76 research outputs found
Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations
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George J. Mitchell: Maine\u27s Environmental Senator
No full textThe State of Maine is blessed with a history of impressive and respected politicians. Among others, the list includes James Blaine, Margaret Chase Smith, and Edmund S. Muskie. The State now must add the name of George J. Mitchell to these ranks. A native son of Waterville, Maine, he attended Bowdoin College, Georgetown University Law Center, and eventually catapulted himself into one of the most powerful political positions in the United States government when he was elected as majority leader of the United States Senate. During his tenure as majority leader, he helped to redefine the position through his strong work ethic, sense of fairness, and orientation toward results in the Senate. This Comment summarizes some of those results through an environmental lens, focusing on Mitchell\u27s contributions to federal environmental legislation in the late 1980s. As Mitchell served in the Senate for fourteen years, six as the majority leader, he sponsored or cosponsored countless pieces of legislation. Environmental protection, however, always was a focus of his public service. In that vein, this Comment canvasses Senator Mitchell\u27s influence on the provisions of the Water Quality Act of 1987, the Clean Air Act Amendments of 1990, and the Oil Pollution Act of 1990, three major legislative accomplishments aimed at protecting the environment. This Comment analyzes those provisions of each Act for which Senator Mitchell fought most ardently and discusses the different tactics and strategies he employed to secure passage of each of these important bills. Finally, this Comment is a tribute to a Maine native who dedicated his life to public service. This Author recognizes that no one Senator could be solely responsible for any of these three pieces of environmental legislation. Nonetheless, only a few Senators held the key to passage of each of these acts. George J. Mitchell was one of the those Senators. Senator Mitchell\u27s contributions to environmental law can be understood only by viewing his Senate career in context. First, Mitchell served as a Federal District Court Judge for the District of Maine
Abstract 685: GPC2 is an oncogene and immunotherapeutic target in high-risk neuroblastoma
No full textAbstract
Background: GD2-directed immunotherapeutic strategies have improved outcomes in neuroblastoma; however, the majority of patients treated suffer relapse and GD2 expression on pain fibers causes dose-limiting toxicities.
Methods: To identify alternative cell surface immunotherapeutic targets, we compared high-risk neuroblastoma (n=126 tumors) and normal tissue RNA sequencing data (GTEx; n=7859 samples from 31 normal tissues) and prioritized genes by differential and absolute expression and cell surface prediction. Genes were further surveyed for somatic copy number gain and correlative expression with MYCN amplification. Differential protein expression and localization were confirmed in neuroblastoma primary tumors (n=98), patient-derived xenografts (n=32; PDXs), cell lines (n=23), and normal pediatric tissues (n=36). Cell lines were subjected to candidate gene gain and loss of function studies (n=11). Additional pediatric tumor RNA sequencing data was surveyed followed by confirmatory immunohistochemistry (IHC). Finally, candidate specific antibodies were isolated from a human Fab phage library and utilized for antibody-drug conjugate (ADC) engineering followed by cytotoxicity studies.
Results: We identified 33 differentially expressed cell surface molecules from which we prioritized glypican-2 (GPC2) for validation given GPC2’s robust differential expression (log-fold change tumor vs. normal tissue = 1.71-9.22; p=1.99 x 10-9-1.88 x10-300), high-level absolute RNA expression (median FPKM=60), and frequent DNA copy number gain associated with higher GPC2 expression (35%, n=182 tumors; p<0.005). GPC2 expression was also higher in MYCN amplified neuroblastomas (p<0.05), MYCN binds the GPC2 promoter shown by chromatin immunoprecipitation (ChIP) sequencing and reporter assays, and MYCN depletion resulted in decreased GPC2 expression. Immunoblot, flow cytometry, immunofluorescence, and IHC analysis of primary tumors, PDXs, and cell lines confirmed dense cell surface GPC2 expression. Medulloblastomas (n=62) were also found to have high GPC2 expression that positively correlated with MYC, MYCN, and GPC2 loci gain (p<0.0001). Pediatric normal tissues had very restricted cell surface GPC2 expression, with only low levels found in the esophagus and skin. GPC2 depletion in neuroblastoma cell lines resulted in apoptosis and growth inhibition and GPC2 forced over-expression increased neuroblastoma cell proliferation (p<0.001 for all assays). Finally, a human GPC2 antibody, D3-GPC2-Fab, was developed and shown to bind GPC2 with high affinity and specificity. D3-GPC2-IgG1 induced internalization of GPC2 and was conjugated to pyrrolobenzodiazepine (PBD) dimers to form an ADC which induced potent and specific cytotoxicity to GPC2 expressing neuroblastoma cells (IC50 = 1.7-11 pM).
Conclusions: GPC2 is an oncogene and immunotherapeutic target in neuroblastoma and potentially other cancers.
Citation Format: Kristopher R. Bosse, Pichai Raman, Maria Lane, Robyn T. Sussman, Jo Lynne Harenza, Daniel Martinez, Sabine Heitzeneder, Zhongyu Zhu, Komal Rathi, Michael Randall, Laura Donovan, Sorana Morrissy, Doncho V. Zhelev, Yang Feng, Jennifer Hwang, Yanping Wang, Bruce Pawel, Tricia Bhatti, Mariarita Santi, Javed Khan, Michael Taylor, Dimiter S. Dimitrov, Crystal Mackall, John M. Maris. GPC2 is an oncogene and immunotherapeutic target in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 685. doi:10.1158/1538-7445.AM2017-685</jats:p
Research in medical education - chances and challenges : international conference, 20th - 22nd May 2009, Heidelberg ; congress abstracts
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Musikstädte as real and imaginary soundscapes: urban musical images as literary motifs in twentieth-century German modernism
No full textPhDThis study examines German literary images of musical life as part of the wider sound identity of the modern German city at the turn of the twentieth century. Focussing on a forty-year period from 1890 to 1930, synonymous with the emergence of the modern German metropolis as an aesthetic object, the project assesses, compares and contrasts how musical life in the Musikstädte was perceived and portrayed by writers in an increasingly noisy urban environment. How does urban musical life influence and condition city writings? What are the differences and similarities between the writings on various musical cities? Can an urban textual sound identity be derived from these differences and similarities? The approach employed to answer these questions is a new, cross-disciplinary one to urban sound in literature, moving beyond reading the key sounds of the urban soundscape using urban musicology, sensorial anthropology and cultural poetics towards a literary contextualisation of the urban aural experience.
The literary motifs of the symphony, the gramophone and urban noise are put under the spotlight through the analysis of a wide range of modernist works by authors who have a special relationship with music. At the centre of this analysis are the Kaffeehausliteratur authors Hermann Bahr, Alfred Polgar and Peter Altenberg, the then Munich-based author Thomas Mann and the lesser known René Schickele. The analysis of these particular works is framed in the music-geographical context of the Musikstadt and literary underpinnings of this topos, ranging from Ingeborg Bachmann to Hans Mayer and, once again, Thomas Mann. In analysing these texts, the methodological approach devised by Strohm, who identifies the blending of a range of urban sounds as a definition of urban space and identity, is applied. His ideas combine historical literary
analysis, musical history and urban sociology. They are rarely used in the analysis of the auditory environment.Arts and Humanities Research Council
Westfield TrustWestfield Trust Studentship
Arts and Humanities Reseach Council (AHRC
Agent-Based Modeling of Culture's Consequences for Trade
No full textIn this thesis, culture is interpreted as a property of a group of people who share the meaning they attach to symbols, have a common way of expressing their opinions and feelings, and share value systems to judge what is good or bad. The unwritten rules of a culture govern the interpretation of observations and emotions and how to react appropriately. The rules are embedded in an individuals’ mind, form childhood on, by interactions with group members. People often are not aware of differences between their own unwritten rules and those of people having a different cultural background. This may result in unwarranted distrust or unwarranted trust, with serious consequences for the future of relationships. Cultural differences are known to have their effects on trade. Signals that indicate benevolence and trustworthiness of a trade partner in one’s own culture may be interpreted differently by people having a different cultural background. Hofstede (2001) has identified five dimensions of cultural differences: ? Given ingroup relation with relatives and community members may have a different impact on professional relationships in different cultures. ? The impact of hierarchical relationships on the freedom of action of trade partners may be different across cultures. ? Some cultures are oriented toward cooperation and care-taking; others are oriented toward performance and competition. ? Xenophobia is a wide-spread phenomenon in some cultures, while people in other cultures may be more open to the unknown. ? In some cultures people are anxious to keep up their status and display their societal success, while in other cultures thrift and perseverance are seen as virtues. Cultural differences may have their effects in trade on the acceptability of potential partners, on progress and success of negotiations, and on the extent to which partners live up to the negotiated contracts. In a research project Meijer (2009) developed a gaming simulation to study the role of trust in supply networks of food products. The game is called the TRUST & TRACING game. In this game, the producers are informed about product quality. The other players either have to trust the suppliers on their quality statements, or they can have the products traced by an independent authority, but the latter will cost them a fee. In addition to the financial considerations, they must take into account that showing distrust may bring damage to their relationships. Experiments with human subjects in different cultures have shown that the considerations lead to different actions in different countries. It was also found that the inclination to grab an opportunity to defect was different across countries. The subject of this thesis is a computer simulation of the TRUST & TRACING GAME. The purposes of the computer simulation are: ? Validation of theories about, implemented in models of, the players’ behaviors ? testing of hypotheses about relations of rules of the game and parameters of individual players with aggregated game statistics, ? the design of useful game configurations to be played with human players. In the computer simulation the players’ rolls are realized by software agents. The questions which are answered in this thesis concern the modeling of culture’s consequences for the decisions taken by the agents. Such an agent is a computer program which simulates the behavior of human players. In a multi-agent simulation a group of software agents is acting and interacting simultaneously. Autonomy is an important property of software agents. The agents decide what to do; there is no central computer program that imposes decisions on them. Important functions of agents in the present simulation are to approach new potential trade partners, to negotiate about a transaction and to exchange proposals, and, when the negotiation has ended successfully, to exchange products, and to decide and request a trace to be performed. The agents’ decision mechanisms are implemented according to models and data available from scientific literature. To model the influence of culture on the decision making, an expert systems approach is taken, using the Synthetic Cultures according to Hofstede en Pedersen (1999). To develop an expert system, knowledge engineers represent knowledge about some domain of application as a set of rules that can be interpreted by a computer system. Since culture is considered as a set of rules, such an approach is a natural way to model it. The development of expert systems always is an interdisciplinary project. In this case the work of Geert Hofstede has been used and an expert on this work and on Synthetic Cultures has been involved in the formulation of the rules. Synthetic Cultures are imaginary cultures in which the effects of a single dimension of culture are emphasized, isolated from the effects of the other dimensions. The purpose is to make the differences related to that dimension teachable. In reality the differences may be less pronounced and may be mixed with differences related with the other dimensions. In this thesis an approach has been elaborated to compute the simultaneous effect of several dimensions. The approach is based on the principle of weak disjunction, which implies that, if several dimensions have a similar effect, only the strongest effects counts. For instance, if dimension A would have an effect of 75% and dimension B would have an effect of 25%, then their simultaneous effect would be 75%. Expert systems must at least have face validity. An expert in the domain of application mustaccept the decisions that the system produces and the reasoning that leads to these decisions, as being believable. For this purpose computations for specific cases can be made, of which the results are judged by the expert. Further, the results of sensitivity analysis can be judged by an expert. Sensitivity analysis of a model is performed by studying how model outputs vary in relation with systematic variation of input parameter. In addition to face validity, the model must be tested empirically. To that end outputs from gaming simulations with human participants can be compared with outputs from multi-agent simulations. For example, Meijer et al. (2006) found different outcomes from the TRUST & TRACING game between games played in the United States and in the Netherlands. Compared with the Dutch, American players are found to be more eager to buy top quality products, have a stronger inclination to opportunism, anticipate to a greater extent on their partners to defect, and have a stronger preference for quality certification. These differences where reproduced by the multi-agent simulation. The main question of this research is, whether an expert systems approach is feasible to develop a valid model of cultural differentiation in multi-agent simulations, to be applied in research with gaming simulations. The conclusions are: 1. Effects of dimensions of culture can be modeled as an expert system based on Synthetic Cultures. Modeling the simultaneous effects of several dimensions as an expert system proved not feasible: the complexity exceeded the intellectual powers of both expert and modeler. 2. The simultaneous effect of several dimensions can be modeled by weak disjunction of effects. The results have face validity and have empirically been verified for a limited number of cases. 3. Sensitivity analysis of this model is a complex undertaking if both cultural parameters and other parameters are simultaneously varied, because of the strong interactions between these types of parameters. When only the culture parameters are varied (with a fixed setting of the other parameters), or only the other parameters are varied (in a fixed cultural setting), straightforward sensitivity analysis is feasible. Furthermore, it was found that the sensitivity of aggregate model outputs may greatly differ from sensitivity of individual level outputs: parameters that do not affect the aggregate system performance, may affect results of individual agents. 4. This thesis proves that multi-agent simulation is a potent instrument to be used in research with gaming simulations, in particular for the purpose of validation of behavioral models. A problematic issue is, that similarity of the outputs of gaming simulations and multi-agent simulations is no sound proof that the agent correctly implements the human decision making mechanism. This issue is known as under-determination. A validation method is proposed, which builds on the model’s composed structure. Under-determination can be avoided by separate validation of the components in micro-games. The results of this research contribute to the methodology of cultural adaptation of intelligent software agents. This is relevant for the development of research instruments (like the TRUST & TRACING game), educational and training applications to make people aware of cultural differences, and affective human-computer interfaces in a globalizing world.MediamaticsElectrical Engineering, Mathematics and Computer Scienc
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