Circ_0009910 promotes imatinib resistance through ULK1-induced autophagy by sponging miR-34a-5p in chronic myeloid leukemia.

BACKGROUND: The occurrence in drug resistance of chronic myeloid leukemia (CML) was accompanied by autophagy activation. Abnormal circular RNAs (circRNAs) participated in this progression. This study attempted to investigate the potential role of circ_0009910 in imatinib resistance of CML cells. METHODS: The expression of circ_0009910 and miR-34a-5p was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The characterization of circ_0009910 was investigated using oligo (dT)18 primers, Actinomycin D and RNase R. Cell viability (IC50 value) and apoptosis were assessed by Cell Counting Kit-8 (CCK8) assay and flow cytometry assay, respectively. The relative protein expression was quantified by western blot. The relationship among miR-34a-5p, circ_0009910 and ULK1 was predicted by online bioinformatics tool, and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP). RESULTS: The expression of circ_0009910 was up-regulated in the serum of imatinib-resistance CML patients and K562/R cells, and associated with unfavorable clinicopathologic features. Circ_0009910 in K562 and K562/R cells was mainly localized in the cytoplasm. Circ_0009910 knockdown inhibited cell proliferation and autophagy, but induced apoptosis in K562/R cells. Circ_0009910 targeted miR-34a-5p to regulate ULK1. MiR-34a-5p depression rescued the effects of circ_0009910 knockdown on apoptosis and autophagy in K562/R cells. CONCLUSION: Circ_0009910 accelerated imatinib-resistance in CML cells by modulating ULK1-induced autophagy via targeting miR-34a-5p, providing a potential target in imatinib resistance of CML.

Exosomes derived from oxLDL-stimulated macrophages induce neutrophil extracellular traps to drive atherosclerosis.

This study aimed to investigate the role and underlying mechanism of exosomes secreted by oxidized low-density lipoprotein (oxLDL)-stimulated macrophages in the progression of atherosclerosis (AS). Exosomes from peripheral blood of AS patients or oxLDL-treated macrophages were co-cultured with human neutrophils. Neutrophil extracellular traps (NETs) were detected by immunofluorescence staining. The levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). The expression levels of miR-146a and superoxide dismutase 2 (SOD2) were determined by quantitative real-time PCR (qRT-PCR) and western blot. The generation of intracellular reactive oxygen species (ROS) was observed by using dichlorofluorescin diacetate (DCFH-DA). ApoE-deficient mice were fed with high-fat diet (HFD) to induce AS. Atherosclerotic plaques were evaluated by Oil red O (ORO) and hematoxylin-eosin (HE) staining. Our results showed that miRNA-146a was enriched in serum-derived exosomes of AS patients and oxLDL-treated macrophage THP-1-derived exosomes. Importantly, exosomal miR-146a secreted by oxLDL-treated macrophages promoted ROS and NETs release via targeting SOD2. In addition, intravenous administration of oxLDL-treated THP-1 cells-derived exosomes into AS mice significantly deteriorated AS in vivo. Our findings indicate that exosomal miR-146a derived from oxLDL-treated macrophages promotes NETs formation via inducing oxidative stress, which might provide a novel scientific basis for the understanding of AS progression.

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients.

BACKGROUND: Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy. METHODS: A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system. RESULTS: Among these 17 poly-miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline-metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model). CONCLUSIONS: The data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy.

Diagnosis and Treatment of Vascular Surgery Related Infection.

Surgical site infection (SSI) is an important component of infections acquired from hospital. The most significant feature of vascular surgery different from other surgeries is frequent application of artificial grafts. Once SSI occurs after vascular operations with grafts, it might results in a serious disaster. Staphylococcus aureus and coagulase-negative Staphylococcus are the most common pathogenic bacteria for SSI after vascular surgery. Although SSI in vascular surgery often lacks of typical clinical characters, some clinical symptoms, laboratory data and certain imaging procedures may help to diagnose. In most cases of SSI after vascular procedures, the artificial grafts must be removed and sensitive antibiotics should be administered. However, for different cases, personalized management plan should be made depending on the severity and location of SSI.

Risk factors for operative morbidity and mortality in gastric cancer patients undergoing total gastrectomy.

AIM: To study the risk factors for morbidity and mortality following total gastrectomy. METHODS: We retrospectively reviewed the records of 125 consecutive patients who underwent total gastrectomy for gastric cancer at the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2003 and March 2008. RESULTS: The overall morbidity rate was 20.8% (27 patients) and the mortality rate was 3.2% (4 patients). Morbidity rates were higher in patients aged over 60 [odds ratio (OR) 4.23 (95% confidence interval (CI) 1.09 to 12.05)], with preoperative comorbidity [with vs without, OR 1.25 (95% CI 1.13 to 8.12)], when the combined resection was performed [combined resection vs total gastrectomy only, OR 2.67 (95% CI 1.58 to 5.06)]. CONCLUSION: Age, preoperative comorbidity and combined resection were independently associated with the rate of morbidity after total gastrectomy for gastric cancer.