Roles of Cilia in Heart Development and Congenital Heart Disease / 中国医学科学院学报

Cilia are protruding cell structures on the cell surface and are found in almost every type of cell.According to the different structures and quantity of tubulins,cilia can be divided into two categories:motor cilia and sensory cilia.Sensory cilia are also called non-motor cilia and primary cilia,due to the composition and number of tubulins.They are closely related to the development of internal organs and many human physiological activities.Recent studies have demonstrated that cilia are involved in regulating the formation of left and right symmetry of the heart structure,and eventually the heart develops into the left-right asymmetry structures.Since congenital heart diseases(CHD)are characterized by abnormalities in the spatial structure of the heart chamber and outflow tract,cilia may play an important role in the pathogenesis of CHD.Cilia,mainly through ciliary transduction signal pathways,regulate both the formation of left and right asymmetrical structures and the polarity and the migration of cells.Therefore,a clear understanding of the regulation mechanism of ciliary signaling pathway on heart development can provide new therapeutic targets and new ideas for the clinical treatment of CHD and may offer new target genes for prenatal screening of CHD.This article summarizes recent advances in the role of cilia in heart development and CHD pathogenesis and its mechanisms.

Research Advances in Lysine-specific Demethylase 6A and Its Application in Treating Leukemia / 中国医学科学院学报

Leukemia is a disease featured by the malignant proliferation of hematopoietic stem cells or progenitor cells in the blood system.While chemotherapy remains its mainstream treatment,disease relapse and drug resistance are still challenging problems.As one of the epigenetic mechanisms,histone methylation is involved in cell proliferation,differentiation,and apoptosis by regulating gene transcription.Recent studies have found that the histone demethylase lysine-specific demethylase 6A(KDM6A),also known as ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),is closely related to the occurrence of a variety of tumors,especially leukemia.KDM6A activates gene expression by demethylating H3K27me3 to H3K27me2 or H3K27me1.Besides,KDM6A can regulate the activation of the target gene transcription through its non-demethylase functions.It can serve as the subunit of complex of proteins associated with Set1,thus getting involved in the regulation of H3K4me1.It can be combined with yeast mating type conversion/sucrose unfermented complex family to promote the formation of an open chromatin conformation.Finally,it can promote the production of H3K27ac.This article reviews the recent studies on the structure and biological activity of histone demethylase KDM6A(UTX)and its role in treating leukemia,thus providing a new research direction for targeted treatment of leukemia.

Value of S100A8 in evaluating the prognosis of children with acute lymphoblastic leukemia / 中国当代儿科杂志

OBJECTIVE@#To study the association between S100A8 expression and prognosis in children with acute lymphoblastic leukemia (ALL).@*METHODS@#The clinical data of 377 children with ALL who were treated with the CCLG-2008-ALL regimen were retrospectively reviewed. ELISA and PCR were used to measure serum protein levels and mRNA expression of S100A8. The Kaplan-Meier method was used for survival analysis and a Cox regression analysis was also performed.@*RESULTS@#The children were followed up for 56 months, and the overall survival rate of the 377 children was 89.1%. The prednisone good response group had significantly lower S100A8 protein and mRNA levels than the prednisone poor response group (P<0.01). In the children with standard or median risk, both S100A8 protein and mRNA levels were associated with event-free survival rate (P<0.05). There were significant differences in S100A8 protein and mRNA levels between the children with different risk stratifications (P<0.01). The children who experienced events had significantly higher S100A8 protein and mRNA levels than those who did not (P<0.01). The Kaplan-Meier survival analysis and the Cox regression model suggested that S100A8 overexpression was an independent risk factor for the prognosis of children with ALL.@*CONCLUSIONS@#High S100A8 expression may be associated with the poor prognosis of children with ALL and is promising as a new marker for individualized precise treatment of children with ALL.

Diagnostic value of endogenous morphine in childhood sepsis / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the plasma concentration of endogenous morphine and the value of endogenous morphine in predicting shock, death, and multiple organ dysfunction syndrome (MODS) in children with sepsis.</p><p><b>METHODS</b>A total of 31 children with sepsis who met the diagnostic criteria were enrolled. According to the presence or absence of shock, they were divided into non-shock group with 19 children and shock group with 12 children. According to the outcome, they were divided into survival group with 22 children and death group with 9 children. According to the presence or absence of MODS, they were divided into non-MODS group with 13 children and MODS group with 18 children. In addition, 16 children with common infection and 31 who underwent physical examination were enrolled as controls. High-performance liquid chromatography-mass spectrometry was used to measure the plasma concentration of endogenous morphine. The receiver operating characteristic (ROC) curve was used to evaluate the value of endogenous morphine in predicting shock, death, and MODS in children with sepsis.</p><p><b>RESULTS</b>No endogenous morphine was detected in the healthy control group. Endogenous morphine was detected in 3 children from the common infection group and in all of 31 children with sepsis. The shock group had a significantly higher plasma concentration of endogenous morphine than the non-shock group (P<0.05). The death group had a significantly higher plasma concentration of endogenous morphine than the survival group (P<0.05). The MODS group had a significantly higher plasma concentration of endogenous morphine than the non-MODS group (P<0.05). The ROC curve showed that endogenous morphine had certain value in predicting shock, death, and MODS in children with sepsis (P<0.05).</p><p><b>CONCLUSIONS</b>There is a significant increase in the plasma concentration of endogenous morphine in children with sepsis, and endogenous morphine has a good value in predicting the risk of shock, death, and MODS.</p>

Effect of different anesthetic methods on postoperative outcomes in elderly patients undergoing hip fracture surgery / 北京大学学报(医学版)

Objective:To investigate the effect of general or regional anesthesia on postoperative cardiopulmonary complications and inpatient mortality after hip fracture surgery in elderly patients.Methods:A retrospective analysis was conducted according to the medical records of 572 elderly patients with hip fractures admitted to our hospital from January 1,2005 to December 31,2014.The age,gender,preoperative comorbidities,length of preoperative bedridden time,mechanism of injury,surgical types,anesthetic methods,major postoperative complications and inpatient mortality were recorded.Multivariate Logistic regression analysis was applied to analyze the impact of different anesthetic methods on inpatient mortality in these patients.Results:Of the 572 patients,392 (68.5％) received regional anesthesia.Inpatient death occurred in 8 (8/572,mortality:1.4％),including 5 cases of RA group (5/392,mortality:1.3％) and 3 cases of GA group (3/180,mortality:1.7％).There was no statistically significant difference between the two groups in inpatient mortality (P ＞ 0.05).Multiple Logistic regression analysis showed that gender (odds ratio:0.18,95％ CI:0.03-1.05,P =0.057),age (odds ratio:1.22,95％ CI:1.07-1.38,P =0.002),preoperative pulmonary comorbidities (odds ratio:12.09,95％ CI:2.28-64.12,P =0.003) and surgical types (odds ratio:9.36,95％ CI:1.34-64.26,P =0.024) were risk factors for inpatient mortality.Postoperative cardiovascular complications occurred in 36 patients (36/572,morbidity:6.3％),with 19 patients in RA group (19/392,morbidity:4.8％),and 17 patients in GA group (17/180,morbidity:9.4％).Multiple Logistic regression analysis showed that age (odds ratio:1.13,95％ CI:1.07-1.19,P ＜ 0.001),hypertension (odds ratio:2.72,95％ CI:1.24-5.96,P =0.012) and preoperative cerebral comorbidities (odds ratio:2.11,95％ CI:0.99-4.52,P =0.054) were risk factors for postoperative cardiovascular complications.Postoperative pulmonary complications occurred in 56 patients (56/572,morbidity:9.8％),with 19 patients in RA group (19/392,morbidity:4.8％),and 37 patients in GA group (37/180,morbidity:20.6％).Multiple Logistic regression analysis showed that age (odds ratio:1.13,95％ CI:1.07-1.19,P ＜0.001),preoperative pulmonary comorbidities (odds ratio:2.89,95％ CI:1.28-7.05,P=0.020),length of preoperative bedridden time (odds ratio:1.11,95％ CI:1.04-1.18,P =0.003) and anesthetic methods (odds ratio:5.86,95％ CI:2.98-11.53,P ＜ 0.001) were risk factors for postoperative pulmonary complications.Conclusion:General anesthesia may not affect the inpatient mortality after hip fracture surgery in elderly patients.Regional anesthesia is associated with a lower risk of pulmonary complications after surgical procedure compared with general anesthesia.

Interaction of WAVE1 and genes involved in multiple drug resistance in children with acute myeloblastic leukemia / 中华儿科杂志

<p><b>OBJECTIVE</b>Multidrug resistance (MDR) is one of the primary causes of suboptimal outcomes in chemotherapy of children with acute myeloblastic leukemia (AML). The mechanisms of drug transport resistance may chiefly contribute to MDR. Expression and/or activity of P-glycoprotein (P-gp), multiple resistance-associated protein-1 (MRP1), lung-resistance related protein (LRP) and breast cancer resistance protein (BCRP) have been considered to be associated with unfavourable outcomes in pediatric AML patients. In previous studies, we found WASP-family verprolin-homologous protein-1 (WAVE1) was involved in the MDR mechanisms in K562/A02 leukemia cells. To investigate the expression of WAVE1, P-gp, MRP1, LRP/MVP and BCRP; and if WAVE1 is involved in MDR of human leukemia cell.</p><p><b>METHODS</b>WAVE1, P-gp, MRP1, LRP, BCRP mRNA and protein expression in bone marrow mononuclear cells (BMMCs) were measured by real-time fluorescence quantitative PCR (RQ-PCR) and Western blot in a cohort of 52 children with acute myeloblastic leukemia. During follow-up, of the 52 patients, 21 were documented as being relapsing or refractory, and 31 were induced into complete continuous remission. Furthermore, HL60 cells and HL60/ADR cells were transiently transfected with PCDNA3.1-WAVE1 reconstructed plasmid and specifically siRNA to WAVE1 respectively, and the expression of WAVE1, MRP1 and BCRP before and after transfection was assessed by real-time PCR and Western blot analysis.</p><p><b>RESULTS</b>(1) The expression levels of WAVE1, P-gp, MRP, LRP and BCRP in refractory/relapsing group were much higher than that in complete continuous remission (CCR) group. (2) WAVE1 mRNA and protein expression in BMMCs of children were at higher levels when they were newly diagnosed or relapsed, compared with complete continuous remission. (3) The WAVE1 expression at mRNA and protein level in HL60/ADR cells was increased by about 353% and 95% respectively as compared with that in HL60 cells. (4) Overexpression of WAVE1 in HL60 cell lines upregulated the expression levels of MRP and BCRP (MRP mRNA and protein level were increased by about 16.54 times and 129% respectively, BCRP was increased by 4.93 times and 96%); whereas suppression of WAVE1 expression by RNA interference downregulated the expression levels of MRP1 and BCRP (MRP mRNA and protein level was only 11% and 43% of pre-disturbance respectively, BCRP was 14% and 71%).</p><p><b>CONCLUSIONS</b>Higher levels of WAVE1 in the BM indicate an unfavorable prognosis in children with AML. WAVE1 is related to the development of AML and involved in the MDR mechanisms, and regulates the level of MRP1 and BCRP.</p>

Role of WAVE1 in K562 leukemia cells invasion and its mechanism / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate role of WASP family verprolin homologous protein 1 (WAVE1) in K562 leukemia cell invasion and its mechanism.</p><p><b>METHODS</b>Immunofluorescence method was used to detect the distribution of WAVE1 and MMP-2 in the cells. K562 cells were transfected with pcDNA3. 1-WAVE1 reconstructed plasmid or with specific siRNA to WAVE1 gene. The invasion ability of K562 cells was examined by Transwell assay. The expression level of WAVE1 and MMP-2 in K562 cells was assayed by real-time PCR and Western blot.</p><p><b>RESULTS</b>(1) WAVE1 and MMP-2 mainly expressed and co-localized in the cell membrane; (2) 24 h and 48 h after transfected with pcDNA3. 1-WAVE1, the MMP-2 mRNA level in K562 cells increased by 295% and 198% while its protein increased by 80% and 23% respectively as compared with control K562 cells. At the same time point after transfected with specific siRNA, the MMP-2 mRNA level decreased by 81% and 28%, and its protein decreased by 36% and 53% respectively as compared with control. (3) The invasion ability of K562 cells was enhanced after transfected with pcDNA3. 1-WAVE1 and depressed after transfected with the specific siRNA.</p><p><b>CONCLUSION</b>The co-localization of WAVE1 and MMP-2 in K562 cells suggests they coordinate in functions; WAVE1 may involve in the migration and invasion of K562 cells through regulating the expression level of MMP-2.</p>

Expression of WAVE1 in childhood acute lymphocytic leukemia and in the apoptosis of Jurkat cells induced by adriamycin / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate whether WASP/Verprolin homologous protein 1 (WAVE1) plays a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).</p><p><b>METHODS</b>WAVE1 mRNA and protein expression in bone marrow mononuclear cells (BMMCs) was measured by RT-PCR and Western blotting respectively in 4 children with ALL relapse, 15 children with ALL in complete remission (CR) and 40 children with newly diagnosed ALL. Ten normal bone marrow samples were used as controls. Jurkat cells were treated with different concentrations of adriamycin (ADM). The cell proliferation was detected with MTT. The apoptosis rate was measured by flow cytometry. WAVE1 mRNA and protein expression of Jurkat cells treated with ADM was detected by RT-PCR and Western blotting respectively.</p><p><b>RESULTS</b>WAVE1 was not expressed or weakly expressed in BMMCs from normal controls and patients with ALL in CR. Higher WAVE1 mRNA and protein expression was found in BMMCs from patients with newly diagnosed ALL and patients with relapse ALL when compared with the controls and the patients in CR (P<0.01). ADM significantly inhibited the proliferation of the Jurkat cells and the inhibitory effect was dose-and time-dependent (P<0.05). After ADM treatment for 24 hrs, the percentage of apoptosis cells increased significantly and WAVE1 mRNA and protein expression of Jurkat cells decreased significantly when compared with the untreated controls (P<0.05).</p><p><b>CONCLUSIONS</b>The WAVE1 expression increased in children with ALL. WAVE1 may be related to the development of ALL and may be severed as a marker for the evaluation of the severity of ALL in children.</p>