The Glue Grant experience: characterizing the post injury genomic response.

Despite ongoing improvements in resuscitation, care, and outcomes, traumatic injury remains a significant health care and economic burden. The causes are multifactorial, but our approach to the clinical management of these patients remains limited by our current understanding of the pathobiology of the disease. A multicenter, multidisciplinary program known as the "Inflammation and the Host Response to Injury" Large Scale Collaborative Research Program was created by the National Institute of General Medical Sciences (NIGMS, U54 GM062119-10) in 2001 in a 10-year effort to address some of these issues. Its primary goal is to describe the human genomic response to severe trauma and burns, and to examine changes in gene expression in the context of different clinical outcomes. The Program has not only successfully implemented clinical care guidelines for managing the severe trauma patient based on the best available evidence to minimize iatrogenic variability, but it has also examined the genome-wide, immune-inflammatory response in total and isolated blood leukocyte populations. This review will address current milestones as well as future directions for the Program.

Calorie restriction influences cell cycle protein expression and DNA synthesis during liver regeneration.

Calorie restriction without essential nutrient deficiency (calorie restriction, CR) abrogates experimental carcinogenesis and extends healthful life span. To test whether CR influences cell-cycle protein expression during the hepatocellular proliferation induced by 70% partial hepatectomy (PH), BALB/c mice were separated into two groups, fed comparable semi-purified diets for 10 weeks that differed 40% in caloric offering, and were then subjected to PH. When PH was performed, CR mice weighed 36% less than ad libitum (AL)-fed mice (P < 0.01), but liver-to-body weight ratios were similar. During the regenerative hyperplasia, hepatocytes of CR mice demonstrated evidence of accelerated entrance and passage through G1 and S phases, and an earlier exit from the cell cycle. The first peak of DNA synthesis occurred 6 hr earlier, and the second peak was significantly greater among CR mice with 38% +/- 13% bromodeoxyuridine (BrdU)-positive hepatocytes, compared with 14% +/- 4% in AL mice (P < 0.01). More E2F-1 expression was induced at the hepatic G1/S boundary just prior to each peak of DNA synthesis in regenerating livers of CR mice (P < 0.01), and 8 hr earlier among CR mice. More hyperphosphorylated retinoblastoma p110 was detected during hepatic G1 and the G1-S transition among CR mice, coincident with the early hepatocellular proliferative wave. Cyclin A was induced during the first peak of DNA synthesis 4 hr earlier among CR mice, and it continued 4 hr longer in AL mice, indicating an earlier post-replicative exit by hepatocytes in CR mice. p21 was induced during the G1 phase at 4 hr post-PH, and was maximally expressed during and after peak DNA synthesis in both dietary groups. These results indicate that CR influences cell cycle protein expression levels, causing hepatocytes to enter into S phase earlier and exit abruptly from the cell cycle, and they support the premise that CR enhances induced cell responsiveness by influencing cell cycle regulatory controls.

Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression.

Tumor antigen-specific T-cell tolerance may limit the efficacy of therapeutic cancer vaccines. Direct presentation of antigens by tumor cells incapable of providing adequate costimulation to tumor-specific T cells has been suggested as the basis for this unresponsiveness. Using parent-into-F1 bone marrow (BM) chimeras, this study unambiguously demonstrates that the induction of this tolerant state requires T-cell recognition of tumor antigen presented by BM-derived antigen-presenting cells (APCs), not tumor cells themselves. In the absence of host APC presentation, tumor-specific T cells remained functional, even in the setting of antigen expressed by B-cell lymphomas residing in secondary lymphoid tissues. The intrinsic APC capacity of tumor cells has therefore little influence over T-cell priming versus tolerance, a decision that is regulated at the level of host APCs. (Blood. 2001;98:1070-1077)