MDA-9/Syntenin: From Glioblastoma Pathogenesis to Targeted Therapy

The most common malignant glioma, glioblastoma multiforme (GBM), remains an intractable tumor despite advances in therapy. Its proclivity to infiltrate surrounding brain tissue contributes greatly to its treatment failure and the grim prognosis of patients. Radiation is a staple in modern therapeutic regimens, though cells surviving radiation become more aggressive and invasive. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/Syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in human melanoma models. We show that MDA-9/Syntenin is robustly expressed in GBM cell lines and patient samples, and expression increases by tumor grade. These findings are confirmed through database analysis, which revealed MDA-9/Syntenin expression correlates with shorter survival times and patient tumors high in MDA-9/Syntenin have a worse prognosis when undergoing radiotherapy. Modulating MDA-9/Syntenin levels produced changes in invasion, angiogenesis, and signaling, indicating MDA-9/Syntenin enhances glioma pathogenesis. Overexpression of MDA-9/Syntenin enhances invasion, while knockdown inhibits invasion, migration, and anchorage-independent growth in soft agar. MDA-9/Syntenin increases activation of c-Src, P38MAPK, and NF-kB, leading to elevated MMP2 expression and IL-8 secretion. Through an orthotopic tumor model, we show that shmda-9 tumor cells formed smaller tumors and had a less invasive phenotype in vivo. Knockdown of MDA-9/Syntenin radiosensitizes GBM cells and significantly reduces post-radiation invasion gains through abrogation of radiation-induced Src and EphA2 activity. In efforts to pharmacologically inhibit MDA-9/Syntenin, we describe the effects of a novel small molecule, PDZ1i, which targets the PDZ1 domain of MDA-9/Syntenin and successfully reduces invasion gains in GBM cells following radiation. While it does not effect astrocyte radiosensitivity, PDZ1i radiosensitizes GBM cells. PDZ1i inhibits crucial GBM signaling including FAK and mutant EGFR, EGFRvIII, and can negate gains in secreted proteases, such as MMP2 and MMP9, following radiation. In a model of glioma, PDZ1i treatment combined with radiation results in less invasive tumors and extends survival. Our findings indicate that MDA-9/Syntenin is a novel and important mediator of GBM pathogenesis, and further identify it as a targetable protein that enhances radiotherapy for treatment in glioma

Increasing Efficiency at the NTF by Optimizing Model AoA Positioning

The National Transonic Facility (NTF) at NASA Langley Research Center (LaRC) is a national resource for aeronautical research and development. The government, military and private industries rely on the capability of this facility for realistic flight data. Reducing the operation costs and keeping the NTF affordable is essential for aeronautics research. The NTF is undertaking an effort to reduce the time between data points during a pitch polar. This reduction is being driven by the operating costs of a cryogenic facility. If the time per data point can be reduced, a substantial cost savings can be realized from a reduction in liquid nitrogen (LN2) consumption. It is known that angle-of-attack (AoA) positioning is the longest lead-time item between points. In January 2005 a test was conducted at the NTF to determine the cause of the long lead-time so that an effort could be made to improve efficiency. The AoA signal at the NTF originates from onboard instrumentation then travels through a number of different systems including the signal conditioner, digital voltmeter, and the data system where the AoA angle is calculated. It is then fed into a closed loop control system that sets the model position. Each process along this path adds to the time per data point affecting the efficiency of the data taking process. Due to the nature of the closed loop feed back AoA control and the signal path, it takes approximately 18 seconds to take one pitch pause point with a typical AoA increment. Options are being investigated to reduce the time delay between points by modifying the signal path. These options include: reduced signal filtering, using analog channels instead of a digital volt meter (DVM), re-routing the signal directly to the AoA control computer and implementing new control algorithms. Each of these has potential to reduce the positioning time and together the savings could be significant. These timesaving efforts are essential but must be weighed against possible loss of data quality. For example, a reduction in filtering can introduce noise into the signal and using analog channels could result in some loss of accuracy. Data quality assessments need to be performed concurrently with timesaving techniques since data quality parameters are essential in maintaining facility integrity. This paper will highlight time saving efforts being undertaken or studied at the NTF. It will outline the instrumentation and computer systems involved in setting of the model pitch attitude then suggest changes to the process and discuss how these system changes would effect the time between data points. It also discusses the issue of data quality and how the potential efficiency changes in the system could affect it. Lastly, it will discuss the possibility of using an open loop control system and give some pros and cons of this method

Combinatorial Roles Of Skeletal Cell Yap And Taz In Bone Growth, Remodeling, And Repair

During bone growth, remodeling, and fracture repair, skeletal lineage cell responses require the coordinated activation of multiple transcriptional programs. As defective genetic regulation of bone formation leads to both developmental and metabolic skeletal diseases, identifying and characterizing novel transcriptional regulators of skeletal growth, remodeling and repair is important to the future development of targeted therapeutics. The functions of the paralogous transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in bone are controversial, with evidence for each either promoting or inhibiting osteogenesis in vitro. Here, we used in vivo mouse models of combinatorial YAP/TAZ deletion from skeletal lineage cells to investigate their physiologic roles in bone growth, remodeling, and fracture repair. First, YAP and TAZ in Osterix-expressing cells combinatorially promoted bone development and growth by regulating osteoblast function, paracrine regulation of osteoclastic remodeling, and bone matrix quality. Furthermore, combinatorial YAP and/or TAZ deletion from Osterix-expressing cells mimicked the clinical skeletal fragility disease, osteogenesis imperfecta, with spontaneous fractures and dysregulated collagen composition leading to reduced bone mechanical properties. Second, YAP and TAZ deletion later in the skeletal lineage, from DMP1-expressing cells, promoted bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated coordination of osteoblast/osteoclast activity and osteocytic perilacunar/canalicular remodeling. Finally, YAP and TAZ in Osterix-expressing cells combinatorially promoted the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. Taken together, these data establish the paralogous transcriptional co-activators, YAP and TAZ, as important regulators of bone formation and function during skeletal growth, remodeling, and fracture repair. Further elucidation of the signaling pathways that control YAP/TAZ-dependent transcriptional regulation during bone function could enable future therapies to reverse skeletal fragility and enhance bone healing

Advanced Capabilities for Wind Tunnel Testing in the 21st Century

Wind tunnel testing methods and test technologies for the 21st century using advanced capabilities are presented. These capabilities are necessary to capture more accurate and high quality test results by eliminating the uncertainties in testing and to facilitate verification of computational tools for design. This paper discusses near term developments underway in ground testing capabilities, which will enhance the quality of information of both the test article and airstream flow details. Also discussed is a selection of new capability investments that have been made to accommodate such developments. Examples include advanced experimental methods for measuring the test gas itself; using efficient experiment methodologies, including quality assurance strategies within the test; and increasing test result information density by using extensive optical visualization together with computed flow field results. These points could be made for both major investments in existing tunnel capabilities or for entirely new capabilities

The Langley Wind Tunnel Enterprise

After 4 years of existence, the Langley WTE is alive and growing. Significant improvements in the operation of wind tunnels have been demonstrated and substantial further improvements are expected when we are able to truly address and integrate all the processes affecting the wind tunnel testing cycle

Langley Ground Facilities and Testing in the 21st Century

A strategic approach for retaining and more efficiently operating the essential Langley Ground Testing Facilities in the 21st Century is presented. This effort takes advantage of the previously completed and ongoing studies at the Agency and National levels. This integrated approach takes into consideration the overall decline in test business base within the nation and reduced utilization in each of the Langley facilities with capabilities to test in the subsonic, transonic, supersonic, and hypersonic speed regimes. The strategy accounts for capability needs to meet the Agency programmatic requirements and strategic goals and to execute test activities in the most efficient and flexible facility operating structure. The structure currently being implemented at Langley offers agility to right-size our capability and capacity from a national perspective, to accommodate the dynamic nature of the testing needs, and will address the influence of existing and emerging analytical tools for design. The paradigm for testing in the retained facilities is to efficiently and reliably provide more accurate and high-quality test results at an affordable cost to support design information needs for flight regimes where the computational capability is not adequate and to verify and validate the existing and emerging computational tools. Each of the above goals are planned to be achieved, keeping in mind the increasing small industry customer base engaged in developing unpiloted aerial vehicles and commercial space transportation systems

Changing patterns of residential rental property investment in Holyoke, Massachusetts

Thesis (M.C.P.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 1991.Includes bibliographical references.by Thomas P. Kegelman.M.C.P

Revitalization of the NASA Langley Research Center's Infrastructure

The NASA Langley Research Center (Langley) was founded in 1917 as the nation's first civilian aeronautical research facility and NASA's first field center. For nearly 100 years, Langley has made significant contributions to the Aeronautics, Space Exploration, and Earth Science missions through research, technology, and engineering core competencies in aerosciences, materials, structures, the characterization of earth and planetary atmospheres and, more recently, in technologies associated with entry, descent, and landing. An unfortunate but inevitable outcome of this rich history is an aging infrastructure where the longest serving building is close to 80 years old and the average building age is 44 years old. In the current environment, the continued operation and maintenance of this aging and often inefficient infrastructure presents a real challenge to Center leadership in the trade space of sustaining infrastructure versus not investing in future capabilities. To address this issue, the Center has developed a forward looking revitalization strategy that ties future core competencies and technical capabilities to the Center Master Facility Plan to maintain a viable Center well into the future. This paper documents Langley's revitalization strategy which integrates the Center's missions, the Langley 2050 vision, the Center Master Facility Plan, and the New Town repair-by-replacement program through the leadership of the Vibrant Transformation to Advance Langley (ViTAL) Team

A Future State for NASA Laboratories - Working in the 21st Century

The name "21 st Century Laboratory" is an emerging concept of how NASA (and the world) will conduct research in the very near future. Our approach is to carefully plan for significant technological changes in products, organization, and society. The NASA mission can be the beneficiary of these changes, provided the Agency prepares for the role of 21st Century laboratories in research and technology development and its deployment in this new age. It has been clear for some time now that the technology revolutions, technology "mega-trends" that we are in the midst of now, all have a common element centered around advanced computational modeling of small scale physics. Whether it is nano technology, bio technology or advanced computational technology, all of these megatrends are converging on science at the very small scale where it is profoundly important to consider the quantum effects at play with physics at that scale. Whether it is the bio-technology creation of "nanites" designed to mimic our immune system or the creation of nanoscale infotechnology devices, allowing an order of magnitude increase in computational capability, all involve quantum physics that serves as the heart of these revolutionary changes