and to provide the scientific evidence for developing drowning prevention strategies. Methods Data were obtained from the death registry system in Ningbo City during 2002-2015 for descriptive analysis, and a linear regression model on an absolute scale or a log scale of the relevant indexes was mainly used to identify the time trends. Results There were all 982 deaths owning to drowning among the Ningbo residents aged under 20 years, with the average crude mortality of 6.23/100000. And the average crude drowning-induced mortality was 8.74/100000, 3.59/100000, 3.85/100000 and 7.64/100000 for the male, female, urban and rural respectively. The standardized mortality rate for drowning showed a significant decreasing trend with the Annual Percent Change (APC) of -9.71% (P<0.001) . APC for the male was -10.03% (P<0.001), higher than -9.64% for the female (P=0.001) . Meanwhile, APC for the urban was-14.51% (P<0.001), also higher than -8.71% for the rural (P<0.001) . The most deaths occurred in the nature water body (90.04%) . Conclusion Though the drowning-induced mortality among the Ningbo residents aged less than 20 years revealed a significance of the decreasing trends, and drowning still emerged as a serious public health issue. Gender parity and regional disparities should take into account when developing some intervention strategies.
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Objective To learn the prevalence of the metabolic syndrome (MS) and related factors among 15-74 year-old residents in Ningbo. Methods Multistage random sampling method was used and 5280 residents aged 15-74 years were interviewed by trained researchers with a structured questionnaire, and physical examination and related metabolic biochemical data were collected as well. The criterion of International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) were applied for MS diagnosis. Results The crude MS prevalence was 29.38%, and the standardized prevalence was 27.59%. The MS prevalence was a little higher in males (28.83%) than in females (26.33%) . The prevalence of MS and its components increased with age, and an abrupt increase of the prevalence of MS started at age of 55 in females. The most common combination of MS individual components was central obesity, high TG, low HDL-C and hypertension. The results of multivariate logistic regression analysis indicated that aging, smoking, family history of fat and hypertension would increase the risk of MS. Conclusion There is a high prevalence of MS in Ningbo residents. It is necessary to screen and find MS high-risk groups as soon as possible, and comprehensive measures should be adopted to reduce the incidence of MS in Ningbo as well, so as to effectively reduce the burden of type 2 diabetes and cardiovascular diseases, and to promote comprehensive health of people.
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Objective This study aimed to evaluate the model of integrated drowning interventions for the floating children in Ningbo City.Methods A two -year program of integrated drowning intervention had been carried out in Ningbo City since 2013,and the floating children in Jiangbei District and Yinzhou District were selected as the experiment and control group respectively.Baseline and final survey was all conducted in these two groups.A total of 7 736 and 7730 students from 1 st -9 th grade in the Migrant Workers'Children Schools were recruited by multi -stage random sampling and surveyed by the self -reported questionnaires in these two surveys respectively.The unconditional logistic regression model was adopted mainly for the multivariate analysis.Results The incidence rate of non -fatal drowning for the floating children in the experiment group after intervention was 4.45%,being significantly lower than 13.12% before intervention (χ2 =188.293,P <0.001).While the incidence rate of non -fatal drowning in the control group after intervention was 7.47%, having no significant difference with 6.90% before intervention (χ2 =0.896,P =0.344).And the probability of non -fatal drowning for the intervention group was 0.762 time of the control group.Conclusion The model of integrated drowning interventions,based on the ecological approach and initiated by Ningbo,was proven to be effective and worth popularizing.
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Objective To explore the current profile of drowning related high risk behaviors among the floating children inNingbo City and to identify the risk factors on these behaviors.Methods A total of 7 600 students from grade 1 -9 ineight urban migrant workers'children schools were recruited and surveyed by the questionnaires.And the logistic regressionmodel was used for the analysis of risk factors.Results In last one year,without adult supervision,the incidence rate ofdrowning related high risk behaviors was 27.53%.The results of multivariate logistic regression showed that males (OR =2.30,95%CI:1.99 ~2.65),senior grade (OR =1.23,95%CI:1.18 ~1.27),other juvenile companion on the way toschools (OR =1.26,95%CI:1.06 ~1.51),being able to swim (OR =2.09,95%CI:1.77 ~2.46)and there being theopen water around school and home (OR =1.75,95%CI:1.52 ~2.00)could increase the incidence of drowning relatedhigh risk behaviors.And higher awareness of drowning prevention (OR =0.99,95%CI:0.98 ~0.99),higher rate ofcorrect attitude (OR =0.99,95%CI:0.98 ~0.99),getting along well with schoolmates (OR =0.69,95%CI:0.51 ~0.95)and with family members (OR =0.33,95%CI:0.24 ~0.46)could reduce the incidence of drowning related highrisk behaviors.Conclusion The incidence rate of drowning related high risk behaviors was high among the floatingchildren in Ningbo City,and males,being able to swim might increase the occurrence of high risk behaviors.
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<p><b>OBJECTIVE</b>To explore the effects of basic fibroblast growth factor (bFGF) on human bone marrow mesenchymal stem cell (hBMMSC) damaged by irradiation and its underlying mechanisms.</p><p><b>METHODS</b>hBMMSC was irradiated with 0, 6, 12 Gy X ray, then flow cytometry, cell counting kit-8 (CCK-8), Western blot and alizarin red staining were used to detect the effects of X ray on apoptosis, proliferation and osteogenic differentiation of hBMMSC; 0, 1, 5, 10, 20 ng/ml bFGF was added to hBMMSC irradiated with X ray for selecting the suitable bFGF reaction concentration; then the Western blot was used to detect the expression of PDGFRα so as to evaluate whether the expression of PDGFRα participated in bFGF-mediated recovery of hBMMSC proliferation and osteogenic differentiation after irradiation.</p><p><b>RESULTS</b>The proliferation and osteogenic differentiation of hBMMSC decreased remarkably after irradiation. bFGF promoted the recovery of proliferation and osteogenic differentiation of irradiated hBMMSC compared with untreated irradiated hBMMSC (P < 0.05); 5 ng/ml bFGF was identified as the optimal concentration. A significant difference in the number of apoptotic cells could be detected only between the 0 Gy group and 12 Gy group at the 24 h time point, while no differences were detected at later time points. Irradiated hBMMSC showed remarkable decrease of PDGFRα expression, while the PDGFRα expression increased after bFGF was added.</p><p><b>CONCLUSION</b>Irradiation dose not show significant effect on apoptosis of hBMMSC, but the bFGF displays a effect on repairing the irradiation damage of hBMMSC and promotes the recovery of hBMMSC proliferation and osteogenic differentiation. The damage of hBMMSC proliferation and osteogenic differentiation associates with downregulation of PDGFRα expression induced by irrediation. PDGFRα involves in repairing effect of bFGF on irradiation damage of hBMMSC.</p>
Subject(s)
Humans , Apoptosis , Bone Marrow Cells , Cell Differentiation , Cell Proliferation , Cells, Cultured , Fibroblast Growth Factor 2 , Mesenchymal Stem Cells , Osteogenesis , Receptor, Platelet-Derived Growth Factor alphaABSTRACT
Objective of this study was to investigate the changes of cyclooxygenase-2 expression and mitochondrial membrane potential in apoptotic NB4 cells induced by arsenic trioxide (As(2)O(3)). The morphological changes in apoptosis process of NB4 cells treated by arsenic trioxide were observed under immunofluorescence microscope and DNA electrophoresis method, and the apoptosis rate of NB4 cells and the variations of mitochondrial membrane potential were detected by flow cytometry. Furthermore, the variations of expression level of cyclooxygenase-2 protein were analyzed by using Western blot method. The results indicated that after NB4 cells were treated with 2 µmol/L As(2)O(3) for 48 hours, some variations of NB4 cells were observed, such as pyknosis, chromatin segmentation, even fragmentation. Meanwhile, the typical DNA Ladder phenomenon was observed. The apoptosis rate of NB4 cells treated with 3 µmol/L As(2)O(3) for 48 hours was 33.34%, Furthermore the apoptosis rate of NB4 cells was enhanced along with the increase of concentration of As(2)O(3). After NB4 cells were treated with 0.5, 1, 2, 4 and 8 µmol/L As(2)O(3) for 48 hours, the mitochondrial membrane potential decreased by 12.8%, 21.6%, 66.9%, 83.7% and 83.8% respectively. The Western blot detection results showed that the expression level of cyclooxygenase-2 protein in NB4 cells was lower than that in control cells and decreased along with the rise of As(2)O(3) concentration, then the negative dose-dependent manner was observed between these 2 groups. It is concluded that As(2)O(3) can effectively induce NB4 cell apoptosis, and the dose-dependent manner existed in certain extent of concentrations. The decrease of mitochondrial membrane potential may be related with NB4 cell apoptosis induced by As(2)O(3). Cyclooxygenase-2 participates in the process of NB4 cell apoptosis induced by As(2)O(3).
Subject(s)
Humans , Apoptosis , Arsenicals , Pharmacology , Cell Line, Tumor , Cyclooxygenase 2 , Metabolism , Leukemia, Promyelocytic, Acute , Metabolism , Membrane Potential, Mitochondrial , Oxides , PharmacologyABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is the hematological malignancy of bone marrow characterized by the rapid proliferation and subsequent accumulation of immature T lymphocyte and mainly occurs in children and adolescents. In 1991, a kind of activating mutation of Notch 1 was found in a subset of T-ALL with chromosomal translocation t(7;9) for the first time. During the past 20 years since then, understanding of the relationship between Notch 1 activating mutation and T-ALL has been deepened and widened. This review briefly discusses the four main subtypes of Notch 1 activating mutations, also focuses on how these mutations change the normal signaling pathways and genes expression during their participation in the pathogenesis of T-ALL, and how these insights will promote the development of newly targeting therapies for patients with this aggressive form of leukemia.
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Humans , Mutation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Genetics , Receptor, Notch1 , GeneticsABSTRACT
This study was aimed to investigate the association between mthfr gene polymorphisms and toxicity of HDMTX in acute lymphocytic leukemia patients. A total of 44 patients were selected, and DNA was extracted from their peripheral blood. PCR-RFLP was used to determine the genotypes of mthfr. The toxicity response of patients received HDMTX chemotherapy was observed. The results showed that the toxicity of HDMTX to carriers of the variant allele at codon 677 (CT or TT) increased, as compared with individuals with the common CC genotype (OR = 3.75, 95% CI 1 - 14, p = 0.04). In contrast, the toxicity of HDMTX to ALL patients with the variant allele at codon 1298 (AC or CC) decreased as compared with the common AA genotype carriers (OR = 0.12, 95% CI: 0.026 - 0.564, p = 0.007). As compared with carriers of the variant allele at coden 1298 (AC or CC), the toxicity of HDMTX to patients with TT genotype at 677 and AA genotype at 1298 increased (OR = 16.5, 95% CI: 0.026 - 0.564). It is concluded that mthfr gene polymorphisms associate with the toxicity of HDMTX chemotherapy in acute lymphocytic leukemia.
Subject(s)
Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Antimetabolites, Antineoplastic , Methotrexate , Methylenetetrahydrofolate Reductase (NADPH2) , Genetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Drug Therapy , GeneticsABSTRACT
To explore the application value of bcr-abl fusion gene deterction microarray in diagnosis, typing, choosing of treatment variant and prognosis judgment, probe for fusion gene detection was designed, oligonucleotide microarray was prepared; total RNA was extracted, reverse-transcripted and labeled by fluorescence, then cDNA was hybridized with microarray in order to detect bcr-abl fusion gene in leukemia cells. The results showed that better reaction conditions were gained by exploration of hybridizotion temperature and elution conditions, bcr-abl fusion gene in leukemia cells was detected by prepared miccroarray. In conclusion, oligonucleotide microarray is effective in detecting the fusion gene and has some unique advantages and certain clinical application value, but has some deficiency too. If microarray can be improved further, it could be used widely in the field of hematology.