ABSTRACT: blood samples as part of a study to determine the effect of the gut microbiome on drug metabolism. these data are to serve for testing and evaluation of ion identity networking.
Project description:This SuperSeries is composed of the following subset Series: GSE12489: Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis GSE12509: Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis Refer to individual Series
Project description:Purpose: Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We aimed to determine whether organoid testing could help guide precision treatment for CRPM patients, as the clinical utility of prospective, functional drug screening including non-standard agents is unknown. Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. Conclusions: Our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.
Project description:We used genome-wide microarray comparative genomic hybridization to carry out a higher resolution evaluation of the effect of MMR competence on genomic alterations occurring in 20 cell lines and to determine if characteristic aberrations arise in MMR proficient and deficient HCT116 cells undergoing selection for methotrexate resistance. Keywords: Comparative Genomic Hybridization
Project description:Osteoarthritis (OA) is a common disabling disease for which no effective pharmacological therapy exists. The progression of osteoarthritis is characterized by the loss of homeostasis in the cartilage. Since in the early stages of the disease, a phenotypic switch is seen in which articular chondrocytes become hypertrophic and promote degradation of the cartilage extracellular matrix, targeting this phenomenon might be the key to developing a disease-modifying osteoarthritis drug (DMOAD). In this study, the signature reversing principle combined with a drug repurposing strategy was used to accelerate the identification and validation of potential DMOADs. Starting from single-cell transcriptomic analysis of patient-derived cartilage, we identified 6 drugs predicted to reduce chondrocyte hypertrophy. Subsequent in vitro evaluation in human chondrocytes and cartilage explants demonstrated that Cobimetinib, a MEK1/2 inhibitor, reduced chondrocyte hypertrophy-related and catabolic gene expression, such as SPP1, COL10A1, MMP13 and ADAMTS5, while promoting collagen type 2 and aggrecan gene expression. Finally, single-cell RNA sequencing performed on osteoarthritic cartilage explants exposed to Cobimetinib ex vivo confirmed the anti-hypertrophic effect of Cobimetinib on hypertrophy-related gene expression and additionally showed a deletion of chondrocytes with a fibrotic phenotype. This study is a proof of concept that omics data together with a drug repurposing strategy accelerate drug discovery in diseases like osteoarthritis and could quickly lead to many new therapeutic roles for safe and effective drugs.
Project description:Tuberculosis (TB) is still a major global health challenge, killing over 1.5 million people each year, and hence, there is a need to identify and develop novel treatments for Mycobacterium tuberculosis (M. tuberculosis). The prevalence of infections caused by nontuberculous mycobacteria (NTM) is also increasing and has overtaken TB cases in the United States and much of the developed world. Mycobacterium abscessus (M. abscessus) is one of the most frequently encountered NTM and is difficult to treat. We describe the use of drug-disease association using a semantic knowledge graph approach combined with machine learning models that has enabled the identification of several molecules for testing anti-mycobacterial activity. We established that niclosamide (M. tuberculosis IC90 2.95 μM; M. abscessus IC90 59.1 μM) and tribromsalan (M. tuberculosis IC90 76.92 μM; M. abscessus IC90 147.4 μM) inhibit M. tuberculosis and M. abscessus in vitro. To investigate the mode of action, we determined the transcriptional response of M. tuberculosis and M. abscessus to both compounds in axenic log phase, demonstrating a broad effect on gene expression that differed from known M. tuberculosis inhibitors. Both compounds elicited transcriptional responses indicative of respiratory pathway stress and the dysregulation of fatty acid metabolism. Further testing against drug-resistant isolates and other NTM is warranted to clarify the usefulness of these repurposed drugs for mycobacteria.
Project description:High cholesterol diet and xenobiotic treatment induce changes in cholesterol homeostasis and drug metabolism. Mice were either 7 days on high cholesterol diet or were treated with phenobarbital. Liver samples were analyzed using Sterolgene v0 cDNA microarrays. Sterolgene microarray is a tool designed to enable focused studies of cholesterol homeostasis and drug metabolism. We show that one week of cholesterol diet down-regulates cholesterol biosynthesis and up-regulates xenobiotic metabolism (Cyp3 family). Phenobarbital treatment also up-regulates xenobiotic metabolism (Cyp2b and Cyp3a families). We can conclude that the Sterolgene series of cDNA microarrays represent novel original tool, enabling focused and cost-wise studies of cholesterol homeostasis and drug metabolism. Keywords: Treatment and diet effects One group of mice was treated i.p. with 50 mg/kg of phenobarbital in vehicle (5% DMSO in corn oil). Untreated group was injected vehicle. Third group was 7 days on 1 % (w/w) cholesterol diet prior vehicle treatment. After 10 h animals were sacrificed and livers were stored. Pools of total RNA from two animals were mixed. Three pools of untreated and phenobarbital treated groups, and two pools of cholesterol diet group were co-hybridized with liver reference on Sterolgene v0 cDNA microarray. No dye-swaps were performed.
Project description:Circulating whole blood transcriptomes can detect the presence of unruptured cerebral aneurysms. Pending additional testing in larger cohorts, this could serve as a foundation to develop a simple blood-based test to facilitate screening and early detection of cerebral aneurysms.