RESUMO
Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Fígado/efeitos dos fármacos , Transcriptoma/genética , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fenótipo , Ratos , Toxicogenética/métodos , Transcriptoma/efeitos dos fármacosRESUMO
Veterinary clinical pathologists are well positioned via education and training to assist in investigations of unexpected results or increased variation in clinical pathology data. Errors in testing and unexpected variability in clinical pathology data are sometimes referred to as "laboratory errors." These alterations may occur in the preanalytical, analytical, or postanalytical phases of studies. Most of the errors or variability in clinical pathology data occur in the preanalytical or postanalytical phases. True analytical errors occur within the laboratory and are usually the result of operator or instrument error. Analytical errors are often ≤10% of all errors in diagnostic testing, and the frequency of these types of errors has decreased in the last decade. Analytical errors and increased data variability may result from instrument malfunctions, inability to follow proper procedures, undetected failures in quality control, sample misidentification, and/or test interference. This article (1) illustrates several different types of analytical errors and situations within laboratories that may result in increased variability in data, (2) provides recommendations regarding prevention of testing errors and techniques to control variation, and (3) provides a list of references that describe and advise how to deal with increased data variability.
Assuntos
Técnicas de Laboratório Clínico/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Erros Médicos/prevenção & controle , Patologia Clínica/normas , Animais , Humanos , Controle de QualidadeRESUMO
Elevated levels of protein tyrosine phosphorylation contribute to a malignant phenotype, although the tyrosine kinases that are responsible for this signaling remain largely unknown. Here we report increased levels of the EphA2 (ECK) protein tyrosine kinase in clinical specimens and cell models of breast cancer. We also show that EphA2 overexpression is sufficient to confer malignant transformation and tumorigenic potential on nontransformed (MCF-10A) mammary epithelial cells. The transforming capacity of EphA2 is related to the failure of EphA2 to interact with its cell-attached ligands. Interestingly, stimulation of EphA2 reverses the malignant growth and invasiveness of EphA2-transformed cells. Taken together, these results identify EphA2 as a powerful oncoprotein in breast cancer.
Assuntos
Neoplasias da Mama/enzimologia , Mama/enzimologia , Transformação Celular Neoplásica/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Animais , Mama/patologia , Neoplasias da Mama/patologia , Adesão Celular/fisiologia , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Humanos , Ligantes , Camundongos , Camundongos Nus , Receptores Proteína Tirosina Quinases/metabolismo , Receptor EphA2 , Frações Subcelulares/enzimologia , Células Tumorais CultivadasRESUMO
A 7-year-old warmblood mare was referred because of a respiratory tract disorder; pulmonary granular cell tumor was diagnosed. Pulmonary granular cell tumor is a locally invasive but rare type of tumor with low metastatic potential. The entire right lung was resected to ensure removal of all neoplastic tissue. The horse recovered well and has minimal difficulties functioning with one lung. Most of these tumors are diagnosed during postmortem examination. To our knowledge, this is the first report of pulmonary granular cell tumor treated by complete lung resection in a horse.