Recommendations for a service framework to access astronomical archives

There are a large number of astronomical archives and catalogs on-line for network access, with many different user interfaces and features. Some systems are moving towards distributed access, supplying users with client software for their home sites which connects to servers at the archive site. Many of the issues involved in defining a standard framework of services that archive/catalog suppliers can use to achieve a basic level of interoperability are described. Such a framework would simplify the development of client and server programs to access the wide variety of astronomical archive systems. The primary services that are supplied by current systems include: catalog browsing, dataset retrieval, name resolution, and data analysis. The following issues (and probably more) need to be considered in establishing a standard set of client/server interfaces and protocols: Archive Access - dataset retrieval, delivery, file formats, data browsing, analysis, etc.; Catalog Access - database management systems, query languages, data formats, synchronous/asynchronous mode of operation, etc.; Interoperability - transaction/message protocols, distributed processing mechanisms (DCE, ONC/SunRPC, etc), networking protocols, etc.; Security - user registration, authorization/authentication mechanisms, etc.; Service Directory - service registration, lookup, port/task mapping, parameters, etc.; Software - public vs proprietary, client/server software, standard interfaces to client/server functions, software distribution, operating system portability, data portability, etc. Several archive/catalog groups, notably the Astrophysics Data System (ADS), are already working in many of these areas. In the process of developing StarView, which is the user interface to the Space Telescope Data Archive and Distribution Service (ST-DADS), these issues and the work of others were analyzed. A framework of standard interfaces for accessing services on any archive system which would benefit archive user and supplier alike is proposed

StarView: The object oriented design of the ST DADS user interface

StarView is the user interface being developed for the Hubble Space Telescope Data Archive and Distribution Service (ST DADS). ST DADS is the data archive for HST observations and a relational database catalog describing the archived data. Users will use StarView to query the catalog and select appropriate datasets for study. StarView sends requests for archived datasets to ST DADS which processes the requests and returns the database to the user. StarView is designed to be a powerful and extensible user interface. Unique features include an internal relational database to navigate query results, a form definition language that will work with both CRT and X interfaces, a data definition language that will allow StarView to work with any relational database, and the ability to generate adhoc queries without requiring the user to understand the structure of the ST DADS catalog. Ultimately, StarView will allow the user to refine queries in the local database for improved performance and merge in data from external sources for correlation with other query results. The user will be able to create a query from single or multiple forms, merging the selected attributes into a single query. Arbitrary selection of attributes for querying is supported. The user will be able to select how query results are viewed. A standard form or table-row format may be used. Navigation capabilities are provided to aid the user in viewing query results. Object oriented analysis and design techniques were used in the design of StarView to support the mechanisms and concepts required to implement these features. One such mechanism is the Model-View-Controller (MVC) paradigm. The MVC allows the user to have multiple views of the underlying database, while providing a consistent mechanism for interaction regardless of the view. This approach supports both CRT and X interfaces while providing a common mode of user interaction. Another powerful abstraction is the concept of a Query Model. This concept allows a single query to be built form a single or multiple forms before it is submitted to ST DADS. Supporting this concept is the adhoc query generator which allows the user to select and qualify an indeterminate number attributes from the database. The user does not need any knowledge of how the joins across various tables are to be resolved. The adhoc generator calculates the joins automatically and generates the correct SQL query

Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

<p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.</p> <p>Results</p> <p>Using ENU to enhance <it>Tsc2</it>^+-kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.</p> <p>Conclusion</p> <p>Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.</p

Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: Effects on mTORC1 and Akt signaling lead to improved survival and function

Tuberous sclerosis (TSC) is a hamartoma syndrome due to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have recently reported (Meikle et al., J Neurosci 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001, both mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 days to over 100 days; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-GSK3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 days only (P7 — P30) displayed a persistent improvement in phenotype with median survival of 78 days. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently due to effects on mTORC1 and Akt signaling, and consequently cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms

Editorial:T cell regulation by the environment

International audienc

Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.

BACKGROUND: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. METHODS: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. RESULTS: Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. CONCLUSIONS: MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. TRIAL REGISTRATION: NCT02013804 ; date of registration December 12, 2013

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease

Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.

Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo

Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.

Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function

The cytotoxic T cell proteome and its shaping by the kinase mTOR

High-resolution mass spectrometry maps the cytotoxic T lymphocyte (CTL) proteome and the impact of mammalian target of rapamycin complex 1 (mTORC1) on CTLs. The CTL proteome was dominated by metabolic regulators and granzymes and mTORC1 selectively repressed and promoted expression of subset of CTL proteins (~10%). These included key CTL effector molecules, signaling proteins and a subset of metabolic enzymes. Proteomic data highlighted the potential for mTORC1 negative control of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P(3)) production in CTL. mTORC1 was shown to repress PtdIns(3,4,5)P(3) production and to determine the mTORC2 requirement for activation of the kinase Akt. Unbiased proteomic analysis thus provides a comprehensive understanding of CTL identity and mTORC1 control of CTL function