Introduction: Sepsis is a complex immunological response to infection characterized by early hyperinflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on SIRS differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing.
Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis.
Specimen part
View SamplesSummary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or desease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function.
Gene profiling in spinal cord injury shows role of cell cycle in neuronal death.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.
Sex, Specimen part
View SamplesTranscriptomic comparison of 5 cell types during lethal and non-lethal influenza infection and further use of these signatures in a top-down systems analysis investigating the relative pathogenic contributions of direct viral damage to lung epithelium vs. dysregulated immunity during lethal influenza infection.
A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.
Sex, Specimen part
View SamplesBackground: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation.
A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts.
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View SamplesAngiogenesis is essential for tissue development, wound healing and tissue perfusion, with its dysregulation linked-to tumorigenesis, rheumatoid arthritis and heart disease. Here we show pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RI subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RI knock-in mice fully resistant to PKA disulphide-activation have deficient angiogenesis in models of hind limb ischaemia and tumour-implant growth. Disulphide-activation of PKA represents a new therapeutic target in diseases with aberrant angiogenesis.
Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice.
Specimen part
View SamplesMyeloid Angiogenic Cells (MACs) were infected with the intracellular, bacterial pathogen Bartonella henselae (B.h.). Infected cells were seeded onto Matrigel coated plates. While uninfected cells showed no phenotypic changes and died over time, infected cells showed strong phenotypic changes and developed into complex 2D chord networks over the course of long term culture (eg 49d). To examine the changes in gene expression associated with the development of the B.h.dependent chord formation phenotype, RNA was isolated from MACs shortly after isolation (d4) and from cells of the chord structures (+B.h. Matrigel). As primary endothelial cells are also know to form chord networks when cultured on Matrigel, a sample of human umbilical vein endothelial cells (HUVECs) cultured on Matrigel for 12hr was also included in the analysis as a control.
Reprogramming of myeloid angiogenic cells by Bartonella henselae leads to microenvironmental regulation of pathological angiogenesis.
Specimen part, Subject, Time
View SamplesThe study was designed to identify differential expressed genes between human oral cavity carcinoma cell lines with and without LDBI knockout Overall design: Three parental human oral cavity carcinoma cell lines were used as control, LDB1 was knocked out in the three parent cell lines to create KO cell lines.
LIM-Only Protein 4 (LMO4) and LIM Domain Binding Protein 1 (LDB1) Promote Growth and Metastasis of Human Head and Neck Cancer (LMO4 and LDB1 in Head and Neck Cancer).
No sample metadata fields
View SamplesWe compared the aorta of 6-weeks-old mice (young) with 18-months-old mice (old). Using the publicly available tools Sylamer and DIANA-mirExTra, we identified an enrichment for miR-29 binding sites in the 3'UTR of genes downregulated in the aged aortas. We subsequently showed that inhibition of miR-29 in aged mice prevented dilation of the aorta.
MicroRNA-29 in aortic dilation: implications for aneurysm formation.
Age, Specimen part
View SamplesEnsuring cooperation among formerly autonomous cells has been a central challenge in the evolution of multicellular organisms. One solution is monoclonality, but this option does not eliminate genetic and epigenetic variability, leaving room for exploitative behavior. We therefore hypothesized that embryonic development must be protected by robust regulatory mechanisms that prevent aberrant clones from superseding wild-type cells. Using a genome-wide screen in murine induced pluripotent stem cells, we identified a network of genes (centered on p53, topoisomerase 1, and olfactory receptors) whose downregulation caused the cells to replace wild-type cells, both in vitro and in the mouse embryowithout perturbing normal development. These genes thus appear to fulfill an unexpected role in fostering cell cooperation.
Safeguards for cell cooperation in mouse embryogenesis shown by genome-wide cheater screen.
Specimen part, Treatment
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