Purpose: To address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC). Experimental Design: Transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived. Results: Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern (''metastatic signature'') derived from primary tumor was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described ''global'' metastatic signature derived by another group from various non-RCC tumors was validated in RCC. Conclusion: Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC.

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This preliminary study showed that tomoxetine was effective in treating adult ADHD and was well tolerated. These promising results provide support for further studies of tomoxetine over an extended period of treatment.

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The mechanisms leading to prostate cancer metastasis are not understood completely. Although there is evidence that the CXC chemokine receptor (CXCR) 4 and its ligand CXCL12 may regulate tumor dissemination, their role in prostate cancer is controversial. We examined CXCR4 expression and functionality, and explored CXCL12-triggered adhesion of prostate tumor cells to human endothelium or to extracellular matrix proteins laminin, collagen, and fibronectin. Although little CXCR4 was expressed on LNCaP and DU-145 prostate tumor cells, CXCR4 was still active, enabling the cells to migrate toward a CXCL12 gradient. CXCL12 induced elevated adhesion to the endothelial cell monolayer and to immobilized fibronectin, laminin, and collagen. Anti-CXCR4 antibodies or CXCR4 knock out significantly impaired CXCL12-triggered tumor cell binding. The effects observed did not depend on CXCR4 surface expression level. Rather, CXCR4-mediated adhesion was established by alpha5 and beta3 integrin subunits and took place in the presence of reduced p38 and p38 phosphorylation. These data show that chemoattractive mechanisms are involved in adhesion processes of prostate cancer cells, and that binding of CXCL12 to its receptor leads to enhanced expression of alpha5 and beta3 integrins. The findings provide a link between chemokine receptor expression and integrin-triggered tumor dissemination.

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Investigated the role of maternal smoking during pregnancy in the etiology of attention deficit hyperactivity disorder (ADHD). Siblings of ADHD (N = 174) and non-ADHD (N = 129) probands were studied. Information on maternal smoking was obtained from mothers in a standardized manner blind to the sibling's ADHD and high-risk status (i.e., whether a sibling of an ADHD or non-ADHD proband). Fifteen (47%) of the high-risk siblings with ADHD had a history of maternal smoking during pregnancy compared with 33 (24%) of the siblings without ADHD (p = 0.009). This positive association remained significant after adjusting for socioeconomic status, parental IQ, and parental ADHD status. Lower IQ scores were found among those high-risk siblings whose mothers smoked during pregnancy compared with those whose mothers did not smoke. These findings extend our previous findings of an association between maternal smoking during pregnancy and ADHD. Moreover, they highlight the importance of programs aimed at smoking prevention in nonsmoking women and smoking cessation in smoking women of child-bearing age.