Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in systemic form after disease establishment. Skin samples were taken at the start of treatment and after 12 weeks.
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in topical form after disease establishement. Skin samples were taken at the start of treatment and after 12 weeks.
Project description:The C3H/HeJ grafted model of alopecia areata was used to determine the efficacy of systemic baricitinib at preventing alopecia or treating established disease. The efficacy of topical baricitinib at treating established alopecia in the C3H/HeJ grafted model was also assessed. Microarrays were performed on skin RNA at week 0 and week 12 after starting treatment in all models. Baricitinib was administered in systemic form at the time of grafting. Skin samples were taken after 12 weeks.
Project description:RNA expression profiling was carried out for systemic sclerosis (scleroderma) on skin biopsies obtained from both diffuse scleroderma (dcSSc) and limited scleroderma (lcSSc) subjects patients and compared to normal subjects. The patient group comprised of 4 dcSSc and 2 lcSSc subjects, all of whom were Caucasian and belonged to the age range of 42-73 (Mean age = 61.6). Patient sample set consisted of 3 females and 3 males. Race matched female volunteers from the same geographical area were recruited as controls (n = 4) and belonged to the age range of 41-62 (Mean age = 52).
Project description:Background: Psoriasis is a chronic disease characterized by the development of scaly red skin lesions and possible co-morbid conditions. The psoriasis lesional skin transcriptome has been extensively investigated, but mRNA levels do not necessarily reflect protein abundance. Methods: Lesional (PP) and uninvolved (PN) skin samples from 14 patients were analyzed using high-throughput complementary DNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: We identified 4122 differentially expressed genes (DEGs) along with 748 differentially expressed proteins (DEPs). Global shifts in mRNA were modestly correlated with changes in protein abundance (r = 0.40). We identified similar numbers of increased and decreased DEGs, but 4-fold more increased than decreased DEPs. Ribosomal subunit and translation proteins were elevated within lesions, without a corresponding shift in mRNA expression (RPL3, RPS8, RPL11). We identified 209 differentially expressed genes/proteins (DEGPs) with corresponding trends at the transcriptome and proteomic levels. Most DEGPs were similarly altered in at least one other skin disease. Psoriasis-specific and non-specific DEGPs had distinct cytokine-response patterns, with only the former showing disproportionate induction by IL-17A in cultured keratinocytes. Conclusions: Our findings reveal global imbalance between the number of increased and decreased proteins in psoriasis lesions, consistent with heightened translation. This effect could not have been discerned from mRNA profiling data alone. We have also identified high-confidence DEGPs and shown that only those most specific to psoriasis are enriched with IL-17A targets. RNA-seq-based comparison between gene expression in psoriasis lesions and uninvolved skin from 14 patients
Project description:mRNA array analysis was carried out using total RNA of skin biopsies from lesional and non-lesional skin of three atopic dermatitits patients and four healthy individuals.
Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival. Study was comprised of three experimental groups (pre-treatment, response, escape). All tumors came from the same PDX model. There were four biological replicates in each group. Four mice were used, with each of the 3 groups per mouse. There were no control or reference samples.
Project description:Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanism is unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists upregulated inflammation. Similarly, AhR signaling via the endogenous FICZ ligand reduced the inflammatory response in the imiquimod-induced model of psoriasis and AhR deficient mice exhibited a substantial exacerbation of the disease, compared to AhR sufficient controls. Non-haematopoietic cells, in particular keratinocytes, were responsible for this hyper-inflammatory response, which involved increased reactivity to IL-1beta and upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders. Total RNA obtained from skin explants taken from psoriatic patients or healthy donors cultured in the presence of AhR agonist or antagonist
Project description:Targeted electrical energy externally applied to a complex wound, including pressure ulcers and venous leg has been shown to improve wound healing. However, how this repair process is stimulated is poorly understood. We examined by microarray analysis the effects of a class IIA medical device that delivers a specific sequence of electrical pulses (e-sequence) to the skin of healthy volunteers during a period of 48 hours.
Project description:MicroRNA microarray profiling analysis was performed on skin biopsies from unwounded mice, and from mice 1 day or 5 days post-wounding (3 mice per groups)