Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse ...outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 10
data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy.
Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically
explore most currently marketed drugs and drug-like ...molecules for their efficacy against a panel of prostate cancer cells.
Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910
drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial
cell lines (RWPE-1 and EP156T). The EC 50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper
or zinc were done in vitro for mechanistic exploration.
Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and
control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were
identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations.
DSF reduced tumor growth in vivo , induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF
was potentiated by copper in vitro .
Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs.
We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically well-known molecules
can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070â8)
Abstract
Increasing amounts of systems toxicology data, including omics results, are becoming publically available and accessible in databases. Data-driven and informatics-tool supported pipeline ...schemas for fitting such data into Adverse Outcome Pathway (AOP) descriptions could potentially aid the development of nonanimal-based hazard and risk assessment methods. We devised a 6-step workflow that integrated diverse types of toxicology data into a novel AOP scheme for pulmonary fibrosis. Mining of literature references and diverse data sources covering previous pathway descriptions and molecular results were coupled in a stepwise manner with informatics tools applications that enabled gene linkage and pathway identification in molecular interaction maps. Ultimately, a network of functional elements coupled 64 pulmonary fibrosis-associated genes into a novel, open-source AOP-linked molecular pathway, now available for commenting and improvements in WikiPathways (WP3624). Applying in silico-based knowledge extraction and modeling, the pipeline enabled screening and fusion of many different complex data types, including the integration of omics results. Overall, the taken, stepwise approach should be generally useful to construct novel AOP descriptions as well as to enrich developing AOP descriptions in progress.
Summary Objectives Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study ...addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux®). Materials and Methods The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann–Whitney U-test and Spearman’s correlation test. Results Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.
Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial ...step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC).
Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity, and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p=0.047).
In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.
Nanotechnology is a key enabling technology with billions of euros in global investment from public funding, which include large collaborative projects that have investigated environmental and health ...safety aspects of nanomaterials, but the reuse of accumulated data is clearly lagging behind. Here we summarize challenges and provide recommendations for the efficient reuse of nanosafety data, in line with the recently established FAIR (findable, accessible, interoperable and reusable) guiding principles. We describe the FAIR-aligned Nanosafety Data Interface, with an aggregated findability, accessibility and interoperability across physicochemical, bio-nano interaction, human toxicity, omics, ecotoxicological and exposure data. Overall, we illustrate a much-needed path towards standards for the optimized use of existing data, which avoids duplication of efforts, and provides a multitude of options to promote safe and sustainable nanotechnology.
The Fiber Pathogenicity Paradigm (FPP) establishes connections between fiber structure, durability, and disease‐causing potential observed in materials like asbestos and synthetic fibers. While ...emerging nanofibers are anticipated to exhibit pathogenic traits according to the FPP, their nanoscale diameter limits rigidity, leading to tangling and loss of fiber characteristics. The absence of validated rigidity measurement methods complicates nanofiber toxicity assessment. By comprehensively analyzing 89 transcriptomics and 37 proteomics studies, this study aims to enhance carbon material toxicity understanding and proposes an alternative strategy to assess morphology‐driven toxicity. Carbon materials are categorized as non‐fibrous, high aspect ratio with shorter lengths, tangled, and rigid fibers. Mitsui‐7 serves as a benchmark for pathogenic fibers. The meta‐analysis reveals distinct cellular changes for each category, effectively distinguishing rigid fibers from other carbon materials. Subsequently, a robust random forest model is developed to predict morphology, unveiling the pathogenicity of previously deemed non‐pathogenic NM‐400 due to its secondary structures. This study fills a crucial gap in nanosafety by linking toxicological effects to material morphology, in particular regarding fibers. It demonstrates the significant impact of morphology on toxicological behavior and the necessity of integrating morphological considerations into regulatory frameworks.
Emerging nanofibers, akin to asbestos, hold potential risks, yet their small size impedes rigidity, challenging toxicity evaluation. This meta‐analysis of omics studies discerns varying effects among non‐fibrous, short/high‐ratio, tangled, and rigid carbon fibers, shedding light on toxicity mechanisms and linking fiber‐like harm to material structures. Surprisingly, previously deemed safe NM‐400 exhibits danger due to its distinctive structure.
GSNO (S-nitrosoglutathione) is emerging as a key regulator in NO signalling as it is in equilibrium with S-nitrosated proteins. Accordingly, it is of great interest to investigate GSNO metabolism in ...terms of competitive pathways and redox state. The present study explored ADH3 (alcohol dehydrogenase 3) in its dual function as GSNOR (GSNO reductase) and glutathione-dependent formaldehyde dehydrogenase. The glutathione adduct of formaldehyde, HMGSH (S-hydroxymethylglutathione), was oxidized with a k(cat)/K(m) value approx. 10 times the k(cat)/K(m) value of GSNO reduction, as determined by fluorescence spectroscopy. HMGSH oxidation in vitro was greatly accelerated in the presence of GSNO, which was concurrently reduced under cofactor recycling. Hence, considering the high cytosolic NAD(+)/NADH ratio, formaldehyde probably triggers ADH3-mediated GSNO reduction by enzyme-bound cofactor recycling and might result in a decrease in cellular S-NO (S-nitrosothiol) content in vivo. Formaldehyde exposure affected S-NO content in cultured cells with a trend towards decreased levels at concentrations of 1-5 mM, in agreement with the proposed mechanism. Product formation after GSNO reduction to the intermediate semimercaptal responded to GSH/GSNO ratios; ratios up to 2-fold allowed the spontaneous rearrangement to glutathione sulfinamide, whereas 5-fold excess of GSH favoured the interception of the intermediate to form glutathione disulfide. The sulfinamide and its hydrolysis product, glutathione sulfinic acid, inhibited GST (glutathione transferase) activity. Taken together, the findings of the present study provide indirect evidence for formaldehyde as a physiological trigger of GSNO depletion and show that GSNO reduction can result in the formation of GST inhibitors, which, however, is prevented under normal cellular redox conditions.
Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we ...demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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