In normal cells, aberrant oncogene expression leads to the accumulation of cytotoxic metabolites, including reactive oxygen species (ROS), which can cause oxidative DNA-damage and apoptosis as an intrinsic barrier against neoplastic disease. The c-Myc oncoprotein is overexpressed in many lymphoid cancers due to c-myc gene amplification and/or 8q24 chromosomal translocations. Intriguingly, p53 is a downstream target of c-Myc and hematological malignancies, such as adult T-cell leukemia/lymphoma (ATL), frequently contain wildtype p53 and c-Myc overexpression. We therefore hypothesized that p53-regulated pro-survival signals may thwart the cell's metabolic anticancer defenses to support oncogene-activation in lymphoid cancers. Here we show that the Tp53-induced glycolysis and apoptosis regulator (TIGAR) promotes c-myc oncogene-activation by the human T-cell leukemia virus type-1 (HTLV-1) latency-maintenance factor p30, associated with c-Myc deregulation in ATL clinical isolates. TIGAR prevents the intracellular accumulation of c-Myc-induced ROS and inhibits oncogene-induced cellular senescence in ATL, acute lymphoblastic leukemia, and multiple myeloma cells with elevated c-Myc expression. Our results allude to a pivotal role for p53-regulated antioxidant signals as mediators of c-Myc oncogenic functions in viral and non-viral lymphoid tumors.

Objective. We have previously reported a defect in neutrophil activation in children with polyarticular juvenile idiopathic arthritis (JIA). The current study was undertaken to determine whether gene expression abnormalities persist in JIA in remission and to use systems biology analysis to elucidate pathologic pathways in polyarticular JIA.Methods. We performed gene expression profiling on neutrophils from children with polyarticular JIA. Children were grouped according to disease status. We studied 14 children with active disease who were taking medication, 8 children with clinical remission of disease who were taking medication (CRM status), and 6 children with clinical remission of disease who were not taking medication (CR status). We also studied 13 healthy children whose age ranges overlapped those of the patients.Results. Neutrophil abnormalities persisted in children with polyarticular JIA even after disease remission was achieved. Children with active disease and those with CRM status showed no differences in expression of specific genes, although they could be separated on cluster analysis. A comparison of children with CR status and healthy control children revealed networks of pro-and antiinflammatory genes that suggested that remission is a state of homeostasis and balance rather than a return to normal immune function. Furthermore, gene overexpression in patients with CR status supports the hypothesis that neutrophils play a role in regulating adaptive immunity in this disease.Conclusion. Neutrophil gene profiling in polyarticular JIA suggests important roles for neutrophils in disease pathogenesis. These findings suggest the presence of complex interactions between innate and adaptive immunity, that are not easily modeled in conventional, linear, reductionist systems.Juvenile idiopathic arthritis (JIA) is a term used to denote a family of diseases of unknown etiology characterized by chronic inflammation of synovial membranes (1). Distinct phenotypes are recognized clinically, with specific immunogenetic markers associated with each of the phenotypes (2,3).While the JIA subtypes have commonly been assumed to have an "autoimmune" origin, our growing understanding of biologic complexity makes any such simple, linear hypothesis of disease pathogenesis unlikely (4). We have hypothesized that the pathogenesis

Objective. The development of biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) is an important issue in pediatric rheumatology. A critical step in this process is determining whether there is biologic meaning to clinically derived terms such as "active disease" and "remission." The aim of this study was to use a systems biology approach to address this question. Methods.We performed gene transcriptional profiling on children who fulfilled the criteria for specific disease states as defined by the consensus criteria developed by Wallace and colleagues. The study group comprised children with active disease (n ‫؍‬ 14), children with clinical remission on medication (CRM; n ‫؍‬ 9), children with clinical remission off medication (CR; n ‫؍‬ 6), and healthy control children (n ‫؍‬ 13). Transcriptional profiles in peripheral blood mononuclear cells (PBMCs) were obtained using Affymetrix U133 Plus 2.0 arrays.Results. Hierarchical cluster analysis and predictive modeling demonstrated that the clinically derived criteria represent biologically distinct states. Minimal differences were seen between children with active disease and those with disease in CRM. Thus, underlying immune/inflammatory abnormalities persist despite a response to therapy. The PBMC transcriptional profiles of children whose disease was in remission did not return to normal but revealed networks of proinflammatory and antiinflammatory genes, suggesting that remission is a state of homeostasis, not a return to a normal state.Conclusion. Gene transcriptional profiling of PBMCs revealed that clinically derived criteria for JIA disease states reflect underlying biology. We also demonstrated that neither CRM nor CR status results in resolution of the underlying inflammatory process, but that these conditions are more likely to be states of balanced homeostasis between proinflammatory and antiinflammatory mechanisms.

Background: While standard reductionist approaches have provided some insights into specific gene polymorphisms and molecular pathways involved in disease pathogenesis, our understanding of complex traits such as atherosclerosis or type 2 diabetes remains incomplete. Gene expression profiling provides an unprecedented opportunity to understand complex human diseases by providing a global view of the multiple interactions across the genome that are likely to contribute to disease pathogenesis. Thus, the goal of gene expression profiling is not to generate lists of differentially expressed genes, but to identify the physiologic or pathogenic processes and structures represented in the expression profile.

Introduction:The craniofacial asymmetry seen in unilateral lambdoid craniosynostosis may not be effectively treated by posterior cranial vault remodeling, endoscopic suturectomy, and helmet therapy, or suturectomy and distraction osteogenesis alone due to limitations in soft-tissue envelope expansion and relapse of the deformity. The authors report a series of unilateral lambdoid craniosynostosis patients treated with a posterior rotational cranial-flap technique using internal distraction osteogenesis. Methods: Posterior cranial vault reconstruction combined with internal distraction was used, aided by preoperative virtual surgical planning. An in situ posterior rotational flap osteotomy was utilized to maximize dural preservation. Primary outcome measures included age-adjusted volume change and age-adjusted percent volume change per mm distraction. Distraction characteristics and perioperative characteristics were also assessed. Results: A total of 5 patients were identified. Mean predistraction intracranial volume was 1087.5 cc (SD ¼ 202.3 cc) and mean postdistraction included intracranial volume was 1266.1cc (SD ¼ 131.8cc). Mean age-adjusted percent included intracranial volume change was 14.1% (SD ¼ 9.6%), and mean percent intracranial volume change per mm distraction was 0.43%/mm distraction (SD ¼ 0.37%/mm distraction). One patient developed a distractor site infection postoperatively that was treated successfully with oral antibiotics. All patients had a Whitaker score of 1 at one year follow up. Conclusions: Posterior cranial vault remodeling using osteogenesis and a rotational cranial flap technique with dural preservation can be effectively used to maximize bone flap viability and limit postoperative relapse in patients with unilateral lambdoid craniosynostosis. Long term analysis as well as comparison to open techniques will need to be interrogated.