Gene fusions have a critical role in cancer progression. Mechanisms associated with the genesis and cell type specificity of these fusions are not well understood. A prototypical gene fusion, TMPRSS2-ERG, involves the 5' untranslated region of the androgen-regulated gene TMPRSS2 with the ERG gene, and is the most common gene fusion associated with prostate cancer. We demonstrate that androgen signaling induces chromosomal proximity between TMPRSS2 and ERG loci, and facilitates the formation of the TMPRSS2-ERG gene fusion when subjected to an agent that causes DNA double strand breaks. These results provide a conceptual framework for the genesis of gene fusions and may provide suggestions as to the general etiology of human prostate cancer.Gene fusions are a hallmark of cancer development (1), but the mechanisms underlying their genesis and cell type specificities are unclear (2).Fusions of the TMPRSS2 and ERG genes, which are located 3 Mb apart on human chromosome 21q22.2, are found in about 50% of prostate cancers and consist of the 5' untranslated region of TMPRSS2, an androgen-regulated gene, fused to the protein-coding sequence of ERG, which encodes an erythroblast transformation-specific (ETS) transcription factor (2). Recently, estrogen was shown to induce rapid chromosomal movements that bring together estrogen receptor α-bound genes on different chromosomes (3). Given the broad similarities between estrogen and androgen signaling, we hypothesized that androgen might likewise induce chromosomal movements and bring together the TMPRSS2 and ERG genes, thereby facilitating the formation of gene fusions.To examine the effects of androgen signaling on the formation of TMPRSS2-ERG, we studied LNCaP prostate cancer cells, which are androgen sensitive but lack this fusion gene (4) (fig.

The purpose of this study was to examine the effects of intermittent versus continuous energy restriction on body composition, resting metabolic rate, and eating behaviors in resistance-trained females. Thirty-eight resistance-trained females (mean ± standard deviation age: 22.3±4.2 years) were randomized to receive either six weeks of a continuous 25% reduction in energy intake (n= 18), or one week of energy balance after every two weeks of 25% energy restriction (eight weeks total; n= 20). Participants were instructed to ingest 1.8 g protein/kilogram bodyweight per day and completed three weekly supervised resistance training sessions throughout the intervention. There were no differences between groups for changes over time in body composition, resting metabolic rate, or seven of the eight measured eating behavior variables (p > 0.05). However, a significant group-by-time interaction for disinhibition (p < 0.01) from the Three-Factor Eating Questionnaire was observed, with values (± standard error) in the continuous group increasing from 4.91 ± 0.73 to 6.17 ± 0.71, while values in the intermittent group decreased from 6.80 ± 0.68 to 6.05 ± 0.68. Thus, diet breaks do not appear to induce improvements in body composition or metabolic rate in comparison with continuous energy restriction over six weeks of dieting, but may be employed for those who desire a short-term break from an energy-restricted diet without fear of fat regain. While diet breaks may reduce the impact of prolonged energy restriction on measures of disinhibition, they also require a longer time period that may be less appealing for some individuals.

The question posed in the 2010-2011 AIAA Design Build Fly competition included three missions, each scored differently. The first mission required that the aircraft fly, without payload, around a predetermined competition course and complete as many laps as possible within a four minute flight time. The second mission required that the aircraft complete three laps with a payload of a steel bar. The bar was required to be a minimum of three inches wide by four inches long; the depth of the bar was determined by the team. The third and final mission required that the aircraft complete three laps with a team-selected payload of golf balls. For the first mission, the team focused on eliminating excess weight while maintaining structural integrity. The aircraft needed to be able to fly quickly and endure multiple g-force turns. For the second mission, the team carried that largest steel bar that would create a predetermined optimized payload ratio. For the third mission, the team maximized the number of golf balls carried through a trade study conducted in a MATLAB optimizer. The optimal number of golf balls was found to be three. Since all payloads must be carried internally, a fully defined fuselage was implemented. In order to uphold the design requirements for the first mission, the fuselage was made streamline and was constructed from ultra lightweight material. Extraneous weight was further eliminated by use of the lightest electrical components available. Nomenclatureࣔࢻ ࣔࢻ = Downwash Derivative ࣔࢻ ࣔࢻ = Propulsion Downwash Derivative β = Variable ࣔࣕ ࣔࢻ = Downwash η = Variable η h = Ratio between Pressure at the Tail and the Freestream Pressure Λ max,t = Sweep at Max Thickness A = Aspect Ratio AVL = Athena Vortex Latice b = Wing Span c = Chord C D = Drag Coefficient C D0

The purpose of this study is to unravel the cellular mechanisms underlying the oncogenic ETS gene fusions, which are a hallmark of prostate cancer development. Recurrent gene fusions involving the 5’untranslated region of the androgen-regulated gene TMPRSS2 and the ETS family genes are observed in a majority of prostate cancers. Among the ETS family gene fusions, the TMPRSS2-ERG fusions involving the 5’untranslated region of TMPRSS2 with the ERG gene are the most common and found in approximately 50% of prostate cancers. However, the origins and functional consequences of ETS gene fusions are not clear. Using dual color fluorescence in situ hybridization (FISH), we demonstrate that stimulation with dihydrotestosterone (DHT) induces proximity between TMPRSS2 and ERG genomic loci in LNCaP cells, which are androgen sensitive and lack the TMPRSS2-ERG gene fusions. This effect was dependent on androgen receptor (AR). Importantly, androgen did not induce proximity between the TMPRSS2 and ERG loci in DU145 human prostate cancer cells, which are androgen insensitive. Further, a combination of androgen signaling and genotoxic stress that induces DNA double strand breaks results in the formation of TMPRSS2-ERG gene fusions in LNCaP cells. Interestingly, we observe that the ERG protein formed as a result of gene fusion binds to the promoter of wild type ERG and activates its transcription. The VCaP cell line that endogenously harbors the TMPRSS2-ERG gene fusion has high levels of wild type ERG. Treatment with androgens induces the expression of both the TMPRSS2-ERG and wild type ERG transcripts in VCaP cells. Lenti virus mediated stable over expression of TMPRSS2-ERG in PC3 cells results in an increase in the expression levels of wild type ERG. This auto-activation of wild type ERG is observed in about 50% of clinically localized and 25% of metastatic prostate cancers harboring the TMPRSS2-ERG gene fusions, but not in ETS negative prostate cancers. Taken together, our studies provide a mechanistic framework for the up-regulation of ERG transcription in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2155. doi:10.1158/1538-7445.AM2011-2155