Electron scale coherent structure as micro accelerator in the Earth's magnetosheath.

Turbulent energy dissipation is a fundamental process in plasma physics that has not been settled. It is generally believed that the turbulent energy is dissipated at electron scales leading to electron energization in magnetized plasmas. Here, we propose a micro accelerator which could transform electrons from isotropic distribution to trapped, and then to stream (Strahl) distribution. From the MMS observations of an electron-scale coherent structure in the dayside magnetosheath, we identify an electron flux enhancement region in this structure collocated with an increase of magnetic field strength, which is also closely associated with a non-zero parallel electric field. We propose a trapping model considering a field-aligned electric potential together with the mirror force. The results are consistent with the observed electron fluxes from ~50 eV to ~200 eV. It further demonstrates that bidirectional electron jets can be formed by the hourglass-like magnetic configuration of the structure.

Plasmapause surface wave oscillates the magnetosphere and diffuse aurora.

Energy circulation in geospace lies at the heart of space weather research. In the inner magnetosphere, the steep plasmapause boundary separates the cold dense plasmasphere, which corotates with the planet, from the hot ring current/plasma sheet outside. Theoretical studies suggested that plasmapause surface waves related to the sharp inhomogeneity exist and act as a source of geomagnetic pulsations, but direct evidence of the waves and their role in magnetospheric dynamics have not yet been detected. Here, we show direct observations of a plasmapause surface wave and its impacts during a geomagnetic storm using multi-satellite and ground-based measurements. The wave oscillates the plasmapause in the afternoon-dusk sector, triggers sawtooth auroral displays, and drives outward-propagating ultra-low frequency waves. We also show that the surface-wave-driven sawtooth auroras occurred in more than 90% of geomagnetic storms during 2014-2018, indicating that they are a systematic and crucial process in driving space energy dissipation.

KRAS and BRAF mutations in serum exosomes from patients with colorectal cancer in a Chinese population.

The efficacy of epidermal growth factor receptor- targeted therapy is significantly associated with Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-raf serine/threonine kinase proto-oncogene (BRAF) mutation in patients with colorectal cancer (CRC), for which the standard gene testing is currently performed using tumor tissue DNA. The aim of the present study was to compare the presence of KRAS and BRAF mutations in the serum exosome and primary tumor tissue from patients with CRC. Genomic DNA were extracted from the tumor tissues of 35 patients with histologically-confirmed CRC and exosomal mRNA were obtained from peripheral blood, which were collected from the corresponding patients prior to surgery. Three mutations in the KRAS gene (codons 12, 13 and 61) and a mutation in the BRAF gene (codon 600) were detected using a polymerase chain reaction-based sequencing method and their presence were compared between tumor tissues and the matched serum exosomes. The KRAS mutation rates in tumor tissues and the matched serum exosomes were 57.6 and 42.4%, respectively, which was not significantly different (P=0.063). The detection rate of the BRAF mutation was 24.2 and 18.2% in tumor tissues and the matched serum exosomes, respectively, and there was no significant difference (P=0.500). The patients with CRC that had a KRAS mutation of codon 12 in exon 2 in their tumor tissues and serum exosomes were significantly older compared with those without this mutation (tumor tissue, P=0.002; serum exosome, P=0.022). The sensitivity of KRAS and BRAF mutation detection using exosomal mRNA was 73.7 and 75%, respectively. The specificity of the detected mutations exhibited an efficiency of 100%, and the total consistency rate was 94.9 and 93.9% for KRAS and BRAF mutations, respectively. These results suggested that serum exosomal mRNA may be used as a novel source for the rapid and non-invasive genotyping of patients with CRC.

Effectiveness of circulating tumor DNA for detection of KRAS gene mutations in colorectal cancer patients: a meta-analysis.

Circulating tumor DNA (ctDNA) can be identified in the peripheral blood of patients and harbors the genomic alterations found in tumor tissues, which provides a noninvasive approach for detection of gene mutations. We conducted this meta-analysis to investigate whether ctDNA can be used for monitoring KRAS gene mutations in colorectal cancer (CRC) patients. Medline, Embase, Cochrane Library and Web of Science were searched for the included eligible studies in English, and data were extracted for statistical analysis according to the numbers of true-positive (TP), true-negative (TN), false-positive (FP) and false-negative (FN) cases. Sensitivity, specificity and diagnostic odds ratio (DOR) were calculated, and the area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. After independent searching and reviewing, 21 studies involving 1,812 cancer patients were analyzed. The overall sensitivity, specificity and DOR were 0.67 (95% confidence interval [CI] =0.55-0.78), 0.96 (95% CI =0.93-0.98) and 53.95 (95% CI =26.24-110.92), respectively. The AUROC was 0.95 (95% CI =0.92-0.96), which indicated the high diagnostic accuracy of ctDNA. After stratified analysis, we found the higher diagnostic accuracy in subgroup of patients detected in blood sample of plasma. The ctDNA may be an ideal source for detection of KRAS gene mutations in CRC patients with high specificity and diagnostic value.

Reversal of multidrug resistance in renal cell carcinoma by short hairpin RNA targeting MDR1 gene.

BACKGROUND: Over-expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, confers multidrug resistance (MDR) in renal cell carcinoma (RCC) and is a major reason for unsuccessful chemotherapy. This study aimed to determine the effct of RNA interference (RNAi) on the reversal of MDR in human RCC. METHODS: We designed and selected one short hairpin RNA (shRNA) targeting MDR1 gene, which is stably expressed from integrated plasmid and transfected by lentivirus fluid in human RCC A498 cell. RESULTS: The MDR1-targeted RNAi resulted in decreased MDR1 gene mRNA level (P < 0.001), almost abolished P-gp expression and reversed MDR to different chemotherapy drugs in the RCC A498 cell line. CONCLUSION: MDR could be reversed by RNAi in human RCC A498 cell line, which may be used for clinical application in future.

[Histone deacetylase inhibitor MS-275 treatment alters immune molecule content and categories in hepatocarcinoma exosomes].

OBJECTIVE: To investigate the effects of the histone deacetylase inhibitor, MS-275, on the immune molecule content and categories in hepatocarcinoma exosomes. METHODS: Exosomes were isolated from the human hepatocarcinoma cell lines, HepG2 and Hep3b, and purified by a combination technique of ultrafiltration centrifugation and sucrose gradient ultracentrifugation. The expressions of heat shock protein (HSP)70, human leukocyte antigen (HLA)-I, HLA-DR, cluster of differentiation (CD) 80 and NY-ESO-1 on exosomes were analyzed with immunoelectron microscopy and Western blotting before and after MS-275 treatment. Intergroup differences were statistically analyzed by the Student's paired t-test. RESULTS: MS-275 treatment of both HepG2 and Hep3b cell types significantly increased the numbers of exosomes, their total protein content, and expression of HSP70, HLA-I and CD80 (per 100 exosomes), as compared to non-treated cells (all, P less than 0.01). MS-275 was also found to induce de novo expression of HLA-DR, but had no significant effect on NY-ESO-1 expression (P more than 0.05). The findings from immunoelectron microscopy confirmed those from Western blotting. CONCLUSION: The histone deacetylase inhibitor, MS-275, can significantly alter the immune molecule content and categories in exosomes of hepatocarcinoma cells. The differential expression profile may reflect an anti-cancer immune response and represent molecular targets for novel anti-hepatoma therapeutic or preventative strategies.

[Effects of fluorouracil-induced Flt3 Ligand gene expression transcriptional regulated by Egr-1 promoter sequences].

AIM: To explore the regulatory effects of Egr-1 promoter sequences in transcriptional targeting by 5-fluorouracil(5-Fu) on the expression of hematopoietic growth factor genes. METHODS: The human Flt3 Ligand(FL) cDNA and the enhanced green fluorescent protein (EGFP) cDNA were linked with IRES and then inserted into the expression vector pCIneo under control of the Egr-1 promoter(Egr-EF). The vector was transferred into human bone marrow stromal cell line HFCL. The transfected cells (HFCL/EF) were exposed to the clinically important anticancer agent 5-fluorouracil. The activity of EGFP in HFCL/EF cells was detected by FACS. The expression of FL in HFCL/EF postchemotherapy was confirmed by ELISA, Western blot and RT-PCR, repectively. The effect of FL in HFCL/EF cultural supernatants on the expansion of CD34(+); cells and CFU-GM was studied. The effect of N-acetylcysteine (a free radical scavenger) on FL production following the exposure to 5-Fu was examined. RESULTS: The activity of EGFP and the amount of secreted FL in HFCL/EF cells exposed to 5-Fu increased compared to those in non-5-Fu group. The effects of FL in HFCL/EF cultural supernatants on the expansion of CD34(+); cells and CFU-GM were more significant than those of non-5-Fu group. N-acetylcysteine significantly decreased the concentration of FL produced by HFCL/EF treated with 5-FU. CONCLUSION: The therapy of hematopoietic growth factor gene regulated by Egr-1 promoter can protect hematopoiesis from 5-Fu injury.

[Effect of doxorubicin induced GM-CSF gene expression regulated by Egr-1 promoter on recovery of hematopoietic function in bearing-melanoma mice].

This study was purposed to investigate the effect of hematopoietic growth factor expression regulated by Egr-1 promoter on the recovery of hematopoietic function in bearing-melanoma mice after chemotherapy with doxorubicin (ADM). The human GM-CSF cDNA and enhanced green fluorescence protein (GFP) cDNA were linked together with internal ribozyme entry site (IRES) and then were inserted into the expression vector pCI-neo under control of the Egr-1 promoter (Egr-EG). This vector was transduced into human bone marrow stromal cell lines HFCL by lipofectamine and was transfused in severe combined immunodeficiency (SCID) mice. The experimental mice were randomly divided into 4 groups (6 mice in each group): (1) HFCL/EG + ADM group in which the HFCL/EG cells were transplanted intravenously in SCID mice bearing melanoma, ADM was given intraperitoneally after 3 days; (2) HFCL + ADM group in which the HFCL cells were transplanted intravenously, ADM was given intraperitoneally after 3 days; (3) HPCL/EG group in which HFCL/EG cells were transplanted alone; (4) HFCL group in which HFCL cells were transplanted alone. The dynamic change of peripheral blood picture was assayed by hemocytometer; the eGFP(+) human stromal cells were detected by flow cytometry; the expression of GM-CSF mRNA and protein were determined by RT-PCR and Western blot respectively. The results indicated that as compared with HFCL/EG and HFCL groups, the leukocyte count in HFCL/EG + ADM group decreased, but decrease level was weaker than that in HFCL + ADM group, meanwhile the recovery of leukocyte count was earlier than that in HFCL + ADM group. The CFU-GM amount between 4 groups showed no significant difference. The detection results showed that the inhibitory rate of tumor was related to chemotherapy, but not to expression of exogenous gene; the eGFP(+) stromal cells existed in bone marrow of mice treated with ADM. The RT-PCR and Western blot assays revealed enhancement of GM-CSF mRNA and protein. It is concluded that the ADM-inducible GM-CSF gene therapy regulated by Egr-1 promoter may promote the hematopoietic recovery after chemotherapy.

[Association of two polymorphisms in ubiquitin carboxy-terminal hydrolase-L1 gene with Parkinson's disease in Shanghai].

OBJECTIVE: To explore the relationship of polymorphisms in the ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) gene with Parkinson's disease(PD)in Shanghai Han Nationality. METHODS: The distribution of a Serine18Tyrosine polymorphism in exon 3(C/A) and a Serine89Phenylalanine polymorphism in exon 4(C/T)of UCH-L1 gene were detected in 164 PD cases and 172 healthy controls, using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) method. RESULTS: (1)The C allelic frequency in exon 3 of UCH-L1 gene in PD patients(62.2%) was significantly higher than that of the healthy controls(51.7%) (OR=1.53, P=0.006), as was the C/C genotype(OR=1.90, P=0.008). (2)There was no significant difference in the distribution of the C/T allele and genotypes in exon 4 between PD patients and healthy controls. CONCLUSION: The C allele in exon 3 of UCH-L1 gene might be one of the risk factors for PD in Shanghai Han Nationality, but the polymorphisms of C/T in exon 4 showed no association with the onset of PD.

[Dopamine beta hydroxylase gene polymorphism and Parkinson's disease].

OBJECTIVE: To investigate the correlation between the polymorphism of dopamine beta hydroxylase(DBH) gene and the susceptibility of Shanghai Chinese Han population to Parkinson's disease(PD). METHODS: Association study was performed in 144 PD patients and 188 healthy control subjects matched for age, sex and origin. Polymorphism of DBH gene was analyzed with polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The allelic frequency of A2 allele of DBH gene was significantly higher in PD patients than in controls(P<0.01).The risk of suffering from PD increased (OR=1.82) in the individual with A2 allele. And the genotypic frequency of A2/A2 was significantly higher in PD patients(OR=2.11, P<0.01),too. On the other hand, the allelic frequency of A1 allele and the genotypic frequency of A1/A2 genotype of DBH gene in PD patients were significantly lower(A1 alleles: OR=0.54, P<0.01; A1/A2 genotypes: OR=0.45, P<0.01). CONCLUSION: The polymorphism in DBH gene might play an important role in the susceptibility of Shanghai Chinese Han population to PD.