A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1-3). However, few of these human trials have shown success (4-7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8-11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3,12,13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14-18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16-18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.In this article, we report on a systematic comparison of the genomic respo...

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

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Limited data are available on the relation between physical fitness and mortality from cardiovascular disease. We examined this question in a study of 4276 men, 30 to 69 years of age, whom we followed for an average of 8.5 years. Examinations at base line included assessment of conventional coronary risk factors and treadmill exercise testing. The heart rate during submaximal exercise (stage 2 of the exercise test) and the duration of exercise were used as measures of physical fitness. Men with incomplete data (n = 308) or who were using cardiovascular drugs (n = 213) were excluded from the analysis. Men who had clinical evidence of cardiovascular disease at base line (n = 649) were analyzed separately. Forty-five deaths from cardiovascular causes occurred among the remaining 3106 men. A lower level of physical fitness was associated with a higher risk of death from cardiovascular and coronary heart disease, after adjustment for age and cardiovascular risk factors. The relative risk of death from cardiovascular causes was 2.7 (95 percent confidence interval, 1.4 to 5.1; P = 0.003) for healthy men with an increment of 35 beats per minute in the heart rate during stage 2, and 3.0 (95 percent confidence interval, 1.6 to 5.5; P = 0.0004) for those with a decrement of 4.4 minutes in the exercise time spent on the treadmill. The corresponding values for death from coronary heart disease were 3.2 (95 percent confidence interval, 1.5 to 6.7; P = 0.003) and 2.8 (95 percent confidence interval, 1.3 to 6.1; P = 0.007), respectively. We conclude that a lower level of physical fitness is associated with a higher risk of death from coronary heart disease and cardiovascular disease in clinically healthy men, independent of conventional coronary risk factors.

CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.