Prolonged Transcriptional Consequences in Survivors of Sepsis.
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ABSTRACT:
SUBMITTER: Laudanski K
PROVIDER: S-EPMC8196560 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3677 genes, biological pathway analysis identified 86 genes significantly down-regulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis including lymphocyte depletion, reduced T lymphocyte activation and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of down-regulation found in non-survivors compared to survivors. The results show that whole blood gene-expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression based assay, to assess immunosuppression and guide immunotherapy in future clinical trials. Daily PAXgene samples for up to 5 days for sepsis survivors (n=26), sepsis nonsurvivors (n=9), and healthy controls (n=18).
2014-02-04 | E-GEOD-54514 | biostudies-arrayexpress
Project description:Sepsis is a life-threatening condition with high hospital mortality. Elevated mortality has also been observed in patients after hospital discharge, associated with post sepsis syndrome (PSS), causing systemic impairments and reduced life quality. The etiology of PSS is still not completely known but certainly involves inflammation. Extracellular vesicles (EV) are recognized as a notable mechanism of intercellular communication in inflammatory processes. It has been reported that EV microRNA (miRNA) production patterns during the acute phase of the disease may persist until after sepsis resolution and are associated with PSS. Methods: We employed mass spectrometry and qPCR to characterize the protein and miRNA composition of plasma-derived EVs of 35 patients during sepsis-related hospitalization and after discharge (post-sepsis) for up to three years. Findings: Fifteen differentially expressed EVs miRNAs (DEMiRs) were identified in septic patients compared to the control group. Predictive analyses revealed that these DEMiRs could influence inflammation by modulating pathways mediated by the activation of NF-κB, STAT3, and TLR4. Thirteen miRNAs (-15b-5p, -16-5p, -20a-5p, -25-3p, -27a-3p, -29a-3p, -30d-5p, -93-5p, -146a-5p, -148a -3p, -191-5p, -195-5p, -223-3p) were downregulated in the death group compared to the survivor group and are candidates for serving as prognostic markers of survival in the Intensive Care Unit. The expression of 11 miRNAs (-15b-5p, -16-5p, -21-5p, -25-3p, -27a-3p, -29a-3p, -30d-5p, -93-5p, -146a-5p -195- 5p and -223-3p) was lower one year after ICU discharge than the control group. Interpretation: The miRNAs identified in the present study represent potential biomarkers for the survival prognosis of post-sepsis patients.
2022-08-03 | GSE210335 | GEO
Project description:There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3677 genes, biological pathway analysis identified 86 genes significantly down-regulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis including lymphocyte depletion, reduced T lymphocyte activation and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of down-regulation found in non-survivors compared to survivors. The results show that whole blood gene-expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression based assay, to assess immunosuppression and guide immunotherapy in future clinical trials.
2014-02-04 | GSE54514 | GEO
Project description:Millions of sepsis survivors annually face long-term neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered in sepsis, and their use affects neuropsychiatric outcomes, but the mechanisms are unknown. We used the cecal ligation and puncture method to induce acute infection in mice and test the hypothesis that corticosteroid treatment during illness has long-term effects on hippocampal function. Functional phenotyping and hippocampal RNA-sequencing were performed in the same survivor mice to identify underlying mechanisms of behavioral and neuroendocrine outcomes. Long-term CLP survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal (HPA) axis activity, and persistent systemic and neuro-inflammation. The relationship between gene expression and behavior suggested a protective role for inflammation and oxidative metabolism after CLP. Corticosterone treatment during illness had distinct effects on hippocampal function in survivors, including object memory impairment. The long-term behavioral effects of corticosterone treatment were associated with persistent downregulation of activity-dependent gene expression in the hippocampus. The results suggest that corticosteroid treatment for sepsis influences hippocampal function in survivors via long-lasting changes to basal hippocampal activity. Neural activity, inflammation, and oxidative metabolism should be explored as future treatment targets to modify neuropsychiatric outcomes in sepsis survivors.
2023-07-31 | GSE225868 | GEO
Project description:Many survivors after trauma suffer from long-term morbidity. The aim of this observational cohort study was to develop a prognostic prediction tool for early assessment of full-time sick leave one year after trauma. Potential predictors were assessed combining individuals from a trauma register with national health registers. Two models were developed using logistic regression and stepwise backward elimination. 4458 individuals were included out of which 488 were on sick leave full-time 12 months after the trauma. One comprehensive and one simplified model were developed including nine and seven predictors respectively. Both models showed excellent discrimination (AUC 0.81). The comprehensive model had very good calibration, and the simplified model good calibration. Prediction models can be used to assess post-trauma sick leave using injury-related variables as well as factors not related to the trauma per se. Among included variables, pre-injury sick leave was the single most important predictor for full-time sick leave one year after trauma. These models could facilitate a more efficient use of resources, targeting groups for follow-up interventions to improve outcome. External validation is necessary in order to evaluate generalizability.
| S-EPMC6329751 | biostudies-literature
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.
| S-EPMC3411958 | biostudies-literature
Project description:Sepsis remains a major cause of death despite advances in medical care. Metabolic deregulation is an important component of the survival process. Metabolomic analysis allows profiling of critical metabolic functions with the potential to classify patient outcome. Our prospective longitudinal characterization of 33 septic and non-septic critically ill patients showed that deviations, independent of direction, in plasma levels of lipid metabolites were associated with sepsis mortality. We identified a coupling of metabolic signatures between liver and plasma of a rat sepsis model that allowed us to apply a human kinetic model of mitochondrial beta-oxidation to reveal differing enzyme concentrations for medium/short-chain hydroxyacyl-CoA dehydrogenase (elevated in survivors) and crotonase (elevated in non-survivors). These data suggest a need to monitor cellular energy metabolism beyond the available biomarkers. A loss of metabolic adaptation appears to be reflected by an inability to maintain cellular (fatty acid) metabolism within a "corridor of safety".
| S-EPMC7711192 | biostudies-literature
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. Herein we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it to either human cells stimulated in vitro with LPS or to the blood cells of septic patients. 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 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 upregulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes upregulated in mouse cells stimulated with LPS are enriched in genes upregulated 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.
| S-EPMC8776114 | biostudies-literature
Project description:In principle, the generation, transmission, and dissipation of supercoiling forces are determined by the arrangement of the physical barriers defining topological boundaries and the disposition of enzymes creating (polymerases and helicases, etc.) or releasing (topoisomerases) torsional strain in DNA. These features are likely to be characteristic for individual genes. By using topoisomerase inhibitors to alter the balance between supercoiling forces in vivo, we monitored changes in the basal transcriptional activity and DNA conformation for several genes. Every gene examined displayed an individualized profile in response to inhibition of topoisomerase I or II. The expression changes elicited by camptothecin (topoisomerase I inhibitor) or adriamycin (topoisomerase II inhibitor) were not equivalent. Camptothecin generally caused transcription complexes to stall in the midst of transcription units, while provoking little response at promoters. Adriamycin, in contrast, caused dramatic changes at or near promoters and prevented transcription. The response to topoisomerase inhibition was also context dependent, differing between chromosomal or episomal c-myc promoters. In addition to being well-characterized DNA-damaging agents, topoisomerase inhibitors may evoke a biological response determined in part from transcriptional effects. The results have ramifications for the use of these drugs as antineoplastic agents.
| S-EPMC100007 | biostudies-literature
Project description:RationaleAlthough caregiver burden is well described in chronic illness, few studies have examined burden among caregivers of survivors of critical illness. In existing studies, it is unclear whether the observed burden is a consequence of critical illness or of preexisting patient illness.ObjectivesTo describe 1-yr longitudinal outcomes for caregivers of patients who survived critical illness, and to compare depression risk between caregivers of patients with and without pre-intensive care unit (ICU) functional dependency.MethodsProspective, parallel, cohort study of survivors of prolonged (greater than 48 h) mechanical ventilation and their informal caregivers. Caregivers were divided into two cohorts on the basis of whether patients were functionally independent (n = 99, 59%), or dependent (n = 70, 41%) before admission. Functional dependency was defined as dependency in one or more activities of daily living or in three or more instrumental activities of daily living. Patient and caregiver outcomes were measured 2, 6, and 12 mo after mechanical ventilation initiation.Measurements and main resultsWe studied three caregiver outcomes: depression risk, lifestyle disruption, and employment reduction. Most patients were male (59.8%), with a mean (SD) age of 56.6 (19.0) yr. Caregivers were mostly female (75.7%), with a mean (SD) age of 54.6 (14.7) yr. Prevalence of caregiver depression risk was high at all time points (33.9, 30.8, and 22.8%; p = 0.83) and did not vary by patient pre-ICU functional status. Lifestyle disruption and employment reduction were also common and persistent.ConclusionsDepression symptoms, lifestyle disruption, and employment reduction were common among informal caregivers of critical illness survivors. Depression risk was high regardless of patient pre-ICU functional status.
| S-EPMC1899280 | biostudies-literature