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Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to downregulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers. [Cancer Res 2007;67(20):9762-70]

This multicenter study compared health-related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2-year survival were collected with the Infant Toddler Quality of Life Instrument or the Child Health Questionnaire Parent Form 50 parent surveys. Family functioning was assessed with the Family Assessment Device (FAD) completed by each participant's family members. Demographic and clinical information were retrieved from the Studies of Pediatric Liver Transplant database. Recipients 5 years of age and older scored lower than a normative sample in physical health (P Ͻ 0.001), general health (P Ͻ 0.001), parental emotional impact (P Ͻ 0.001), and disruption of family activities (P Ͻ 0.001). Younger children, 2 to 5 years of age, scored lower than controls in global health (P ϭ 0.004) and general health perceptions (P Ͻ 0.001) but did not differ in subscales measuring physical and psychosocial outcomes. Univariate analysis among the subscales identified demographic but not clinical variables as significant predictors of HRQOL. Mean scores of FAD scales were below published thresholds indicating healthy family functioning. As reported in previous studies, parents of older recipients reported higher levels of stress, although their level of family function appears normal. Significant associations were also observed between FAD scores and demographic variables, suggesting that further investigation of the impact of race, parental marital status, and socio-economic status on the patient rehabilitation process is needed. Liver Transpl 14: 460-468, 2008. © 2008 AASLD. Received May 9, 2007 accepted August 17, 2007. See Editorial on Page 415Children account for 12%-15% of all liver transplants performed each year in the United States. Liver transplantation is an expensive, complex intervention for children with life-threatening liver disease. With improved immunosuppressive regimens and operative techniques, 10-year patient survival rates currently approach 80%.1 Yet, patient and graft survival are not the only outcomes of interest in this population. The expectation is that these survivors will lead healthy lives, performing everyday activities, free from the burden of chronic illness. Analysis of health-related quality of life (HRQOL) in these patients is an initial step in determining if these expectations are being fulfilled. HRQOL refers to those aspects of quality of life that are directly related to health and are potentially affected by the health-care system. The 5 aspects of health that comprise HRQOL include physical health, mental

Post transplant lymphoproliferative disorder (PTLD) causes significant morbidity and mortality in pediatric recipients of liver transplantation (LT). Objective Describe the incidence of PTLD and symptomatic Epstein Barr virus disease (SEBV) in a large multicenter cohort of children who have undergone LT focused on the risk factors and changes in incidence over time. Methods Prospective determination of SEBV and PTLD in 2283 subjects who had undergone a first LT with at least 1 year of follow up in the Studies of Pediatric Liver Transplantation database. SEBV was defined by specific criteria and PTLD required tissue confirmation. Incidences of SEBV and PTLD were determined by Kaplan Meier. Univariate and multivariate modeling of risk factors were performed using standard methods. Results SEBV occurred in 199, of whom 174 (87.4%) were EBV negative at LT. 75 patients developed PTLD of whom 64 (85.3%) were EBV negative at LT. Of 2048 patients with at least 2 years of follow-up, 8.3% developed SEBV and 2.8% PTLD by the second year post-LT. There was a lower incidence of SEBV (11.3% vs 5.9, p<0.0001) and PTLD (4.2 vs. 1.7, p=0.0011) in 2002-07 compared to 1995-2001. Tacrolimus and cyclosporine trough blood levels in the first year post transplant were significantly lower and fewer children were receiving steroids in 02-07. Era of LT, EBV negative recipient status, younger age, biliary atresia and frequent rejection episodes were associated with an increased risk for SEBV and PTLD in univariate analysis. Age, biliary atresia and EBV recipient status were correlated. In multivariate analysis era of LT, EBV recipient status and frequent rejection episodes was associated with SEBV and PTLD. Conclusions The incidence of SEBV and PTLD is decreasing in pediatric LT recipients coincident with a reduction in immunosuppression. Younger recipients and those with multiple rejections remain at higher risk for SEBV and PTLD.