Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.
CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray.
Specimen part
View SamplesUsing PAXgene tubes, peripheral blood samples were collected from seven patients >18 years with documented pdm(H1N1) influenza, bilateral chest infiltrates, and in need of ventilation support. Significant co-morbidity was exclusion criterion. Expression profiles were compared with 7 age matched controls. Using a false discovery rate < 5% and an absolute fold change > 2, 370 genes were differentially expressed in case and controls.
Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza.
Sex, Age, Specimen part, Subject
View SamplesThe identifcation of alternatively spliced transcript variants specific to particular biological processes in tumours should increase our understanding of cancer. Hypoxia is an important factor in cancer biology and associated splice variants may present new markers to help with planning treatment. A method was developed to analyse alternative splicing in exon array data, using probeset multiplicity to identify genes with changes in expression across their loci, and a combination of the splicing index and a new metric based on the variation of reliability weighted fold changes to detect changes in the splicing patterns. The approach was validated on a cancer/normal sample dataset in which alternative splicing events had been confirmed using RT-PCR. We then analysed ten head and neck squamous cell carcinomas using exon arrays and identified differentially expressed splice variants in five samples with high versus five with low levels of hypoxia-associated genes (Winter et al, 2007; Cancer Res 67:3441-9). The analysis identified a splice variant of LAMA3 (Laminin 3), LAMA3-A, known to be involved in tumour cell invasion and progression. The full-length transcript of the gene (LAMA3-B) did not appear to be hypoxia-associated. The results were confirmed using qualitative real time PCR. In a series of 59 prospectively-collected head and neck tumours (Winter et al, 2007; Cancer Res 67:3441-9), expression of LAMA3-A had prognostic significance whereas LAMA3-B did not. This work illustrates the potential for alternatively spliced transcripts to act as biomarkers of disease prognosis with improved specificity for particular tissues or conditions over assays which do not discriminate between splice variants.
Exon array analysis of head and neck cancers identifies a hypoxia related splice variant of LAMA3 associated with a poor prognosis.
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View SamplesTo identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment.
Specific extracellular matrix remodeling signature of colon hepatic metastases.
Sex, Age, Specimen part, Subject
View SamplesPathological bone changes differ considerably between inflammatory arthritic diseases, and most studies have focused on bone erosion. Collagen Induced Arthritis (CIA) is a model for Rheumatoid Arthritis, which, in addition to bone erosion, demonstrates bone formation at the time for clinical manifestations. The objective of this study was to use the CIA model to study bone remodelling by performing a gene expression profiling time-course study on the CIA model.
Kinetics of gene expression and bone remodelling in the clinical phase of collagen-induced arthritis.
Specimen part
View SamplesWe have investigated the initial responses in human lung tissue explants to Mtb infection, focusing primarily on gene expression patterns in different tissue resident innate cell types Overall design: Cells sorted from uninfected and infected lung tissue (24 hrs. post infection)
<i>Mycobacterium tuberculosis</i> Invasion of the Human Lung: First Contact.
Specimen part, Subject
View SamplesWe have investigated the initial responses in human lung tissue explants to Mtb infection, focusing primarily on gene expression patterns in different tissue resident innate cell types Overall design: Cells sorted from uninfected and infected lung tissue (24 hrs. post infection)
<i>Mycobacterium tuberculosis</i> Invasion of the Human Lung: First Contact.
Specimen part, Subject
View SamplesFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. In order to advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells (PBMCs) from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with 2.5-fold difference in expression (P = 0.05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, pro-apoptotic proteins, and B- and T-cell differentiation were down-regulated in patients with FHL. Genes associated with the canonical pathways of IL-6, IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of anti-apoptotic proteins were overexpressed in patients with FHL. This, first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underly the immunobiology of FHL.
Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis.
Specimen part
View SamplesSarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis.
Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis.
Specimen part, Disease, Race
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.
Sex, Age
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