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]

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We report the management of a patient with the late onset of chronic graft-versus-host disease (GVHD) after orthotopic liver transplantation. GVHD is a rare complication of solid organ transplants that usually presents early after transplantation and is fatal in the majority of cases. Our patient differs from the typical patient with GVHD in that the onset of her disease was very late. Although most treatment to date consisted of an increase in immunosuppressive therapy, our patient showed an excellent response to a reduction. This resulted in the abatement of the symptoms of GVHD and the preservation of her allograft function.

Airway, sweat-duct, and other epithelial cells in patients with cystic fibrosis display abnormal ion transport. To test whether the kidney, the organ most exquisitely adapted for ion transport, has a similar defect, we measured the levels of calcium excretion and searched for microscopic nephrocalcinosis in patients with cystic fibrosis. Thirty-eight specimens of kidney tissue were stained for calcium deposits, and 24-hour levels of urinary calcium excretion were measured in 14 patients and 15 control subjects. Microscopic nephrocalcinosis was observed in 35 of the 38 specimens (92 percent), and hypercalciuria (greater than 182 mg per gram of creatinine) in 5 of the 14 patients (36 percent). Notably, nephrocalcinosis was detected near the time of birth (in six patients under one year old, including two neonates and one stillborn infant), which supports the hypothesis that such renal calcium deposits reflect the genomic defect and are not due to longstanding pulmonary dysfunction, chronic infection, therapeutic agents, or disease progression. None of the patients with hypercalciuria or nephrocalcinosis had clinical evidence of renal dysfunction. The finding of microscopic nephrocalcinosis near the time of birth in patients with cystic fibrosis suggests a primary abnormality of calcium metabolism in the kidney. Studies of the pathophysiologic features of the kidney in cystic fibrosis may elucidate the molecular alterations observed in this disorder.