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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Conclusion. ESE-1 is expressed in synovial tissues in RA and, to a variable extent, in OA, and is specifically induced in synovial fibroblasts, chondroDr. Libermann

Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.

Cyclooxygenase‐2 (COX‐2) is a key enzyme in the production of prostaglandins that are major inflammatory agents. COX‐2 production is triggered by exposure to various cytokines and to bacterial endotoxins. We present here a novel role for the Ets transcription factor ESE‐1 in regulating the COX‐2 gene in response to endotoxin and other pro‐inflammatory stimuli. We report that the induction of COX‐2 expression by lipopolysaccharide (LPS) and pro‐inflammatory cytokines correlates with ESE‐1 induction in monocyte/macrophages. ESE‐1, in turn, binds to several E26 transformation specific (Ets) sites on the COX‐2 promoter. In vitro analysis demonstrates that ESE‐1 binds to and activates the COX‐2 promoter to levels comparable to LPS‐mediated induction. Moreover, we provide results showing that the induction of COX‐2 by LPS may require ESE‐1, as the mutation of the Ets sites in the COX‐2 promoter or overexpression of a dominant‐negative form of ESE‐1 inhibits LPS‐mediated COX‐2 induction. The effect of ESE‐1 on the COX‐2 promoter is further enhanced by cooperation with other transcription factors such as nuclear factor‐κB and nuclear factor of activated T cells. Neutralization of COX‐2 is the goal of many anti‐inflammatory drugs. As an activator of COX‐2 induction, ESE‐1 may become a target for such therapeutics as well. Together with our previous reports of the role of ESE‐1 as an inducer of nitric oxide synthase in endothelial cells and as a mediator of pro‐inflammatory cytokines in vascular and connective tissue cells, these results establish ESE‐1 as an important player in the regulation of inflammation.

The nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and salicylic acid and the short chain fatty acid butyrate are effective colon cancer chemopreventive agents that increase reactive oxygen species (ROS) generation in colon cancer cells. Here we demonstrate that these agents sensitize the normally resistant human HT-29 colon cancer cell line to apoptosis induced by TNF-alpha or a Fas ligating antibody. The role of ROS in this sensitization is supported by the finding that direct exposure of the cells to H2O2 is sufficient for sensitization. Neither TNF-alpha nor Fas ligation alter basal or chemopreventive agent-activated ROS generation, suggesting that the death ligands and chemopreventive agents act in a complementary fashion. The dual chemopreventive agent/death ligand treatments do not increase Fas, TNF receptor 1, Bak or c-myc expression (although salicylic acid moderately induces of Fas expression). Cell death does correlate with alterations in NF-kappa B activity: the NSAIDs, butyrate and H2O2 enhance c-Rel complex formation by TNF-alpha and provide an overall enhancement of NF-kappa B activation by Fas. The antioxidant N-acetylcysteine (NAC) blocks cell death and NF-kappa B activation induced by Fas ligation, suggesting a potential role for NF-kappa B in Fas-induced apoptosis in these cells. The effects of NAC on TNF-alpha-induced cell death are more complex, with NAC being marginally protective and itself enhancing the formation of c-Rel containing complexes at higher concentrations (25 mM). The influence of NSAIDs and butyrate on ROS generation and death ligand sensitivity may be relevant to their ability to suppress colon carcinogenesis.

In this review, we have discussed the class-prediction and discovery methods that are applied to gene expression data, along with the implications of the findings. We attempted to present a unified approach that considers both class-prediction and class-discovery. We devoted a substantial part of this review to an overview of pattern classification/recognition methods and discussed important issues such as preprocessing of gene expression data, curse of dimensionality, feature extraction/selection, and measuring or estimating classifier performance. We discussed and summarized important properties such as generalizability (sensitivity to overtraining), built-in feature selection, ability to report prediction strength, and transparency (ease of understanding of the operation) of different class-predictor design approaches to provide a quick and concise reference. We have also covered the topic of biclustering, which is an emerging clustering method that processes the entries of the gene expression data matrix in both gene and sample directions simultaneously, in detail.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and short-chain fatty acids are effective suppressors of colorectal cancer that may work in part by accentuating apoptosis of transformed cells. Since reactive oxygen species (ROS) can play an important role in regulating cell growth and cell death, we determined the effect of the NSAIDs indomethacin and salicylic acid, and the short-chain fatty acids butyrate and propionate on ROS metabolism in the HT-29 human colorectal carcinoma cell line. We find that all of these agents increase cellular peroxide generation, as determined by two independent assays. Arachidonic acid was also found to increase ROS generation, and could synergize with indomethacin in this reaction. The NSAIDs and short-chain fatty acids under study all possess a carboxyl group, and this carboxyl group is essential for salicylic acid's ability to increase ROS production. Although the two NSAIDs examined increase peroxide production, they were both found to suppress superoxide generation by vitamin K3 (menadione), a redox cycling compound similar to those found in the colon. The short-chain fatty acids did not have this activity. The ability of these NSAIDs and short-chain fatty acids to alter cellular ROS metabolism may contribute to their chemopreventive activity.