ABSTRACT: Enhanced performance of next-generation sequencing diagnostics compared to standard of care microbiological diagnostics in patients suffering from septic shock
Project description:Sepsis and septic shock remain leading causes of morbidity and mortality for patients in Intensive care unit. In their early phase, immune cells produce various cytokines which lead to the prompt activation of the immune system. Polymorphonuclear leukocytes (PMNs) respond to different signals producing inflammatory factors and executing their antibacterial mechanisms, resulting in the engulfment and elimination of invading pathogens. However, long-term activation caused by various inflammatory signals produced during sepsis progression, can lead to the alteration of PMN signaling and subsequent defects in their functionality. Here we analyzed the PMNs samples from 34 patients in septic shock, we focused on PMNs gene expression and proteome changes caused by septic shock. We reveal that, compared to those of patients who survived, PMNs from patients who had a fulminant outcome were characterized by a dysfunctional hyper-activation, showing an altered metabolism, higher longevity and recent exit from cell cycle. We believe that this multi-omics approach, although limited, served to pinpoint the alterations in PMNs’ functionality, which may be reverted by targeted treatments.
Project description:Septic shock is the most common cause of death in intensive care units. The aim of this study is to investigate the role of circular RNA (circRNA) and mRNA expression profiles and functional networks in aortic tissue of septic shock.
Project description:Septic shock is the most common cause of death in intensive care units. The aim of this study is to investigate the role of circular RNA (circRNA) and mRNA expression profiles and functional networks in aortic tissue of septic shock.
Project description:Normal children, children with SIRS, children with sepsis, and children with septic shock. Objectives: To advance our biological understanding of pediatric septic shock, we measured the genome-level expression profiles of critically ill children representing the systemic inflammatory response syndrome (SIRS), sepsis, and septic shock spectrum. Experiment Overall Design: Prospective observational study involving microarray-based bioinformatics.
Project description:Normal children, children with SIRS, children with sepsis, and children with septic shock. Objectives: To advance our biological understanding of pediatric septic shock, we measured the genome-level expression profiles of critically ill children representing the systemic inflammatory response syndrome (SIRS), sepsis, and septic shock spectrum. Keywords: Normal vs diseased
Project description:The peripheral whole-blood transcriptome analysis has been used to the identification of biomarkers in different clinical syndromes. The ability to simultaneously measure the gene expression levels of the whole transcriptome is providing a broader view of clinical syndromes such as sepsis. The aim of this study was to assess the gene expression profiles of post-surgical patients with septic shock compared with patients without sepsis.
Project description:Gene expression changes in the blood was studied by RNAseq Results: Strong differences between patients groups, specific expression changes for heathy control (Hlty), uncomplicated infection (Inf1_P), sepsis (Seps_P), septic shock (Shock_P), follow-up of sepsis (Seps_FU), follow-up of septic shock (Shock_FU) groups.
Project description:Sepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which can compromise outcome. Even taking the latest clinical and scientific research data into account, the immunosuppressive events occurring during a septic episode are incompletely understood. Moreover, there is a lack of data on the way epigenetics can modulate immunosuppression, which in turn affects patient survival. To advance current understanding of the mechanisms underlying immunosuppression, in this study we explored DNA methylation changes using the Infinium MethylationEPIC v1.0 BeadChip Kit in leukocytes from patients suffering from sepsis, septic shock, and critically ill patients as controls, within the first 24 h after admission in the Intensive Care Unit of a tertiary hospital. The top 100 differentially methylated positions (DMPs) between septic shock and critically ill patients enabled us to clearly distinguish between the 3 groups of patients. Interestingly, the top 6,657 DMPs were associated with organ dysfunction and lactate levels. Two different analysis approaches (based on the use of DMRcate and mCSEA) comparing septic shock and critically ill patients revealed a total of 1,256 differentially methylated regions (DMRs) involved in critical immune system-related pathways. Among the individual genes exhibiting significant differential methylation, IL10, TREM1, IL1B, and TNFAIP8 showed the largest methylation differences among the different groups when analyzing their methylation levels by DNA bisulfite pyrosequencing. Our findings indicate that DNA methylation profile undergoes the most substantial changes in patients with septic shock, and that these changes are linked to disease severity. Importantly, IL10 and S100A8, which are closely related to immunosuppression, were hypomethylated in septic shock patients.
Project description:Mortality due to sepsis remains unacceptably high, especially for septic shock patients. Murine models have been used to better understand pathophysiology mechanisms. However, the mouse model is still under debate. Here we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it with that of human cells stimulated in vitro with LPS on the one hand, and with that of blood cells in septic patients on the other hand. We identified a molecular signature composed of 2331 genes with an FDR median of 0%. This molecular signature is highly enriched in regulated genes in peritoneal macrophages stimulated with LPS. There is a significant enrichment in several inflammatory signaling pathways, and in disease terms, such as pneumonia, sepsis, systemic inflammatory response syndrome, severe sepsis, an inflammatory disorder, immune suppression, and septic shock. A significant overlap between the genes up-regulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes up-regulated in mouse cells stimulated with LPS are enriched in genes up-regulated in human cells stimulated in vitro and in septic patients, who are at high risk of death. Our results support the hypothesis of common molecular and cellular mechanisms between mouse and human sepsis.
