Bioinformatics study of the TNFRSF1A mechanism involved in acute liver injury in sepsis through the mTOR signaling pathway.

OBJECTIVES: This study analyzed potential key genes involved in the mechanism of acute liver injury induced by sepsis through bioinformatics techniques, aiming to provide novel insights for the identification of early-stage sepsis-induced acute liver injury and its diagnosis. METHODS: Gene chip data sets containing samples from acute liver injury induced by sepsis and control groups (GSE22009 and GSE60088) were selected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) with |log fold change| >1 and p<0.05 were screened with the GEO2R tool, which was also used for the selection of upregulated DEGs in the chips with p<0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology, and protein-protein interaction (PPI) analyses were then conducted. Results were visualized using R language packages, including volcano plots, Venn diagrams, and boxplots. The intersection of candidate genes with relevant genes in the Comparative Toxicogenomics Database (CTD) was performed, and the clinical significance of these genes was explored through a literature review. A rat model of acute liver injury was developed by inducing sepsis with the cecum ligation and puncture method. Real-time PCR was performed to determine the gene expression in rat liver tissues. RESULTS: A total of 646 upregulated DEGs were determined in GSE22009 and 146 in GSE60088. A Venn diagram was used to find the intersection of the upregulated DEGs between the two data sets, and 67 DEGs associated with sepsis-mediated acute liver damage were obtained. Enrichment analysis from the KEGG pathway showed that DEG upregulation was primarily associated with various pathways: TNF, NF-κB, IL-17, ferroptosis, mTOR, and JAK-STAT signaling pathways. DEGs resulted in three clusters and 15 candidate genes, as revealed by the PPI network and module analyses. Intersection with sepsis-induced acute liver injury-related genes in the CTD resulted in the identification of three significant differentially co-expressed genes: CXCL1, ICAM1, and TNFRSF1A. Sepsis-induced liver tissue indicated the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA, as compared with the control group (p<0.05). CONCLUSION: The key genes identified and related signaling pathways provided insights into the molecular mechanisms of sepsis-induced acute liver injury. In vivo studies revealed the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA in sepsis-mediated injured liver tissues, providing a theoretical basis for early diagnosis and targeted treatment research.

Clinical characteristics and prognostic risk factors of candidemia in non-neutropenic patients: a retrospective cohort study.

This study aimed to determine the clinical characteristics and the prognostic risk factors in non-neutropenic patients with candidemia. Data were retrospectively collected through the medical record information system. Non-neutropenic patients with candidemia were relatively aged, with a more than one-third rate of in-hospitalization mortality. In multivariate analysis, APACHE II score (adjusted odds ratio [aOR], 1.138; 95% confidence interval [CI], 1.067-1.213), septic shock (aOR, 5.704; 95% CI, 2.639-12.326) and RRT (aOR, 16.152; 95% CI, 2.628-99.275) (all P < 0.01) were independent related with non-survivors. In conclusion, non-neutropenic patients with candidemia have a high in-hospitalization mortality, and APACHE II, septic shock, and RRT are independently factors.

Incidence, clinical characteristics, risk factors and outcomes of patients with mixed Candida/bacterial bloodstream infections: a retrospective study.

PURPOSE: The mixed Candida/bacterial bloodstream infections (mixed C/B-BSIs) is worthy of particular attention recently, and we analyzed the incidence, co-pathogens, clinical characteristics, risk factors, and outcomes of mixed C/B-BSIs compared with monomicrobial candidemia (mono-candidemia) in adult patients in China. METHODS: All hospitalized adults with candidemia were recruited for this retrospective observational study from January 1, 2013, to December 31, 2019. RESULTS: Of the 296 patients with candidemia, 78 cases (26.3%) were mixed C/B-BSIs. Candida albicans (C. albicans) was the most common Candida species among all candidemia, and Klebsiella pneumoniae (K. pneumoniae) was the most concomitant bacteria (30.6%), followed by Acinetobacter baumannii (A. baumannii) (12.9%) and Enterococcus faecium (E. faecium) (11.8%) in mixed C/B-BSIs. In the multivariable analysis, prior ß-lactams exposure [adjusted odds ratio (aOR), 1.97; 95% confidence interval (CI), 1.01-3.87], burn injury (aOR, 6.35; 95% CI 1.82-22.21) and continuous renal replacement therapy (CRRT) (aOR, 3.00; 95% CI 1.46-6.17) were independent risk factors for mixed C/B-BSIs. Compared with mono-candidemia, patients with mixed C/B-BSIs developed with more proportion of septic shock (55.1% vs. 39.9%, P < 0.05), prolonged stay in ICU [22.0(12.0-57.0) vs. 9.5(0.0-37.0) days, P < 0.001] and longer mechanical ventilation time [19.0(4.5-40.8) vs. 6.0(0.0-24.8) days, P < 0.001]. The in-hospital mortality in patients with mixed C/B-BSIs was higher than those with mono-candidemia (59.0% vs. 34.9%, P < 0.001). Survival analysis revealed that 28-day and 60-day mortality were significantly higher in patients with mixed C/B-BSI than in those with mono-candidemia (57.7% vs. 31.7%, P < 0.001; 59.0% vs. 34.9%, P < 0.001; respectively). CONCLUSIONS: There is a high rate of mixed C/B-BSIs cases among candidemia, and K. pneumoniae is the predominant coexisting species. Prior ß-lactams exposure, burn injury, and CRRT are independent risk factors for mixed C/B-BSIs. The mortality of patients with mixed C/B-BSIs is significantly higher than those with mono-candidemia, this deserves further attention for clinicians.

Clinical Features, Strain Distribution, Antifungal Resistance and Prognosis of Patients with Non-albicans Candidemia: A Retrospective Observational Study.

PURPOSE: Candida albicans (C. albicans) candidemia has been well reported in previous studies, while research on non-albicans Candida (NAC) bloodstream infections remains poorly explored. Therefore, the present study aimed to investigate the clinical characteristics and outcomes of patients with NAC candidemia. PATIENTS AND METHODS: We recruited inpatients with candidemia from January 2013 to June 2020 in a tertiary hospital for this retrospective observational study. RESULTS: A total of 301 patients with candidemia were recruited in the current study, including 161 (53.5%) patients with NAC candidemia. The main pathogens in NAC candidemia were Candida tropicalis (C. tropicalis) (23.9%), Candida parapsilosis (15.6%) and Candida glabrata (10.3%). Patients with NAC candidemia had more medical admissions (P=0.034), a higher percentage of hematological malignancies (P=0.007), a higher frequency of antifungal exposure (P=0.012), and more indwelling peripherally inserted central catheters (P=0.002) than those with C. albicans candidemia. In a multivariable analysis, prior antifungal exposure was independently related to NAC candidemia (adjusted odds ratio [aOR], 0.312; 95% confidence interval [CI], 0.113-0.859). Additionally, NAC was obviously resistant to azoles, especially C. tropicalis had a high cross-resistance to azoles. However, no significant differences were noted in the mortality rates at 14 days, 28 days and 60 days between these two groups. CONCLUSION: NAC is dominant in candidemia, and prior antifungal exposure is an independent risk factor. Of note, although the outcomes of NAC and C. albicans candidemia are similar, drug resistance to specific azoles as well as cross-resistance frequently occurs in patients with NAC candidemia, and this drug resistance deserves attention in clinical practice and further in-depth investigation.

Clinical characteristics, risk factors and outcomes of mixed Candida albicans/bacterial bloodstream infections.

PURPOSE: The purpose of this study was to explore the clinical features, risk factors, and outcomes of mixed Candida albicans/bacterial bloodstream infections (mixed-CA/B-BSIs) compared with monomicrobial Candida albicans bloodstream infection (mono-CA-BSI) in adult patients in China. METHODS: All hospitalized adults with Candida albicans bloodstream infection (CA-BSI) were recruited for this retrospective observational study from January 1, 2013, to December 31, 2018. RESULTS: Of the 117 patients with CA-BSI, 24 patients (20.5%) had mixed-CA/B-BSIs. The most common copathogens were coagulase-negative Staphylococcus (CNS) (24.0%), followed by Klebsiella pneumoniae (20.0%) and Staphylococcus aureus (16.0%). In the multivariable analysis, a prior ICU stay > 2 days (adjusted odds ratio [OR], 7.445; 95% confidence interval [CI], 1.152-48.132) was an independent risk factor for mixed-CA/B-BSIs. Compared with patients with mono-CA-BSI, patients with mixed-CA/B-BSIs had a prolonged length of mechanical ventilation [17.5 (4.5, 34.8) vs. 3.0 (0.0, 24.5), p = 0.019] and prolonged length of ICU stay [22.0 (14.3, 42.2) vs. 8.0 (0.0, 31.5), p = 0.010]; however, mortality was not significantly different. CONCLUSIONS: There was a high rate of mixed-CA/B-BSIs cases among CA-BSI cases, and CNS was the predominant coexisting species. A prior ICU stay > 2 days was an independent risk factor for mixed -CA/B-BSIs. Although there was no difference in mortality, the outcomes of patients with mixed -CA/B-BSIs, including prolonged length of mechanical ventilation and prolonged length of ICU stay, were worse than those with mono-CA-BSI; this deserves further attention from clinicians.

Correlation between nitric oxide content in exhaled breath condensate and the severity of acute respiratory distress syndrome.

Nitric oxide (NO) can induce necrosis and detachment of branchial epithelium, aggregate inflammation and induce acute respiratory distress syndrome (ARDS). The detection of NO in exhaled breath condensate (EBC) has not been widely applied in evaluating ARDS condition. This study thus tested NO in EBC of ARDS patients, in order to provide non-invasive method to monitor disease condition of ARDS. ARDS patients in ICU of our hospital were recruited in parallel with healthy controls. NO contents in EBC and serum were measured in both control group and ARDS patients before/after treatment, and between survived and dead patients. APACHE II score, PaO2/FiO2, and PaO2 were also quantified and analyzed for their correlation with NO contents. Correlation between EBC and serum NO contest was also analyzed. ARDS patients had significantly higher EBC/serum NO contents before treatment compared to control. NO levels were remarkably decreased after treatment (P<0.05). Survival patients had decreased APACHEII score, and EBC/serum NO, plus elevated PaO2/FiO2, and PaO2 after treatment. Dead patients had elevated APACHEII score, EBC/serum NO with prolonged treatment, plus decreased PaO2/FiO2, and PaO2 (P<0.05). EBC/serum NO in ARDS patients were positively correlated with APACHE II score, and negatively correlated with PaO2/FiO2, and PaO2 (P<0.05). NO level in EBC was positively correlated with serum level in ARDS patients (P<0.05). The detection of EBC NO content can reflect hypoxia and disease condition of ARDS patients, and benefits treatment efficacy evaluation and prognostic judgement. EBC NO can replace serum NO due to satisfactory correlation.

NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation.

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKß phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKß phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury.