Prediction of DNA Repair Inhibitor Response in Short Term Patient-Derived Ovarian Cancer Organoids
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PROVIDER: PRJNA489929 | ENA |
REPOSITORIES: ENA
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Project description:Prediction of DNA Repair Inhibitor Response in Short Term Patient-Derived Ovarian Cancer Organoids
| PRJNA489928 | ENA
Project description:Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404-21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.
| S-EPMC6365285 | biostudies-literature
Project description:Study of the short term (within the first 330 seconds) transcriptional response of S.cerevisiae upon a sudden addition of glucose. Keywords: glucose pulse, chemostat culture, glucose catabolite repression
2005-12-16 | GSE3821 | GEO
Project description:<p>In this study, 34 ovarian tumor organoids generated from 23 patients underwent paired DNA damage repair defect functional analyses and whole exome sequencing analysis to compare genetic mutational status to DNA repair functional capacity. 22 of the patients had high grade serous cancer and 1 of the patients had low grade serous cancer. A normal control, fresh parent tumor, and cells from the organoid culture generated from the parent tumor underwent whole exome sequencing analysis and the data from the sequencing analysis is provided here.</p>
| phs001685 | dbGaP
Project description:In vitro prediction of developmental toxicity during early discovery phases of drug development has the potential to guide decision-making toward prioritizing candidate drugs that are less likely to later show teratogenicity in vivo. Such screening would reduce animal use in preclinical studies, including full-scale regulatory reproductive toxicology. we evaluate an assay format based on short-term toxicogenomic responses in pluripotent embryonic stem cells (ESC). We exposed attached undifferentiated cells of the mouse ESC cell line R1 for 6h to 10 known teratogenic and 9 non-teratogenic pharmaceutical drugs . We used microarry to access genome-wide gene expression response and identify gene signatures to classify teratogens and non-teratogens.
2015-12-01 | GSE57639 | GEO
Project description:Short-term intensive fasting rejuvenates erythropoiesis
| PRJNA827182 | ENA
Project description:Gene sequencing of ovarian cancer cell lines after short-term hyperthermia
| PRJEB98443 | ENA
Project description:Two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the “Classical” and “Basal-like” subtypes. However, the “molecular” classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. We constructed a PDO library for morphologic and RNA-seq analyses and drug response assays in vitro. PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) or densely proliferating inside (DP type). RNA-seq analysis revealed that the “morphological” subtype (GL vs. DP) roughly corresponded to the “molecular” subtype (“Classical” vs. “Basal-like”). The proposed “morphological” classification predicted clinical treatment response and prognosis; the median overall survival of patients with GL type were significantly longer than that of those with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK and autophagy inhibition. PDAC PDOs facilitated subtype determination and clinical outcome prediction, thereby advancing precision medicine for PDAC.
2024-04-11 | GSE228801 | GEO
Project description:Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction
| PRJNA951666 | ENA
Project description:OBJECTIVE: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). BACKGROUND: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we show how short-term CR protects the mouse heart from ischemia. METHODS: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food over a period of 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. Prior to MI (d8), the left ventricles (LV) of AL and CR mice were collected for Western blot, DNA and microRNA (miR) analyses. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI. RESULTS: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). cDNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CONCLUSIONS: Short-term CR for only 7d represents a preconditioning strategy that limits infarct size. It is associated with a unique gene and miR signature, including the activation of specific pro-survival kinases. These findings may have implications for therapeutic use of short-term CR. .
2015-05-08 | GSE68646 | GEO