A RBM47 and IGF2BP1 mediated circular FNDC3B-FNDC3B mRNA imbalance is involved in the malignant processes of osteosarcoma.

BACKGROUND: Circular RNAs (circRNAs) are a class of noncoding RNAs that are involved in the progression of many human cancers. The precise gene locus and the roles of circular RNA from Fibronectin type III domain containing 3B (FNDC3B) in OS and its mechanisms of action have not been fully explored. MATERIALS AND METHODS: qRT-qPCR assay was used to determine gene expressions. CCK8 Assay, EdU assay, wound-healing assay, transwell invasion assay and in vivo xenograft assay were used to perform functional investigations. RNA-FISH, immunofluorescence, RIP assay, RNA stability analysis were applied in mechanistic studies. RESULTS: We found that circFNDC3B downregulated and FNDC3B mRNA upregulated in OS, and might be potential biomarkers for indicating disease progression and prognosis of OS patients. CircFNDC3B acted as a tumor suppressor gene to restrain OS progression and FNDC3B functioned as an oncogene to promote OS progression in vitro and in vivo. RNA binding protein RNA binding motif protein 47 (RBM47) could bind to the flanking introns of circFNDC3B to facilitate the generation of circFNDC3B, resulting in the reduction of FNDC3B mRNA and the circFNDC3B-FNDC3B mRNA imbalance. CircFNDC3B also inhibited FNDC3B mRNA expression by reducing its stability via competitively binding to Insulin-like growth-factor-2 mRNA binding protein (IGF2BP1). CONCLUSION: This study demonstrated that RBM47 and IGF2BP1 mediated circular FNDC3B/FNDC3B mRNA imbalance was involved in the malignant processes of OS.

Microbiota-driven interleukin-17 production provides immune protection against invasive candidiasis.

BACKGROUND: The intestinal microbiota plays a crucial role in human health, which could affect host immunity and the susceptibility to infectious diseases. However, the role of intestinal microbiota in the immunopathology of invasive candidiasis remains unknown. METHODS: In this work, an antibiotic cocktail was used to eliminate the intestinal microbiota of conventional-housed (CNV) C57/BL6 mice, and then both antibiotic-treated (ABX) mice and CNV mice were intravenously infected with Candida albicans to investigate their differential responses to infection. Furthermore, fecal microbiota transplantation (FMT) was applied to ABX mice in order to assess its effects on host immunity against invasive candidiasis after restoring the intestinal microbiota, and 16S ribosomal RNA gene sequencing was conducted on fecal samples from both uninfected ABX and CNV group of mice to analyze their microbiomes. RESULTS: We found that ABX mice displayed significantly increased weight loss, mortality, and organ damage during invasive candidiasis when compared with CNV mice, which could be alleviated by FMT. In addition, the level of IL-17A in ABX mice was significantly lower than that in the CNV group during invasive candidiasis. Treatment with recombinant IL-17A could improve the survival of ABX mice during invasive candidiasis. Besides, the microbial diversity of ABX mice was significantly reduced, and the intestinal microbiota structure of ABX mice was significantly deviated from the CNV mice. CONCLUSIONS: Our data revealed that intestinal microbiota plays a protective role in invasive candidiasis by enhancing IL-17A production in our model system.

Corrigendum: Carbapenem-Resistant E. cloacae in Southwest China: Molecular Analysis of Resistance and Risk Factors for Infections Caused by NDM-1-Producers.

[This corrects the article DOI: 10.3389/fmicb.2018.00658.].

Carbapenem-resistant and cephalosporin-susceptible Pseudomonas aeruginosa: a notable phenotype in patients with bacteremia.

PURPOSE: Pseudomonas aeruginosa is recognized as a major cause of severe and potentially life-threatening infection. However, P. aeruginosa isolates with the phenotype of being carbapenem resistant and cephalosporin susceptible (Carb-R/Ceph-S) have not been thoroughly characterized to date. The aim of this study was to assess the mechanisms, risk factors, and clinical impact of Carb-R/Ceph-S P. aeruginosa bacteremia on mortality. PATIENTS AND METHODS: We conducted a retrospective case-case-control study of the risk factors and clinical outcomes of hospitalized patients with Carb-R/Ceph-S P. aeruginosa bacteremia from 2011 to 2017 in Chongqing, China. Case patients infected with Carb-R/Ceph-S P. aeruginosa, carbapenem-susceptible and cephalosporin-susceptible (Carb-S/Ceph-S) P. aeruginosa, and controls with no P. aeruginosa bacteremia were compared at a ratio of 1:1:2. Real-time reverse transcription polymerase chain reaction was performed to assess resistance mechanisms. A multivariate logistic regression model was performed to investigate several potential predictors for mortality. RESULTS: We collected 63 Carb-R/Ceph-S P. aeruginosa isolates during the study period. None of these isolates possessed carbapenemase or extended-spectrum ß-lactamase-encoding genes. The overall 30-day mortality rate was 27.0%. Real-time reverse transcription polymerase chain reaction analysis showed that an overexpression of efflux systems and decreased expression of OprD were associated with Carb-R/Ceph-S P. aeruginosa. Multivariate analysis indicated that 30-day readmission, central venous catheters, and exposure to carbapenems were unique independent predictors for acquiring Carb-R/Ceph-S P. aeruginosa bacteremia. Additionally, hematologic malignancy was a peculiar predictor for Carb-S/Ceph-S P. aeruginosa bacteremia. Notably, total parenteral nutrition was the only common factor of both Carb-R/Ceph-S and Carb-S/Ceph-S groups compared to controls. In a multivariate analysis for the outcome, intensive care unit admission and septic shock were identified as the independent predictors for mortality. CONCLUSION: Our findings can potentially improve the ability of physicians to identify the high-risk patients, and carbapenems were noted to potentially increase the risk of Carb-R/Ceph-S P. aeruginosa. Additionally, cephalosporin should be considered a valuable therapeutic option for such cases of bacteremia.

Clinical characteristics and predictors of mortality in patients with candidemia: a six-year retrospective study.

Although candidemia has been reported globally, little is known about the differences in candidemia episodes between ICU and surgical wards or the correlation between serum biomarkers and mortality from candidemia. A retrospective study of hospitalized patients with candidemia was conducted in southwest China. A total of 198 non-duplicate candidemia episodes were identified between January 2011 and December 2016. Candida albicans was the leading species causing candidemia (34.9%), and 78.8% of these isolates were susceptible to fluconazole. More than half of candidemic patients were hospitalized in surgical wards, but the incidence of these surgical patients was much lower than that of ICU patients. Compared with surgical patients, patients admitted to ICU were more frequently subjected to extensive invasive procedures, severe clinical presentations, and heavy exposure to antibiotics. In addition, the mortality in ICU was significantly higher than that in surgical wards. Multivariable analysis revealed that ascites, catheter-related candidemia, ICU admission, septic shock, and concomitant bacterial infection were independent factors associated with mortality. Moreover, we observed that high PCT and BDG levels as well as low PLT counts were also associated with mortality from candidemia. Better understanding of the specific predictors in different wards could facilitate the identification of high-risk candidates to receive early antifungal therapy, thus improving the outcomes of critically ill patients with candidemia.

Carbapenem-Resistant E. cloacae in Southwest China: Molecular Analysis of Resistance and Risk Factors for Infections Caused by NDM-1-Producers.

Carbapenem-resistant Enterobacteriaceae (CRE) has been considered a serious global threat, but carbapenem resistance remains relatively uncommon in E. cloacae, especially in China. The aim of this study was to characterize carbapenem-resistant E. cloacae (CR-ECL) isolates from 2012 to 2016 in Southwest China. Our study revealed that 20 (15.2%) of the 132 CR-ECL isolates obtained from patients were identified as NDM-1, with most isolates carrying the IncFIIA plasmids. Notably, we initially observed that the E. cloacae strain co-harbored NDM-1 and IMP-8 carbapenemases simultaneously. Analysis of the genetic environment of these two genes has revealed that the highly conserved regions (blaNDM-1-bleMBL-trpF-tat) are associated with the dissemination of NDM-1, while IS26, intI1, and tniC could be involved in the spread of IMP-8. Molecular epidemiology studies showed the nosocomial outbreak caused by NDM-1-producing E. cloacae ST88. Transferring from another hospital and previous carbapenem exposure were identified as independent risk factors for the acquisition of NDM-1-producing E. cloacae. These findings emphasize the need for intensive surveillance and precautions to monitor the further spread of NDM-1 in China.

Up-regulation of chemokine CXCL13 in systemic candidiasis.

Candida albicans is the leading cause of healthcare associated bloodstream infections. Chemokine CXCL13 is well-known involved in inflammation, but its role in candidemia has not been assessed. Our study firstly demonstrated that serum CXCL13 levels were significantly elevated in candidemic patients compared with bacteremic patients and control subjects by ELISA, and CXCL13 concentrations were positively and significantly correlated with clinical Sequential Organ Failure Assessment (SOFA) scores and several laboratory parameters in patients. Moreover, ROC curve analysis showed the diagnostic efficiency of CXCL13 was superior to CRP and PCT. To further study the role of CXCL13, a mouse model was established. Importantly, the data showed the dramatically elevated levels of CXCL13 in mice serum and infected kidney, were significantly correlated with renal fungal burden and pathology scores. In conclusion, our results indicated that CXCL13 had strong potential as a novel biomarker of diagnosis and prognosis for candidemia.

Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections.

Heteroresistance is common in a variety of microbes, however carbapenem heteroresistance among invasive Pseudomonas aeruginosa infections has not been thoroughly characterised to date. The objective of this study was to investigate the mechanisms, molecular epidemiology and risk factors for invasive carbapenem-heteroresistant P. aeruginosa (CHPA) infections between 2011 and 2015 in Chongqing, China. A significant increase in the rates of heteroresistance to imipenem and meropenem was observed during the study period. Mechanistic analysis revealed that efflux system overexpression and decreased OprD could have contributed to carbapenem heteroresistance in P. aeruginosa. It was also observed that all of the subpopulations produced enhanced levels of biofilm compared with their native strains. Moreover, previous carbapenem exposure was identified as a common independent risk factor for imipenem-heteroresistant (IPM-HR) and meropenem-heteroresistant (MEM-HR) isolates, but patients infected with MEM-HR isolates were at higher risk of poor outcomes than those with IPM-HR isolates. Most importantly, there was a remarkable increase in the prescription of carbapenems during the study period, which was demonstrated to correlate significantly with the quarterly increasing prevalence of IPM-HR and MEM-HR isolates, respectively. These findings show the necessity of routine detection of carbapenem-heteroresistant strains and that strict control of carbapenem use is critical to reduce CHPA infections in hospitalised patients.

IL-27/IL-27 Receptor Signaling Provides Protection in Clostridium difficile-Induced Colitis.

Background: Clostridium difficile is a leading cause of nosocomial infection. The role of cytokine interleukin-27 (IL-27) in the immunopathology of C. difficile infection (CDI) remains unknown. Methods: The production of IL-27 was determined in human and murine CDI. Furthermore, wild-type (WT) and IL-27 receptor-deficient (WSX-1-/-) mice were treated with an antibiotic mixture and infected with C. difficile to investigate the effects of IL-27 on host response to CDI. Results: IL-27 production was elevated during CDI in humans and mice. Infected WSX-1-/- mice experienced increased weight loss, enhanced colonic histology damage, less C. difficile clearance, and decreased survival compared to WT controls during CDI. IL-27 administration reduced CDI-associated mortality and tissue pathology with improved C. difficile clearance in WT mice after C. difficile challenge. Mechanistically, IL-27-mediated host defense against CDI was associated with downregulation of IL-17A and IL-23, but upregulation of IL-10 and interferon-gamma during CDI. Conclusions: Our data suggest a previously unrecognized role for IL-27 in the pathogenesis of CDI, potentially providing new insight for IL-27-mediated protection against C. difficile-induced pathology.

Chemokine CXCL13 expression was up-regulated in Clostridium difficile infection.

Clostridium difficile infection (CDI) is the leading cause of antibiotic- and healthcare-associated diarrhea. CXCL13 is a well-known CXC chemokine involved in inflammation, but its role in CDI remains unknown. In this study, serum and fecal samplings were collected from 51 CDI patients, 50 diarrhea patients without CDI and 50 healthy control subjects to determine the CXCL13 levels by enzyme-linked immunosorbent assay (ELISA). Besides, a mouse model of C. difficile infection was established, and murine serum and colon tissues were collected for detection of CXCL13 expression using quantitative real-time RT-PCR, ELISA, Western blot, or immunohistochemistry. We found that CXCL13 concentration in serum and fecal samples from CDI patients was significantly higher compared with that from diarrhea patients without CDI and that from healthy controls. Elevated serum CXCL13 positively and significantly correlated with blood markers of inflammation and yielded an increased area under the ROC curve of 0.929. In murine C. difficile infection, CXCL13 were also dramatically increased in serum and infected colon tissues at the transcriptional and protein levels. The elevated CXCL13 levels positively and significantly correlated with inflammatory scores. Therefore, CDI is associated with enhanced release of CXCL13. This study indicated that CXCL13 may be pathogenically involved in CDI and served as a potential new biomarker for diagnosis and prognosis in CDI.