Unknown,Transcriptomics,Genomics,Proteomics

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Whole blood gene expression in Vietnamese dengue patients

ABSTRACT: Dengue is a pan-tropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. Predicting patients who may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host-transcriptional features in 24 DSS patients and 56 sex-, age-, virus serotype-matched uncomplicated dengue patients. In the first instance we defined the âearly dengueâ profile. The transcriptional signature in acute versus convalescent samples (â¤72hrs post illness-onset) was defined by an over-abundance of interferon-inducible transcripts (31% of the 551 over-abundant transcripts), and canonical gene ontology terms that included response to virus, immune response, innate immune response and inflammatory response. Pathway and network analysis identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB and SP1 as key transcriptional factors mediating the early response. Strikingly, the only differences in the transcriptional signatures of early DSS and uncomplicated dengue cases was the greater abundance of several neutrophil-associated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil-degranulation (BPI, ELA2, DEF1A). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also the genotype of the infecting virus, as genome-length sequences of DENV-1 (n=15) and DENV-2 (n=3) viruses sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV-1 and 9 DENV-2). Collectively, these data suggest an hitherto unrecognised association between neutrophil activation, pathogenesis and the development of DSS and point to future strategies for guiding prognosis. 112 patients: 80 with uncomplicated dengue, 32 with dengue shock syndrome

ORGANISM(S): Homo sapiens

SUBMITTER: Bruce Birren

PROVIDER: E-GEOD-25001 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated âtissue slice graftsâ (TSGs) as an improved tumorgraft model of RCC. Experimental Design: Cores of fresh RCC were precision-cut at 300-Î¼m and implanted under the renal capsule of RAG2-/-Î³C-/- mice. Engraftment rate, histology, biomarker expression, genetic fidelity and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a non-invasive method to measure tumor volume, and response to a targeted therapy was determined. Results: All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified non-invasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and VHL status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared to controls. Conclusions: The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared to other preclinical platforms. Three pairs of tissue slice graftes and parent tumors were included in the study. Tissue slice grafts and parent tumors were preserved in Allprotect tissue reagent (Qiagen, Valencia, CA) at -20Â°C prior to RNA extraction using an AllPrep DNA/RNA/Protein Mini Kit (Qiagen, Valencia, CA). The quality of RNA was determined using an Agilent 2100 Bioanalyzer (Agilent Biotechnologies, Santa Clara, CA). Microarray hybridization was performed using Illumina Human HT-12 v4 Beadchips (Illumina Inc., San Diego, CA) according to the manufacturerâs directions. Expression data was rank invariant normalized using BeadStudio software (Illumina Inc.).

Project description:Ongoing, lifelong neurogenesis maintains the neuronal population of the olfactory epithelium in the face of piecemeal neuronal turnover and restores it following wholesale loss. The molecular phenotypes corresponding to different stages along the progression from multipotent globose basal cell (GBC) progenitor to differentiated olfactory sensory neuron are poorly characterized. We used the transgenic expression of GFP and cell surface markers to FACS-isolate Sox2-GFP(+) GBCs, Neurog1-GFP(+) GBCs and immature neurons, and OMP-GFP(+) mature neurons from normal adult mice. In addition, the latter two populations were also collected 3 weeks after olfactory bulb ablation, a lesion that results in persistently elevated neurogenesis. Global profiling of mRNA from the populations indicates that all stages of neurogenesis share a cohort of >2100 genes that are upregulated compared to sustentacular cells. A further cohort of >1200 genes are specifically upregulated in GBCs as compared to sustentacular cells and differentiated neurons. The increased rate of neurogenesis caused by olfactory bulbectomy had little effect on the transcriptional profile of the Neurog1-GFP(+) population. In contrast, the abbreviated lifespan of OMP-GFP(+) neurons born in the absence of the bulb correlated with substantial differences in gene expression as compared to the mature neurons of the normal epithelium. Detailed examination of the specific genes upregulated in the different progenitor populations revealed that the chromatin modifying complex proteins LSD1 and coREST were expressed sequentially in upstream Sox2-GFP(+) GBCs and Neurog1-GFP(+) GBCs/immature neurons. The expression patterns of these proteins are dynamically regulated after activation of the epithelium by methyl bromide lesion. Total RNA was isolated from dissected, dissociated and FACS-purified olfactory mucosal cells from normal adult mice or mice 3 weeks after unilateral bulbectomy. Cells were purified with FACS using endogenous GFP fluorescence from various transgenic lines and cell surface labeling. Two to seven adult mice were used per replicate and three replicates per condition were performed using Illumina bead arrays. 21 samples from olfactory mucosa were analyzed in this series and 3 samples were from a commercially available reference RNA sample. Universal mouse reference RNA from Stratagene was used as a general control and Normal olfactory mucosa was used as a tissue specific control.

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Whole blood gene expression in Vietnamese dengue patients

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