Project description:The beneficial effects of glucocorticoids (GCs) in acute lymphoblastic leukemia (ALL) are based on their ability to induce apoptosis. Omics technologies such as DNA microarray analysis are widely used to study the changes in gene expression and have been successfully implemented in biomarker identification. In addition, time series studies of gene expression enable the identification of correlations between kinetic profiles of glucocorticoid receptor (GR) target genes and diverse modes of transcriptional regulation. This study presents a genome-wide microarray analysis of both our and published Affymetrix HG-U133 Plus 2.0 data in GCs-sensitive and -resistant ALL. GCs-sensitive CCRF-CEM-C7-14 cells were treated with dexamethasone at three time points (0 h, 2 h and 10 h). The treated samples were then compared to the control (0 h). The published data used were as follows: GSE2677: GSM51674: B-ALL-24-24h GSM51675: B-ALL-24-6h GSM51676: B-ALL-24-0h GSM51680: B-ALL-17-24h GSM51681: B-ALL-17-8h GSM51682: B-ALL-17-0h GSM51677: B-ALL-13-24h GSM51678: B-ALL-13-8h GSM51679: B-ALL-13-0h GSM51683: B-ALL-31-24h GSM51684: B-ALL-31-6h GSM51685: B-ALL-31-0h GSM51686: B-ALL-32-24h GSM51687: B-ALL-32-6h GSM51688: B-ALL-32-0h GSM51689: B-ALL-33-24h GSM51690: B-ALL-33-6h GSM51691: B-ALL-33-0h GSM51692: B-ALL-37-24h GSM51693: B-ALL-37-6h GSM51694: B-ALL-37-0h GSM51695: B-ALL-38-24h GSM51696: B-ALL-38-6h GSM51697: B-ALL-38-0h GSM51698: B-ALL-40-24h GSM51699: B-ALL-40-6h GSM51700: B-ALL-40-0h GSM51701: B-ALL-43-24h GSM51702: B-ALL-43-6h GSM51703: B-ALL-43-0h GSM51707: T-ALL-25-24h GSM51708: T-ALL-25-6h GSM51709: T-ALL-25-0h GSM51704: T-ALL-20-24h GSM51705: T-ALL-20-8h GSM51706: T-ALL-20-0h GSM51710: T-ALL-2-24h GSM51711: T-ALL-2-8h GSM51712: T-ALL-2-0h GSE2842 GSM60545: S-Line-PreB-6h-EtOH GSM60546: S-Line-PreB-6h-GC GSM60547: S-Line-PreB-24h-GC GSM60542: S-Line-C7H2-6h-EtOH GSM60543: S-Line-C7H2-6h-GC GSM60544: S-Line-C7H2-24h-GC GSM60560: R-Line-CEMC1-6h-EtOH GSM60561: R-Line-CEMC1-6h-GC GSM60562: R-Line-CEMC1-24h-GC GSM60564: R-Line-C7R1-6h-EtOH GSM60566: R-Line-C7R1-6h-GC GSM60576: R-Line-C7R1dim-low-6h-EtOH GSM60578: R-Line-C7R1dim-low-6h-GC GSM60579: R-Line-C7R1dim-low-24h-GC GSM60581: R-Line-PreB-6h-EtOH GSM60583: R-Line-PreB-6h-GC GSM60584: R-Line-PreB-24h-EtOH GSM60586: R-Line-PreB-24h-GC GSM60548: C-Line-CEMC1-ratGR-6h-EtOH GSM60549: C-Line-CEMC1-ratGR-6h-GC GSM60550: C-Line-CEMC1-ratGR-24h-GC GSM60551: C-Line-C7R1dim-high-6h-EtOH GSM60552: C-Line-C7R1dim-high-6h-GC GSM60553: C-Line-C7R1dim-high-24h-GC

Project description:This submission includes MS data for the paper titled "Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism", submitted to Cell Chemical Biology.Summary:Diacylglycerol lipase (DAGL) produce 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, in vivo active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain in animal models of both inflammatory and neuropathic pain. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues, all without causing adverse CNS effects of seizures. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.Raw files for the selectivity experiment profiling of A1480LS in THP1 cells are listed below. Search and quantification results bearing the same file stem are also provided, as well as the fasta database that was used: uniprot_HumanComplete_121105_cdhit98_plus_Reverse_wContaminants150305.fasta.- RAH-NB1-208_A_03.rawRaw files for the in vivo time course experiment in rat kidneys are listed below. A Skyline export bearing the same name is also provided, as well as the fasta database that was used: uniprot_6organism_constructs_contaminants_20190213_forPRMJOB.fasta.- NN-NB2-213_A1.raw: 0h, Vehicle- NN-NB2-213_A2.raw: 0h, Vehicle- NN-NB2-213_A3.raw: 0h, Vehicle- NN-NB2-213_A4.raw: 0h, Vehicle- NN-NB2-213_B1.raw: 1h, A1480LS- NN-NB2-213_B2.raw: 1h, A1480LS- NN-NB2-213_B3.raw: 1h, A1480LS- NN-NB2-213_B4.raw: 1h, A1480LS- NN-NB2-213_B5.raw: 4h, A1480LS- NN-NB2-213_B6.raw: 4h, A1480LS- NN-NB2-213_B7.raw: 4h, A1480LS- NN-NB2-213_B8.raw: 4h, A1480LS- NN-NB2-213_B9.raw: 8h, A1480LS- NN-NB2-213_B10.raw: 8h, A1480LS- NN-NB2-213_B11.raw: 8h, A1480LS- NN-NB2-213_B12.raw: 12h, A1480LS- NN-NB2-213_C1.raw: 12h, A1480LS- NN-NB2-213_C2.raw: 12h, A1480LS- NN-NB2-213_C3.raw: 12h, A1480LS- NN-NB2-213_C4.raw: 24h, A1480LS- NN-NB2-213_C5.raw: 24h, A1480LS- NN-NB2-213_C6.raw: 24h, A1480LS- NN-NB2-213_C7.raw: 24h, A1480LS- NN-NB2-213_C8.raw: 32h, A1480LS- NN-NB2-213_C9.raw: 32h, A1480LS- NN-NB2-213_C10.raw: 32h, A1480LS- NN-NB2-213_C11.raw: 32h, A1480LS

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Let-7 and lin-46 are the essential targets of the LIN28 RNA-binding protein in temporal patterning [smallRNA-seq TC2]

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