Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Imiquimod treated Basal Cell Carcinoma

ABSTRACT: Imiquimod is a Toll-like receptor (TLR)-7 agonist capable of inducing complete clearance of basal cell carcinoma (BCC) and other cutaneous malignancies. We hypothesized that the characterization of the early transcriptional events induced by imiquimod may provide insights about immunological events preceding acute tissue and/or tumor rejection. We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (N = 22) or vehicle cream (N=14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hrs for 4 or 8 days). RNA was amplified and hybridized to 17.5K cDNA arrays. All treatment schedules similarly affected the transcriptional profile of BCC; however, the q12 X 4days regimen, associated with highest effectiveness, induced the most changes with 637 genes unequivocally stimulated by imiquimod. A minority of transcripts (98 genes) confirmed previous reports of interferon-Â involvement. The remaining 539 genes portrayed additional immunological functions predominantly involving the activation of cellular innate and adaptive immune-effector mechanisms. Importantly, these effector signatures recapitulate previous observations of tissue rejection in the context of cancer immunotherapy, acute allograft rejection and autoimmunity. This study based on a powerful and reproducible model of cancer eradication by innate immune mechanisms provides the first insight in humans of the early transcriptional events associated with immune rejection. This model is likely representative of constant immunological pathways through which innate and adaptive immune responses combine to induce tissue destruction. Keywords: compound treatment design We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (N = 22) or vehicle cream (N=14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hrs for 4 or 8 days). RNA was amplified and hybridized to 17.5K cDNA arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Francesco Marincola

PROVIDER: E-GEOD-5121 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection.

Panelli Monica C MC Stashower Mitchell E ME Slade Herbert B HB Smith Kina K Norwood Christopher C Abati Andrea A Fetsch Patricia P Filie Armando A Walters Shelley-Ann SA Astry Calvin C Aricó Eleonora E Zhao Yingdong Y Selleri Silvia S Wang Ena E Marincola Francesco M FM

Genome biology 20070101 1

<h4>Background</h4>Imiquimod is a Toll-like receptor-7 agonist capable of inducing complete clearance of basal cell carcinoma (BCC) and other cutaneous malignancies. We hypothesized that the characterization of the early transcriptional events induced by imiquimod may provide insights about immunological events preceding acute tissue and/or tumor rejection.<h4>Results</h4>We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected t ...[more]

PMID: 17222352

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Project description:Abstract: Hematopoietic stem cells (HSCs) are used in transplantation therapy to reconstitute the hematopoietic system. Human cord blood (hCB) transplantation has emerged as an attractive alternative treatment option when traditional HSC sources are unavailable, however, the absolute number of hCB HSCs transplanted is significantly lower than bone marrow or mobilized peripheral blood stem cells (MPBSCs). We previously demonstrated that dimethyl-prostaglandin E2 (dmPGE2) increased HSCs in vertebrate models. Here, we describe preclinical analyses of the therapeutic potential of dmPGE2-treatment using human and non-human primate HSCs. dmPGE2 significantly increased total human hematopoietic colony formation in vitro and enhanced engraftment of unfractionated and CD34+ hCB following xenotransplantation. In non-human primate autologous transplantation, dmPGE2-treated CD34+ MPBSCs showed stable multilineage engraftment over one year post-infusion. Together, our analyses indicated that dmPGE2 mediates conserved responses in HSCs from human and non-human primates, and provided sufficient preclinical information to support proceeding to an FDA-approved phase 1 clinical trial. In order to identify the potential mechanism of action of dmPGE2 on gene expression and HSC function, and to possibly explain the muted response of rhesus CD34+ MPBSCs to dmPGE2 exposure, microarray gene expression analysis was conducted. Human and rhesus CD34+ MPBSCs were exposed to DMSO control or dmPGE2 at a dose of either 10 and 50 uM as described above, and processed for microarray analysis at 0, 2, 6, 12 and 24 hours post treatment. Four human donors contributed 8 to 10 samples each at varying time points and dosage for a total of 37 samples (2 samples were technical repeats). Six rhesus macaques contributed 3 to 9 samples each at varying time points and dosage for a total of 28 samples (4 samples were technical repeats). Pooled PBMC's from 6 donors aphereses were used as a reference sample.

Project description:Three experiments, corresponding to the three figures in the article, are represented in this set. Each experiment was an ex vivo treatment time course as described in the paper. For each of the experiments, mRNA was isolated at the indicated time points, cDNA was directly prepared by reverse transcription in the presence of Cy5-labeled dUTP, and the expression profiled using Cy3-labeled cDNA prepared by reverse transcription of Stratagene Universal Human Reference RNA as a control. One experiment, corresponding to Figure 1 in the paper, is a set of infection, or mock-infection time courses, in which each of three cell types: primary human dermal fibroblasts, primary human macrophages, or HELA cells were respectively infected with Monkeypox virus, Vaccinia virus, or Ebola virus, or mock-infected. Infected cells or mock-infected cells were harvested and lysed at the indicated times after infection and mRNA isolated for analysis following the protocol described above. The second experiment, corresponding to Figure 2 in the paper, is a set of treatments of human dermal fibroblasts, each in 24-well plates with either: PBS only (mock), interferon alpha (IFN-alpha) at 0.6 pM final concentration (Sigma, St. Louis, MO), tumor necrosis factor alpha (TNF-alpha) at 0.6 pM final concentration (Sigma), PMA at 25ng/mL final concentration plus ionomycin at 1micromolar final concentration, polyinosinic-polycytidylic acid as potassium salt (poly(I-C)) at 100 microg/mL final concentration (Sigma), Escherichia coli 055:B5 lipopolysaccharide (LPS) at 1microg/mL final concentration (Sigma), or dexamethasone at 1 micromolar final concentration (Sigma). Cells were harvested and lysed at the indicated times and mRNA isolated for analysis following the protocol described above. The third experiment, corresponding to Figure 3 in the paper, is a set of infections or mock-infections of human dermal fibroblasts, or human primary macrophages, with Monkeypox virus or Vaccinia virus, respectively, followed by treatment with either ionomycin + phorbol myristic acid (PMA) or with poly(I-C). The intention of the experiment was to investigate whether prior infection altered the response of the cells to the chemical agents. Cells were harvested and lysed at the indicated times and mRNA isolated for analysis following the protocol described above. Description of sample characteristics: Time: Time after infection or Mock infection Infection: Ebola-Zaire/killed Monkeypox Virus/Mock infection/Monkaypox Virus/None/Pre infection/Vaccinia NY/Vaccinia WR Compound Based Treatment: Dexamethasone/Interferon-alpha/Ionomycin + PMA/LPS/PBS/polyinosinic-polycytidylic acid/TNF-alpha Cell Type: Primary Human Dermal Fibroblast/Primary Human Macrophage/HeLa Figure in article: Numbers group slides that are represented in the same figure of the article. A stimulus or stress experiment design type is where that tests response of an organism(s) to stress/stimulus. e.g. osmotic stress, behavioral treatment

Dataset Information

Imiquimod treated Basal Cell Carcinoma

Publications

Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection.

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