Head and neck squamous cell carcinoma (HNSCC) is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies for HNSCC and the understanding of its biology both depend upon clinically relevant animal models. An increasingly promising xenograft model, the patient derived xenograft (PDX), is developed by surgically implanting tumor tissue directly from a patient into an immunocompromised mouse. We transplanted 30 HNSCC primary tumors directly into mice. The histology and stromal components were analyzed using immunohistochemistry. Gene expression analysis with Affymetrix U133A-microarrays was conducted on patient tumors, including third generation and one tenth generation PDX; one PDX-derived cell line; and 2 established HNSCC cell lines. Five of 30 (17%) transplanted tumors could be serially passaged and used for therapeutic and mechanistic studies. One cell line has been established from a tongue primary. The tumors maintained the histologic appearance of the parent tumor although human stromal components were lost upon engraftment. One PDX model was derived from an HPV-positive tumor. From the >54,000 probes tested, there were widespread differences in gene expression between the tumors growing in mice vs. the corresponding human tumors from which they were derived. For genes differing between parent tumors and human cell lines in culture, the PDXs expression pattern was very similar to that of the parent tumors. There were also widespread expression differences between the human tumors that subsequently grew in mice vs. those that did not - suggesting that this model enriches for cancers with distinct biological features. Our results demonstrate the feasibility of a PDX model of HNSCC. Gene expression patterns suggest that the PDX more closely recapitulated the parental tumor than do cells in culture. The histology of the tumors in mice is similar to that of the same tumor in humans. Additionally, gene expression patterns and histology are stable over multiple generations.
Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers.
Specimen part, Cell line
View SamplesTissue injury, such as incisional wound, results in an inflammatory response as well as acute to chronic mechanical and thermal pain. It is now understood that there is a strong contribution of these immune cells to the pain phenotype.
CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity.
Sex, Age
View SamplesWe have established that BMP6 is an important endogenous regulator of human osteoblast differentiation. Our preliminary experiment showed that 8 hour BMP6 treatment induced early osteoblast markers in hMSC.
GAGE: generally applicable gene set enrichment for pathway analysis.
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View SamplesThe root epidermis of Arabidopsis provides a simple and experimentally useful model for studying the molecular basis of cell fate and differentiation. The goal of this study was to define the transcript changes in the root epidermis of mutants associated with root epidermis cell specification, including mutants that lack a visible phenotypic alteration (try, egl3, myb23, and ttg2). Transcript levels were assessed by purifying populations of root epidermal cells using fluorescence-based cell-sorting with the WER::GFP transgene. These microarray results were used to compare the effects of single and double mutants on the gene regulatory network that controls root epidermal cell fate and differentiation in Arabidopsis.
Tissue-specific profiling reveals transcriptome alterations in Arabidopsis mutants lacking morphological phenotypes.
Specimen part
View SamplesGlioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFR and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of PDGFR and the analysis of GBM signaling pathways using proteomics. We discovered the tubulin-binding protein Stathmin1 (STMN1) as a PDGFR phospho-regulated target and that this mis-regulation conferred selective sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFR GBMs with VB in mice drastically prolonged survival and was dependent on STMN1. Our work provides a rationale for evaluating genotype-specific anti-microtubule drugs as cancer treatment in select GBM patient populations.
A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine.
Specimen part, Treatment
View SamplesThe transcriptional responses of human hosts towards influenza viral pathogens are important for understanding virus-mediated immunopathology. Despite great advances gained through studies using model organisms, the complete temporal host transcriptional responses in a natural human system are poorly understood. In a human challenge study using live influenza (H3N2/Wisconsin) viruses, we conducted a clinically uninformed (unsupervised) factor analysis on gene expression profiles and established an ab initio molecular signature that strongly correlates to symptomatic clinical disease. This is followed by the identification of 42 biomarkers whose expression patterns best differentiate early from late phases of infection. In parallel, a clinically informed (supervised) analysis revealed over-stimulation of multiple viral sensing pathways in symptomatic hosts and linked their temporal trajectory with development of diverse clinical signs and symptoms. The resultant inflammatory cytokine profiles were shown to contribute to the pathogenesis because their significant increase preceded disease manifestation by 36 hours. In subclinical asymptomatic hosts, we discovered strong transcriptional regulation of genes involved in inflammasome activation, genes encoding virus interacting proteins, and evidence of active anti-oxidant and cell-mediated innate immune response. Taken together, our findings offer insights into influenza virus-induced pathogenesis and provide a valuable tool for disease monitoring and management in natural environments.
Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection.
Specimen part
View SamplesAs rats do not develop neuropathic pain like hypersensitivity as neonates post nerve injury but do as adults we have used these arrays to help define the processes involved in this process.
T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity.
Specimen part, Treatment
View SamplesThe root epidermis of Arabidopsis provides a simple and experimentally useful model for studying the molecular basis of cell fate and differentiation. The goal of this study was to define the larger gene regulatory network that governs the differentiation of the root hair and non-hair cell types of the Arabidopsis root epidermis. Transcript levels in the root epidermis of wild-type and mutant lines were assessed by purifying populations of root epidermal cells using fluorescence-based cell-sorting. Further, the role of the plant hormones auxin and ethylene on root epidermis development was assessed by defining transcript levels in the root epidermis of plants grown on media containing IAA or ACC. These microarray results were used to construct a comprehensive gene regulatory network that depicts the transcriptional control of root epidermal cell fate and differentiation in Arabidopsis.
A gene regulatory network for root epidermis cell differentiation in Arabidopsis.
Specimen part
View SamplesThe goal of this study was to analyze global gene expression in specific populations of nociceptor sensory neurons, the neurons that detect damaging/noxious stimuli.
Bacteria activate sensory neurons that modulate pain and inflammation.
Specimen part
View SamplesThe goal of this study was to analyze global gene expression in specific populations of somatosensory neurons in the periphery, including major, non-overlapping populations that include nociceptors, pruriceptors, and prorioceptors. The mammalian somatosensory nervous system encodes the perception of specific environmental stimuli. The dorsal root ganglion (DRG) contains distinct somatosensory neuron subtypes that innervate diverse peripheral tissues, mediating the detection of thermal, mechanical, proprioceptive, pruriceptive, and nociceptive stimuli. We purified discrete subtypes of mouse DRG somatosensory neurons by flow cytometry using fluorescently labeled mouse lines (SNS-Cre/TdTomato, Parv-Cre/TdTomato) in combination with Isolectin B4-FITC surface staining (IB4). This allowed identification of transcriptional differences between these major populations, revealing enrichment of voltage-gated ion channels, TRP channels, G-protein coupled receptors, transcription factors, and other functionally important classes of genes within specific somatosensory neuron subsets.
Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity.
Specimen part
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