1,721,303 research outputs found
Bayesian model choice for multivariate ordinal data
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
Combination of immunodoulatory cyclophosphamide with anti-PD-1 monoclonal antibody therapy to improve survival in preclinical models of neuroblastoma
No full textNeuroblastoma (NB) is one of the most common childhood cancers, constituting 8% of paediatric cancers, and 15% of paediatric cancer deaths. The majority of patients have high risk disease, with poor outcome despite intensive treatment regimens. Current therapies, which include chemotherapy and radiotherapy, are highly toxic, with significant treatment related mortality, and there is little scope for further intensification. Alternatives strategies, such as immunotherapy are a priority for improving patient outcomes. A number of different immunotherapies, such as antiGD2 antibody therapy, have shown promise in NB, but combining these with conventional chemotherapy regimens is challenging. Classically, chemotherapy has been regarded as immunosuppressive but recent work has highlighted that this may not entirely be accurate for certain immunogenic chemotherapies. Furthermore, immunomodulatory antibodies such as checkpoint inhibitors have shown efficacy in adult cancers such as melanoma, with little investigation into their potency in paediatric tumours. Although NB tumours are not particularly inherently immunogenic, the application of an ‘immunogenic’ chemotherapy may render them susceptible to further immunomodulatory immunotherapy.Firstly this study aimed to identify the immunomodulating effects of cyclophosphamide (CPM) treatment on immune cells, within murine NB models. To achieve this, CPM’s ability to induce ‘immunogenic cell death’ (ICD) markers both in vitro and in vivo was investigated. Induction of ectoCRT, Hsp-70 and HMGB1 expression was observed. Secondly, effects of different doses of CPM on the immune cell infiltrates in the tumour microenvironment were studied in vivo using syngeneic murine NB models. It was demonstrated that low dose CPM was able to selectively deplete and possibly reduce the suppressive activity tumour infiltrating Treg cells in both NXS2 and 9464D NB models, alongside maintaining and activating CD8+ and CD4+ T cells. Additionally, using an apoptosis resistant NB cell line and mouse strain, investigation into whether ICD induction or Treg depletion is most critical aspect of CPM immunomodulation was conducted. It was observed that overexpression of BCL-2 either in the tumour cell line in vitro or Treg cells in vivo, prevented apoptosis and CPM dependent depletion.Finally, it was assessed whether immunogenic CPM could be efficiently combined with immunomodulatory antibody therapy to slow tumour growth, utilising a combination of syngeneic and spontaneous transgenic NB models. Experiments utilising the three in vivo models demonstrated that combination of CPM with anti-PD-1 antibody led to an increase in survival over monotherapies alone, which was further enhanced by a metronomic weekly dosing strategy. Ongoing work is exploring this approach, to refine and establish the most effective chemotherapy and antibody combination in NB preclinical models, along with defining the mechanisms behind combination efficacy
Bayesian model determination for multivariate ordinal and binary data
No full textDifferent conditional independence specifications for ordinal categorical data are compared by calculating a posterior distribution over classes of graphical models. The approach is based on the multivariate ordinal probit model where the data are considered to have arisen as truncated multivariate normal random vectors. By parameterising the precision matrix of the associated multivariate normal in Cholesky form, ordinal data models corresponding to directed acyclic conditional independence graphs for the latent variables can be specified and conveniently computed. Where one or more of the variables are binary this parameterisation is particularly compelling, as necessary constraints on the latent variable distribution can be imposed in such a way that a standard, fully normalised, prior can still be adopted. For comparing different directed graphical models a reversible jump Markov chain Monte Carlo (MCMC) approach is proposed. Where interest is focussed on undirected graphical models, this approach is augmented to allow switches in the orderings of variables of associated directed graphs, hence allowing the posterior distribution over decomposable undirected graphical models to be computed. The approach is illustrated with several examples, involving both binary and ordinal variables, and directed and undirected graphical model classes
Bayesian disclosure risk assessment: predicting small frequencies in contingency tables
Full text linkWe propose an approach for assessing the risk of individual identification in the release of categorical data. This requires the accurate calculation of predictive probabilities for those cells in a contingency table which have small sample frequencies, making the problem somewhat different from usual contingency table estimation, where interest is generally focussed on regions of high probability. Our approach is Bayesian and provides posterior predictive probabilities of identification risk. By incorporating model uncertainty into our analysis, we can provide more realistic estimates of disclosure risk for individual cell counts than are provided by methods which ignore the multivariate structure of the data set.<br/
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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