Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary.
Memory T cells specific for murine cytomegalovirus re-emerge after multiple challenges and recapitulate immunity in various adoptive transfer scenarios.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion.
Specimen part, Cell line
View SamplesGene-expression in siRNA treated U2OS and hTERT-RPE1 cells showed that CASP8AP2, NPAT and HINFP do not regulate expression of each other, and do not have any common target genes, except histones. Most histone genes are downregulated in U2OS cells following loss of CASP8AP2, NPAT or HINFP. In normal cells, highly-expressed histone genes were downregulated, albeit less than in tumor cells following loss of CASP8AP2. The p53 target genes were upregulated relatively late, clearly after the changes in expression of histone genes were observed.
Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion.
Cell line
View SamplesThe tumor suppressor p53 can induce various biological responses. Yet it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using ChIP-seq (deposited in Sequence Read Archive database as SRP007261) revealed p53 default program, i.e. the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, RITA or 5-FU in breast cancer cells, despite different biological outcomes triggered by these compounds. Parallel analysis of gene expression allowed identification of 280 previously unknown p53 target genes, including p53-repressed AURKA. The consensus p53 binding motif was present more frequently in p53-induced, than in repressed targets, indicating different mechanisms of gene activation versus repression. We identified several possible cofactors of p53, and found that STAT3 antagonised p53-mediated repression of a subset of genes, including AURKA. Finally, we showed that the expression of the novel p53 targets correlates with p53 status and survival in breast cancer patients.
Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis.
Cell line, Treatment
View SamplesHMG-CoA reductase inhibitors, statins, have beneficial vascular effects beyond their cholesterol-lowering action. These pleiotropic effects include an anti-inflammatory effect on macrophages. Since macrophages play a central role in atherogenesis, we further characterized the effects on peripheral blood monocyte-macrophages (HPBM). Using Affymetrix gene chip analysis of simvastatin-treated HPBM, we found that simvastatin treatment lead to the downregulation of the expression of many proinflammatory genes including several chemokines (e.g. MCP-1, MIP-1 alpha and , RANTES, several other CC and CXC chemokines, IL-2 receptor-, and leukemia inhibitory factor), members of the tumor necrosis factor family (e.g. lymphotoxin beta and TRAIL), VCAM-1, ICAM-3, and tissue factor (TF). Simvastatin also modulated the expression of several transcription factors essential for the inflammatory response: simvastatin downregulated the expression of NF-kappaB relA/p65 subunit and ets-1 transcription factor, and upregulated the expression of a novel atheroprotective transcription factor, Kruppel-like factor 2 (KLF-2). The effects of simvastatin on KLF-2 and its target genes were dependent on protein prenylation, since inhibitors of protein prenylation had a similar inhibitory effect in THP-1 derived macrophages. Additionally, by lentiviral overexpression KLF-2 we showed that the effect of simvastatin on MCP-1 and TF were dependent on KLF-2. We concluded that simvastatin had a strong anti-inflammatory effect on macrophages, which includes upregulation of the atheroprotective transcription factor KLF-2. These findings further explain the beneficial pleiotropic effects of statins on cardiovascular diseases.
Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2.
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View SamplesMost hepatocellular carcinomas in younger patients from Peru arise from non-cirrhotic livers. Histological examination of the non-tumor liver tissues highlights the presence of clear cell foci in a significant fraction of Peruvian patients with hepatocellular carcinoma.
Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America.
Specimen part, Disease stage, Subject
View SamplesDespite widespread use of sunscreens that minimize erythema by blocking ultraviolet B (UVB) radiation, incidence rates of melanoma continue to rise. In considering this disparity between intervention and disease prevalence, we investigated the in vivo transcriptome of human skin treated with sunscreen and solar-simulated radiation (ssR). A focal skin area of healthy participants was exposed to ssR at 1 minimal erythema dose (MED), 0.1 MED or 100 J/m2 with or without prior application of sunscreen, or to non-UVB-spectrum of ssR (solar-simulated UVA/visible/infrared radiation: ssA). Skin biopsies were analyzed using expression microarrays.
Transcriptional signatures of full-spectrum and non-UVB-spectrum solar irradiation in human skin.
Sex, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.
Specimen part, Cell line
View SamplesWe report the dual role of FoxA1 in androgen receptor recruitment to the chromatin of androgen responsive prostate cancer cell line LNCaP-1F5 using ChIP-sequencing. Depletion of FoxA1 reprograms both androgen and glucocorticoid receptor recruitment and subsequent gene expression. The ChIP-seq has been performed using AR, FoxA1, GR, H3K4me2 antibodies. We have also mapped the DNaseI-hypersensitive sites (DHS) using deep sequencing.
Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.
Cell line
View SamplesGene expression analysis of BJhTERT RhoA-KO and PC3 mRFP was performed before and after six days confrontation in co-cultivation. Analyses of original and control fibroblasts was also performed.
RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo.
Specimen part
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