Predictive value of testing the sensitivity of anticancer treatment on tumorspheres from patients with metastatic colorectal cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer
PROVIDER: 2536654 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Choline kinase α (CHKα) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKα in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKα expression, associated with differentiation. CHKα protein expression was directly correlated with sensitivity to MN58b, a CHKα inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKα knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKα inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKα was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKα did not relate to survival, nuclear CHKα distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKα inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKα inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response.
2018-03-28 | GSE112335 | GEO
Project description:Choline kinase alpha (CHKA) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKA in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKA expression and a good correlation between protein expression and sensitivity to MN58b, a CHKA inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKA knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKA inhibition and, in vitro, MN58b had synergistic effects with gemcitabine, 5-fluorouracil and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKA was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKA did not relate to survival, nuclear CHKA distribution was observed in 43% of samples and was associated with survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKA inhibitors, we cultured IMIM-PC-2 cells with continuous incremental concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified up-regulation of ABCB1 and ABCB4 multidrug resistance transporters and functional studies confirmed that their up-regulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKA inhibition merits further attention as a therapeutic option in patients with PDAC.
2017-08-11 | GSE60321 | GEO
Project description:The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
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Project description:Is the transcriptome of cumulus cells a good predictor of the embryo’s developmental competence? The objective of this study was to analyze the transcriptional differences between cumulus cells from oocytes exhibiting different developmental potentials following individual in vitro embryo production and transfer by RNA‐seq. Cumulus cells were allocated into three groups according to the developmental potential of their enclosed oocyte: (1) not able to develop to the blastocyst stage (Bl–), (2) able to develop to the blastocyst stage but failing to establish a pregnancy (P–), or (3) able to develop to the blastocyst stage and to establish a clinical pregnancy (P+).
2024-04-25 | GSE265779 | GEO
Project description:BackgroundTo facilitate community-based epidemiologic studies of pediatric leukemia, we validated use of ICD-9-CM diagnosis codes to identify pediatric leukemia cases in electronic medical records of six U.S. integrated health plans from 1996-2015 and evaluated the additional contributions of procedure codes for diagnosis/treatment.ProceduresSubjects (N = 408) were children and adolescents born in the health systems and enrolled for at least 120 days after the date of the first leukemia ICD-9-CM code or tumor registry diagnosis. The gold standard was the health system tumor registry and/or medical record review. We calculated positive predictive value (PPV) and sensitivity by number of ICD-9-CM codes received in the 120-day period following and including the first code. We evaluated whether adding chemotherapy and/or bone marrow biopsy/aspiration procedure codes improved PPV and/or sensitivity.ResultsRequiring receipt of one or more codes resulted in 99% sensitivity (95% confidence interval [CI]: 98-100%) but poor PPV (70%; 95% CI: 66-75%). Receipt of two or more codes improved PPV to 90% (95% CI: 86-93%) with 96% sensitivity (95% CI: 93-98%). Requiring at least four codes maximized PPV (95%; 95% CI: 92-98%) without sacrificing sensitivity (93%; 95% CI: 89-95%). Across health plans, PPV for four codes ranged from 84-100% and sensitivity ranged from 83-95%. Including at least one code for a bone marrow procedure or chemotherapy treatment had minimal impact on PPV or sensitivity.ConclusionsThe use of diagnosis codes from the electronic health record has high PPV and sensitivity for identifying leukemia in children and adolescents if more than one code is required.
| S-EPMC9933870 | biostudies-literature
Project description:PurposeOutcome misclassification in retrospective epidemiologic analyses has been well-studied, but little is known about such misclassification with respect to sequential statistical analysis during surveillance of medical product-associated risks, a planned capability of the US Food and Drug Administration's Sentinel System.MethodsUsing a vaccine example, we model and simulate sequential database surveillance in an observational data network using a variety of outcome detection algorithms. We consider how these algorithms, as characterized by sensitivity and positive predictive value, impact the length of surveillance and timeliness of safety signal detection. We show investigators/users of these networks how they can perform preparatory study design calculations that consider outcome misclassification in sequential database surveillance.ResultsNon-differential outcome misclassification generates longer surveillance times and less timely safety signal detection as compared with the case of no misclassification. Inclusive algorithms characterized by high sensitivity but low positive predictive value outperform more narrow algorithms when detecting rare outcomes. This decision calculus may change considerably if medical chart validation procedures were required.ConclusionsThese findings raise important questions regarding the design of observational data networks used for pharmacovigilance. Specifically, there are tradeoffs involved when choosing to populate such networks with component databases that are large as compared with smaller integrated delivery system databases that can more easily access laboratory or clinical data and perform medical chart validation.
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Project description:ObjectivesPlasma troponins, measured by fourth-generation assays, are associated with increased mortality and morbidity after cardiac surgery. They also offer predictive information in addition to EuroSCORE, a widely used risk model after cardiac surgery. However, preoperatively measured troponin has provided no additional information to postoperative values. Whether these facts hold true also for the high-sensitivity fifth-generation troponin assay and the better calibrated risk model, EuroSCORE II, is unknown. We hypothesized that preoperative and/or postoperative high-sensitivity troponin T (hs-TnT) would increase the predictive value of EuroSCORE II.MethodsConsecutive coronary artery bypass grafting (CABG) and other cardiac surgical patients were prospectively enrolled in a university hospital. Plasma samples and EuroSCORE II variables were collected. The primary and secondary end-points were 180-day mortality and any major adverse event within 30 days, and 961-day mortality. The data were analysed by Kaplan-Meier survival curves, regression analyses, receiver operator characteristic curves and decision curve analysis.ResultsMortality rates in 180 days were 3.5% (15/428) in CABG and 6.4% (14/220) in other cardiac surgical patients. Survival curves differed only in patients with not only high postoperative hs-TnT value (>500 ng/l), but also high preoperative hs-TnT value (>14 ng/l), compared with patients with both hs-TnT values low. Adding hs-TnT to EuroSCORE II improved the prediction of 180-day mortality in other cardiac surgical patients (maximum net benefit of 1.5%), but not in CABG patients. Regarding major adverse events, adding hs-TnT to EuroSCORE II improved the prediction in both CABG patients and other cardiac surgical patients (maximum net benefits of 3 and 7%).ConclusionsElevated postoperative hs-TnT was predictive of mortality only when combined with elevated preoperative hs-TnT. Hs-TnT measurements added information to the EuroSCORE II regarding major adverse events in all cardiac surgical patients and regarding 180-day mortality in non-CABG patients.
| S-EPMC4986738 | biostudies-literature
Project description:Transcriptional profiling was conducted on RNA from 16 prostatic cancer cell lines to identify genes whose expression level correlate with sensitivity of an anti-tumor agent Experiment Overall Design: Baseline gene expression profiling was performed using 16 prostatic cancer cell lines to identify expression signatures highly correlated with in vitro sensitivity to a particular agent
2008-06-16 | E-GEOD-9633 | biostudies-arrayexpress
Project description:The purpose of the present study is to investigate the benefit of anti-cancer therapy administered on the basis of drug sensitivity testing. This concerns colorectal cancer patients who have previously received standard treatment.
| 2251938 | ecrin-mdr-crc
Project description:This study tested whether high spider fearful individuals' implicit and explicit attitudes toward spiders are sensitive to exposure treatment, and whether post-treatment implicit and/or explicit attitudes are related to the generalization of treatment effects. Self-reported explicit and implicit attitudes (indexed with a pictorial Extrinsic Affective Simon Task) were assessed in high spider fearful, treatment-seeking individuals (n = 60) before and after a one-session exposure in vivo treatment and at 2-month follow-up. A group of non-fearful participants (n = 30) completed the same assessments once. Results show that implicit attitudes did not change following treatment over and above test-retest effects. In contrast, explicit attitudes did change favorably following treatment, but negative explicit attitudes at post-treatment were associated with less pronounced overt approach behavior at follow-up. These findings support the idea that residual negative explicit attitudes interfere with the generalization of treatment effects.
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