Evolution of NASA's Near-Earth Tracking and Data Relay Satellite System (TDRSS)

NASA's Tracking and Data Relay Satellite System (TDRSS) is now in its 23rd year of operations and its spacecraft fleet includes three second-generation spacecraft launched since the year 2000; a figure illustrates the first generation TDRSS spacecraft. During this time frame the TDRSS has provided communications relay support to a broad range of missions, with emphasis on low-earth-orbiting (LEO) spacecraft that include unmanned science spacecraft (e.g., Hubble Space Telescope), and human spaceflight (Space Shuttle and Space Station). Furthermore, the TDRSS has consistently demonstrated its uniqueness and adaptability in several ways. First, its S- and K-band services, combined with its multi-band/steerable single-access (SA) antennas and ground-based configuration flexibility, have permitted the mission set to expand to unique users such as scientific balloons and launch vehicles. Second, the bent-pipe nature of the system has enabled the introduction of new/improved services via technology insertion and upgrades at each of the ground terminals; a specific example here is the Demand Access Service (DAS), which, for example, is currently providing science-alert support to NASA science missions Third, the bent-pipe nature of the system, combined with the flexible ground-terminal signal processing architecture has permitted the demonstration/vaIidation of new techniques/services/technologies via a real satellite channel; over the past 10+ years these have, for example, included demonstrations/evaluations of emerging modulation/coding techniques. Given NASA's emerging Exploration plans, with missions beginning later this decade and expanding for decades to come, NASA is currently planning the development of a seamless, NASA-wide architecture that must accommodate missions from near-earth to deep space. Near-earth elements include Ground-Network (GN) and Near-Earth Relay (NER) components and both must efficiently and seamlessly support missions that encompass: earth orbit, including dedicated science missions and lunar support/cargo vehicles; earth/moon transit; lunar in-situ operations; and other missions within approximately 2 million km of earth (e.g., at the sun/earth libration points). Given that the NER is an evolution of TDRSS, one element of this NASA-wide architecture development activity is a trade study of future NER architecture candidates. The present paper focuses on trade study aspects associated with the NER, highlights study elements, and provides representative interim results

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance

Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anti-cancer drugs. We found that stroma-mediated resistance is surprisingly common – particularly to targeted agents. We further characterized the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most of these patients exhibit some degree of innate resistance1-4. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed stromal HGF expression in patients with BRAF-mutant melanoma and a statistically significant correlation between stromal HGF expression and innate resistance to treatment. Dual inhibition of RAF and MET resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance

Next Generation Bipolar Plates for Automotive PEM Fuel Cells

The results of a successful U.S. Department of Energy (DoE) funded two-year $2.9 MM program lead by GrafTech International Inc. (GrafTech) are reported and summarized. The program goal was to develop the next generation of high temperature proton exchange membrane (PEM) fuel cell bipolar plates for use in transportation fuel cell applications operating at temperatures up to 120 °C. The bipolar plate composite developed during the program is based on GrafTech’s GRAFCELL resin impregnated flexible graphite technology and makes use of a high temperature Huntsman Advanced Materials resin system which extends the upper use temperature of the composite to the DoE target. High temperature performance of the new composite is achieved with the added benefit of improvements in strength, modulus, and dimensional stability over the incumbent resin systems. Other physical properties, including thermal and electrical conductivity of the new composite are identical to or not adversely affected by the new resin system. Using the new bipolar plate composite system, machined plates were fabricated and tested in high temperature single-cell fuel cells operating at 120 °C for over 1100 hours by Case Western Reserve University. Final verification of performance was done on embossed full-size plates which were fabricated and glued into bipolar plates by GrafTech. Stack testing was done on a 10-cell full-sized stack under a simulated drive cycle protocol by Ballard Power Systems. Freeze-thaw performance was conducted by Ballard on a separate 5-cell stack and shown to be within specification. A third stack was assembled and shipped to Argonne National Laboratory for independent performance verification. Manufacturing cost estimate for the production of the new bipolar plate composite at current and high volume production scenarios was performed by Directed Technologies Inc. (DTI). The production cost estimates were consistent with previous DoE cost estimates performed by DTI for the DoE on metal plates. The final result of DTI’s analysis for the high volume manufacturing scenario ($6.85 /kW) came in slightly above the DoE target of $3 to$5/kW. This estimate was derived using a “Best Case Scenario” for many of the production process steps and raw material costs with projections to high volumes. Some of the process improvements assumed in this “Best Case Scenario” including high speed high impact forming and solvent-less resins, have not yet been implemented, but have a high probability of potential success

HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal Carcinoma

VHL tumor suppressor loss results in hypoxia inducible factor-alpha (HIF-α) stabilization, and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1α and HIF-2α on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-α expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient, HIF-1α/HIF-2α expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2α displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-α effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies

Governance and Susceptibility in Conflict Resolution: Possibilities Beyond Control

Governmentality analysis offers a nuanced critique of informal Western conflict resolution by arguing that recently emerged alternatives to adversarial court processes both govern subjects and help to constitute rather than challenge formal regulation. However, this analysis neglects possibilities for transforming governance from within conflict resolution that are suggested by Foucault's contention that there are no relations of power without resistances. To explore this lacuna, I theorise and explore the affective and interpersonal nature of governance in mediation through autoethnographic reflection upon mediation practice, and Levina's insights about the relatedness of selves. The paper argues that two qualitatively different mediator capacities - technical ability and susceptibility - operate in concert to effect liberal governance. Occasionally though, difficulties and failures in mediation practice bring these capacities into tension and reveal the limits of governance. By considering these limits in mediation with Aboriginal Australian people, I argue that the susceptibility of mediator selves contains prospects for mitigating and transforming the very operations of power occurring through conflict resolution. This suggests options for expanded critical thinking about power relations operating through informal processes, and for cultivating a susceptible sensibility to mitigate liberal governance and more ethically respond to difference through conflict resolution

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors

A Phase II Trial of Sorafenib in Metastatic Melanoma with Tissue Correlates

Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib