Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor-positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observedwith PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PRmodulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored

10381 Summary and Abstracts Collection -- Robust Query Processing

Dagstuhl seminar 10381 on robust query processing (held 19.09.10 - 24.09.10) brought together a diverse set of researchers and practitioners with a broad range of expertise for the purpose of fostering discussion and collaboration regarding causes, opportunities, and solutions for achieving robust query processing. The seminar strove to build a unified view across the loosely-coupled system components responsible for the various stages of database query processing. Participants were chosen for their experience with database query processing and, where possible, their prior work in academic research or in product development towards robustness in database query processing. In order to pave the way to motivate, measure, and protect future advances in robust query processing, seminar 10381 focused on developing tests for measuring the robustness of query processing. In these proceedings, we first review the seminar topics, goals, and results, then present abstracts or notes of some of the seminar break-out sessions. We also include, as an appendix, the robust query processing reading list that was collected and distributed to participants before the seminar began, as well as summaries of a few of those papers that were contributed by some participants

Odorant receptor genes and their expression in migratory Atlantic salmon (Salmo salar, L.)

Being anadromous, the Atlantic salmon (Salmo salar, L.), spends part of its life cycle in fresh water and part of it at sea. They undertake return migrations of up to 4000km, negotiating complex oceanic environments, dendritic river systems and making numerous choices at river junctions to return to specific natal sites. As the fish near coastal waters, olfaction has been shown to be pivotal in the selection of the appropriate estuary and identification of the natal stream. Juvenile salmon are thought to imprint on biotic and/or abiotic environmental odours around the time of parr-smolt transformation (PST), and retain this information at least partly within the olfactory sensory neurons. These olfactory cues are then exploited with remarkable precision by adult migrants returning to the natal stream to spawn. Variation in olfactory receptors (OR) and pheromone receptors (or vomeronasal receptors: VNRs) expressed by these sensory neurons may therefore play a vital role in the maintenance of the structure of salmon populations, enabling numerous reproductively isolated communities to exist within one catchment area. Here, the isolation and characterisation of both OR and VNR genes from S.salar has facilitated further elucidation of the olfactory changes associated with parr-smolt transformation. Both sets of primary receptors have representatives expressed in male germ cells as well as olfactory tissue. Real-time quantitative RT-PCR has revealed that a group of OR genes (SORB) is expressed at a higher level during the early stages of PST. One group of VNR genes (SVRA) however, shows a peak of expression later in PST. There were also expression differences observed between families of fish. Only one family showed a significant increase in expression of SORB and SVRA, the other family presumably using other receptor types not included in this study. Molecular evidence therefore indicates that there is more than one incidence of specific-olfactory sensitivity involved in the smelting process. The stimulation of expression of two independent groups of chemosensory receptors indicates that both odours and semiochemicals play a role in olfactory imprinting. The odorant receptors involved in olfactory imprinting appear to vary between families of fish which suggests interfamilial differences in odour stimuli

NASA/ASEE Summer Faculty Fellowship Program

This document is a collection of technical reports on research conducted by the participants in the 1993 NASA/ASEE Summer Faculty Fellowship Program at KSC. The basic common objectives of the Program are: to further the professional knowledge of qualified engineering and science faculty members; to stimulate an exchange of ideas between participants and NASA; to enrich and refresh the research and teaching activities of participants' institutions; and to contribute to the research objectives of the NASA centers. 1993 topics include wide band fiber optic communications, a prototype expert/information system for examining environmental risks of KSC activities, alternatives to premise wiring using ATM and microcellular technologies, rack insertion end effector (RIEE) automation, FTIR quantification of industrial hydraulic fluids in perchloroethylene, switch configuration for migration to optical fiber network, and more

Three Essays on Finance and Product Market Competition

This dissertation consists of three essays on finance and product market competition. In the first essay, I investigate corporate agility, the importance of which is emphasized in both field and academic research but understudied empirically. Using the business descriptions provided in firms’ 10-K filings with the SEC as the main input, I construct a novel measure of corporate agility and confirm its validity. Next, I identify various firm flexibility measures as the determinants of corporate agility. I next find that product market performance improves with agility in the short-run and firm survival likelihood increases with agility in the long-run. I also document that the benefits of corporate agility are particularly realized when firms face industry-wide common shocks such as R&D or M&A waves, or trade barrier reductions and that firms increase agility at the expense of short-term profitability. Lastly, I find that agility is a negative predictor of future returns even after controlling for other firm risks and characteristics. In the second essay, I investigate negative externalities of innovations along supply chains by analyzing the effects of customers’ innovations on suppliers’ trade credit provision. I find that suppliers extend more trade credit after customers innovate, and the effect is robust to controlling for various firm characteristics and industry-specific market conditions and to addressing potential endogeneity issues. The effect is mainly driven by the holdup channel as opposed to the demand channel or the financing channel. Next, I document that greater technological overlap between customers’ innovation and suppliers’ innovations attenuates the effect. Lastly, I find that suppliers adopt more conservative financial policies and innovate more by learning from customer’s innovation. In the third essay, I investigate industry spillover effects of corporate fraud. Using a sample of securities class action lawsuits, I document that fraud mitigates financial constraints of product market rivals. This positive intra-industry spillover effect is stronger for firms in more concentrated industries or firms with less analyst coverage. In contrast, fraud worsens financial constraints for firms in the top-supplier and top-customer industries of the fraud firms. The negative spillover effect is dependent on trade credit provision

Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex