ABSTRACT
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.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/genetics , Gene Regulatory Networks/drug effects , Liver/drug effects , Transcriptome/genetics , Animals , Endoplasmic Reticulum Stress/drug effects , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Humans , Liver/metabolism , NF-E2-Related Factor 2/genetics , Phenotype , Rats , Toxicogenetics/methods , Transcriptome/drug effectsABSTRACT
Simultaneous measurements of cerebral blood flow have been performed in baboons to assess the correlation between the acute and invasive nondiffusible microsphere technique and the noninvasive xenon-enhanced CT method. Blood flows in small tissue volumes (approximately 1 cm3) were directly compared. The results of these studies demonstrate a statistically significant association between the two methods (P less than .001). Similar correlations were obtained by both the Kendall tau (tau) and the Spearman (r) methods. The problems and limitations of such correlations are discussed.
Subject(s)
Cerebrovascular Circulation , Radioisotopes , Tomography, X-Ray Computed , Xenon , Animals , Brain/diagnostic imaging , Microspheres , Papio , Radionuclide ImagingABSTRACT
A reproducible noninvasive monkey model for global brain ischemia with exact insult (no flow x 16 min) to the brain, with survival and with standardized preischemic, ischemic and postischemic variables is described. This model allowed us to demonstrate for the first time: 1) that a substantial part of brain damage early postischemia is reversible and amenable especially to barbiturate treatment; 2) that the postischemic brain shows increased vulnerability for additional insults. Optimal postischemic intensive monitoring and immobilization for 24-48 hours is important for improved outcome; 3) that immediate postischemic reperfusion pressure (MAP 110-150 mm Hg) significantly improves the outcome; 4) that heparinisation during ischemia has no protective effect and 5) that postischemic heparinisation and intravenous hemodilution does not ameliorate the outcome. The protective effect of trimetaphan against neurogenic pulmonary edema can be explained by the prevention of pulmonary hypertension but its protective effect on the development of secondary cerebral edema has to be elucidated.
Subject(s)
Disease Models, Animal , Ischemic Attack, Transient/therapy , Animals , Ischemic Attack, Transient/pathology , Macaca mulattaABSTRACT
Brain protection during ischemia by barbiturates has been clearly demonstrated in many different experiments. Only recently the therapeutic value of large doses of thiopental administered early after cerebral circulatory arrest has been demonstrated experimentally in monkey. Noncontrolled studies in humans also indicate beneficial effect, however the treatment is not without potential complication. Controlled randomized studies in humans are needed to document its beneficial effect. Such studies have several unique medico-legal and ethical implications since the treatment has to be started in an unconscious patient and as early as possible after a totally unexpected cardiac arrest. Informed consent, ethical and medicolegal consideration of randomized controlled clinical trials is discussed and a modified approach to clinical trials in humans is suggested. The modification would not alter the scientific value of the studies, but resolve the ethical and medico-legal problems.