Ontology highlight
ABSTRACT:
PROVIDER: PRJNA414086 | ENA |
REPOSITORIES: ENA
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Project description:Chronic Pseudomonas aeruginosa infections evades antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P.aeruginosa towards clinically relevant antibiotics leads to phenotypic convergence towards distinct states. These states are associated with collateral sensitivity towards several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In depth investigation of chronic P.aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.
2018-10-23 | PXD007972 | Pride
Project description:Phenotypic convergence in response to drug exposure supports exploitation of collateral sensitivity to counter drug resistance
| PRJEB22929 | ENA
Project description:BIOMEDE (NCT02233049) was a phase II, biopsy-driven clinical trial in DIPG patients with randomisation of stratification between dasatinib, erlotinib and everolimus. Methylation array profiling was carried out alongside drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. Alongside exome, RNAseq, phospho-proteomics, these data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatment
2020-08-31 | E-MTAB-9282 | biostudies-arrayexpress
Project description:Melanoma therapeutic strategies that select against resistance by exploiting MYC-driven evolutionary convergence
| PRJNA390137 | ENA
Project description:The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
2019-01-26 | GSE100672 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72927 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72732 | GEO
Project description:In vitro culture methods underpin many experimental approaches to biology and drug discovery. The modification of established cell culture methods to be more biologically relevant, or to optimise growth, is traditionally a laborious task. Emerging metabolomics technology enables rapid evaluation of intra- and extra-cellular metabolites, and can be applied to the rational development of cell culture medium. In this study, untargeted semi-quantitative, and targeted quantitative, metabolomic analyses of fresh and spent media revealed the major nutritional requirements for growth of bloodstream-form Trypanosoma brucei. The standard culture medium (HMI11) contained unnecessarily high concentrations of 32 nutrients that were subsequently removed to more closely resemble concentrations normally found in blood. Our new minimal medium (CMM) supports in vitro growth equivalent to HMI11, and causes no significant perturbation of metabolite levels for 94% of the detected metabolome (< 3-fold change; a = 0.05). Importantly, improved sensitivity was observed for drug activity studies in whole cell phenotypic screens, and in metabolomics mode of action assays. 400-fold decreases in IC50 were observed for pentamidine and methotrexate, suggesting inhibition of activity by nutrients present in HMI11. CMM is suitable for routine cell culture and offers important advantages for metabolomics studies and drug activity screening.
2015-05-14 | MTBLS49 | MetaboLights
Project description:Interferons (IFNs) play a major role in controlling viral infections including HIV/SIV infections. Persistent up-regulation of interferon stimulated genes (ISGs) is associated with chronic immune activation and progression in SIV/HIV infections, but the respective contribution of different IFNs is unclear. We analyzed the expression of IFN genes and ISGs in tissues of SIV infected macaques to understand the respective roles of type I and type II IFNs. Both IFN types were induced in lymph nodes during early stage of primary infection and to some extent in rectal biopsies but not in PBMCs. Induction of Type II IFN expression persisted during the chronic phase, in contrast to undetectable induction of type I IFN expression. Global gene expression analysis with a major focus on ISGs revealed that at both acute and chronic infection phases most differentially expressed ISGs were inducible by both type I and type II IFNs and displayed the highest increases, indicating strong convergence and synergy between type I and type II IFNs. These results suggest that IFN- strongly contribute to shape ISG upregulation in addition to type I IFN. The analysis of functional signatures of ISG expression revealed temporal changes in IFN expression patterns identifying phasespecific ISGs.
2017-10-30 | E-MTAB-6068 | biostudies-arrayexpress
Project description:RNA turnover is a primary source of gene expression variation, in turn promoting cellular adaptation. Mycobacteria leverage reversible mRNA stabilization to endure hostile conditions. Although ribonuclease E is essential for RNA turnover in several species, its role in mycobacterial single cell physiology and functional phenotypic diversification remains unexplored. Here, by integrating live-single-cell and quantitative-mass-spectrometry approaches, we show that ribonuclease E forms dynamic foci, which are associated with cellular homeostasis and single-cell fate, and we discover a versatile molecular interactome. We prove the interaction between ribonuclease E and the nucleoid-associated protein HupB, which is particularly pronounced during drug treatment and intracellularly, where we also observed marked increase of phenotypic diversity. Disruption of ribonuclease E expression affects HupB levels, impairing Mycobacterium tuberculosis growth homeostasis during treatment, intracellular replication and host spread. Our work lays the foundation for rational drug design against Mycobacterium tuberculosis diversification capacity, undermining its cellular balance and fitness landscape.
2022-03-25 | PXD025674 | Pride