Abstract
As most of treatment options do not work very well for metastatic cancer. Patients with metastatic cancer have a greatly lower survival rate compared with patients with local cancer. ...Metastasis remains a life-threat to cancer patients and an unmet medical need. The RBP Hu antigen R (HuR) is overexpressed in virtually all malignancies tested, including breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. We found that silencing of HuR inhibited cell invasion in vitro in breast cancer. Using RIP-seq (ribonucleoprotein immunoprecipitation-sequencing), a transcription factor FOXQ1, which is recently revealed to implicate in breast cancer invasion and metastasis processes, is found to be a direct HuR target. Furthermore, exogenous introduction of FOXQ1 can rescue cell invasive ability inhibited by HuR knockout. Taken together, HuR-FOXQ1 signaling axis is a potential target for blocking breast cancer metastasis. RNA-binding proteins had previously been considered “undruggable” due to lack of a well-defined binding pocket for target RNAs. Using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that inhibit HuR-mRNA interaction at nM to sub-µM potency. Our lead compound, KH-3, potently inhibits breast cancer cell growth and decreases cell invasion in vitro similar to HuR knockout, as well as increasing the expression of epithelial marker E-cadherin. FOXQ1 overexpression abolishes the effect of KH-3 on blocking metastasis in breast cancer cells, demonstrating that the HuR inhibitor KH-3 inhibits cell metastasis by blocking FOXQ1 function. Moreover, KH-3 treatment disrupts HuR-FOXQ1 interaction in RNP-IP and FOXQ1 3′-UTR luciferase reporter assays. In vivo efficacy studies show that KH-3 not only exhibits potent antitumor efficacy in orthotopic xenograft models of breast cancer, but also efficiently blocks lung metastasis in experimental metastatic cancer model. In conclusion, we identified a potent and specific small molecule disrupter of HuR-FOXQ1 interaction for potential novel anti-metastatic therapy of breast cancer with HuR overexpression.
Citation Format: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Yu Zhan, Jiajun Liu, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 867.
•Cyanobacterial blooms are an ecological and public health issue.•Bloom loss processes are less studied than bloom formation processes.•This review presents bloom loss processes and management ...implications.•We show bloom disappearance is controlled by complex biotic and abiotic processes.•We discuss challenges for predicting effects of climate change on loss processes.
Cyanobacterial blooms present substantial challenges to managers and threaten ecological and public health. Although the majority of cyanobacterial bloom research and management focuses on factors that control bloom initiation, duration, toxicity, and geographical extent, relatively little research focuses on the role of loss processes in blooms and how these processes are regulated. Here, we define a loss process in terms of population dynamics as any process that removes cells from a population, thereby decelerating or reducing the development and extent of blooms. We review abiotic (e.g., hydraulic flushing and oxidative stress/UV light) and biotic factors (e.g., allelopathic compounds, infections, grazing, and resting cells/programmed cell death) known to govern bloom loss. We found that the dominant loss processes depend on several system specific factors including cyanobacterial genera-specific traits, in situ physicochemical conditions, and the microbial, phytoplankton, and consumer community composition. We also address loss processes in the context of bloom management and discuss perspectives and challenges in predicting how a changing climate may directly and indirectly affect loss processes on blooms. A deeper understanding of bloom loss processes and their underlying mechanisms may help to mitigate the negative consequences of cyanobacterial blooms and improve current management strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this paper, we investigate the cooperative distributed energy generation and energy trading for future smart grid. In our model, a group of energy users, who are equipped with the capabilities of ...distributed energy generation, are allowed to trade energy in a cooperative manner with the goal to minimize their total energy-provisioning cost while meeting the local demand of each individual energy user. Moreover, each user also expects to benefit from the cooperative energy generation and trading with the others. Motivated by these objectives, we first jointly determine the optimal energy scheduling decisions for all energy users such that their total energy-provisioning cost can be minimized. Then, based on the optimal energy scheduling decisions, we further determine the optimal transaction costs associated with the users' energy trading to ensure that each of them can positively benefit from the cooperation. Extensive numerical results are provided to show the advantages of the proposed cooperative energy generation and trading model as well as our proposed algorithms to achieve the optimal solutions.
Methods A total of 404 ViV procedures using SXT or S3 balloon expandable devices from the Valve-in-Valve International Data (VIVID) registry were included. Conclusions In this multicenter experience, ...excellent clinical outcomes with low complication rates were achieved after aortic ViV implantation with the S3 transcatheter heart valve.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In response to NASA's announced requirement for Earth hazard monitoring sensor-web technology, a multidisciplinary team involving sensor-network experts (Washington State University), space ...scientists (JPL), and earth scientists (USGS cascade volcano observatory (CVO)), is developing a prototype dynamic and scaleable hazard monitoring sensor-web and applying it to volcano monitoring. The combined optimized autonomous space - in-situ sensor-web (OASIS) will have two-way communication capability between ground and space assets, use both space and ground data for optimal allocation of limited power and bandwidth resources on the ground, and use smart management of competing demands for limited space assets. It will also enable scalability and seamless infusion of future space and in-situ assets into the sensor-web. The prototype will be focused on volcano hazard monitoring at Mount St. Helens, which has been active since October 2004. The system is designed to be flexible and easily configurable for many other applications as well. The primary goals of the project are: 1) integrating complementary space (i.e., Earth observing one (EO-1) satellite) and in-situ (ground-based) elements into an interactive, autonomous sensor-web; 2) advancing sensor-web power and communication resource management technology; and 3) enabling scalability for seamless infusion of future space and in-situ assets into the sensor-web. To meet these goals, we are developing: 1) a test-bed in-situ array with smart sensor nodes capable of making autonomous data acquisition decisions; 2) efficient self-organization algorithm of sensor-web topology to support efficient data communication and command control; 3) smart bandwidth allocation algorithms in which sensor nodes autonomously determine packet priorities based on mission needs and local bandwidth information in real-time; and 4) remote network management and reprogramming tools. The space and in-situ control components of the system will be integrated such that each element is capable of autonomously tasking the other. Sensor-Web data acquisition and dissemination will be accomplished through the use of the open geospatial consortium sensor-web enablement protocols. The three-year project will demonstrate end-to-end system performance with the in-situ test-bed at Mount St. Helens and NASA's EO-1 platform.
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