Filters
Technology
Platform
GSE74407
Homo sapiens
9 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
The Epidermal Growth Factor Receptor (EGFR)/ligand system is centrally involved in multiple homeostatic functions of the epithelia. Epithelial cells are the primary targets of humanized antibodies and small molecule inhibitors against this system, whereby the constellation of skin-specific side effects of these drugs stems from a profound disturbance of keratinocyte biology. So far, the molecular mechanisms underlying these toxic events have been investigated only broadly. Here we show that keratinocyte response to anti-EGFR drugs comprises the development of a type 1 interferon (IFN) molecular signature including enhanced expression of IFN-kappa. Mechanistically, nuclear accumulation of IRF1 precedes this signature as well as the enhanced expression of a chemokine cluster we previously identified as a relevant pro-inflammatory component of EGFR inhibition. In fact, either silencing of IRF1 transcript expression, or antibody-mediated blockade of type 1 IFN receptor function and consequent abrogation of STAT1 activation, leads to impairment of this gene transcription profile. High levels of IRF1 and IFN-kappa can be clearly observed in the early skin lesions of patients treated with cetuximab. Type 1 IFN signaling could be crucially implicated in the triggering of the inflammatory mechanisms active in the skin of patients under treatment with anti-EGFR drugs.
Publication Title
Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 54 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P .0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL.
Publication Title
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P .0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL.
Publication Title
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Combination of platinum-based chemotherapy and radiation is currently the standard treatment for locally advanced lung cancer patients. However, therapeutic resistance to these therapies may arise from the presence of cancer stem cells (CSCs). To investigate the CSCs hypothesis of chemo-radiation resistance, we used microarray assay to profile CSCs-like cisplatin-resistant lung cancer cells (CDDP-R) versus its parental cells. CDDP-R cells were established by exposing H460 lung cancer cells to 3M cisplatin for 7 days, followed by 0.8% methylcellulose selection over 14 consecutive days.We found that CDDP-R cells expressed higher levels of stem cell markers, including CD133 and ALDH. They are more resistant to cisplatin- and etoposide-induced apoptosis and to high radiation dose (20Gy). Clonogenic assays suggest that CDDP-R cells were more resistant to radiation than parental H460 cells (DER=1.21, p<0.01). Xenograft studies suggest that CDDP-R cells were more tumorigenic (p<0.001). Microarray and comprehensive protein interaction networks analyses revealed IGFBP3 as a highly ranked hub protein which plays an important role in the mechanism of cisplatin resistance. We found reduced level of IGFBP3 and enhanced IGFR-1 activation upon IGF stimulation in CDDP-R cells. The specific targeting of IGF-1R using siRNA resulted in significant sensitization of CDDP-cells (DER=1.17, p<0.05) to radiation compared with the parental H460 cells. Our findings suggest that CDDP-R cells have the characteristics of CSCs and constitute a suitable model to study lung CSCs. Profiling of CSCs-like H460 cells led to the identification of IGF as an important pathway for chemo- and radiotherapy resistance in lung cancer.
Publication Title
Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Extracellular-regulated kinases (ERK1/2 and 5) are known to play important roles in growth and drug resistance of various cancers. Here we show roles of inhibition of ERK1, ERK2, or ERK5 on gene expression profiles of epithelioid malignant mesothelioma (MM) cells (HMESO).
Publication Title
Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Neutrophil recruitment is pivotal to host defense against microbial infection, but also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by bioinformatic pathways analysis of the gene expression profiles in the skin lesions of leprosy. In erythema nodosum leprosum (ENL), which occurs in patients with lepromatous leprosy (L-lep), and is characterized by neutrophil infiltration in lesions, the most overrepresented biologic functional group was 'cell movement' including E-selectin, which was coordinately regulated with IL-1beta. In vitro activation of TLR2, upregulated in ENL lesions, triggered induction of IL-1beta, which together with IFN-gamma, induced E-selectin expression on, and neutrophil adhesion to endothelial cells. Thalidomide, an effective treatment for ENL, inhibited this neutrophil recruitment pathway. The gene expression profile of ENL lesions comprised an integrated pathway of TLR2/FcR activation, neutrophil migration and inflammation, providing insight into mechanisms of neutrophil recruitment in human infectious disease.
Publication Title
Integrated pathways for neutrophil recruitment and inflammation in leprosy.
Sample Metadata Fields
Specimen part
View Samples- Macaca mulatta, Mus musculus, Homo sapiens, Rattus norvegicus
- 46 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip, Illumina ratRef-12 v1.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Aging is a complex phenomenon involving functional decline in multiple physiological systems. We focused on skeletal muscle to identify pathways that modulate function and healthspan by global expression profiles and specific mechanisms fundamental to aging processes. Our experimental design integrated comparative analysis of mice, rats, rhesus monkeys and humans and targeted three key time points during their lifespans. Pathways related to oxidative stress, inflammation and nutrient signaling, which function collectively to affect the quality and status of mitochondria, emerged across all species with age. Notably, mitochondrial transcript levels were better preserved in aging human muscle, suggesting an evolution-driven fitness more robust than in other species. The identification of these conserved pathways uncovers common molecular mechanisms intrinsic to health and lifespan, while unveiling of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.
Publication Title
Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.
Sample Metadata Fields
Sex, Specimen part
View Samples- Rattus norvegicus
- 15 Downloadable Samples
- Illumina ratRef-12 v1.0 expression beadchip
Description
Aging is a complex phenomenon involving functional decline in multiple physiological systems. We focused on skeletal muscle to identify pathways that modulate function and healthspan by global expression profiles and specific mechanisms fundamental to aging processes. Our experimental design integrated comparative analysis of mice, rats, rhesus monkeys and humans and targeted three key time points during their lifespans. Pathways related to oxidative stress, inflammation and nutrient signaling, which function collectively to affect the quality and status of mitochondria, emerged across all species with age. Notably, mitochondrial transcript levels were better preserved in aging human muscle, suggesting an evolution-driven fitness more robust than in other species. The identification of these conserved pathways uncovers common molecular mechanisms intrinsic to health and lifespan, while unveiling of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.
Publication Title
Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.
Sample Metadata Fields
Sex, Specimen part
View Samples