1,721,662 research outputs found
Rational enzyme-directed prodrug development : exploiting tumour hypoxia to target the bioactivation of cytotoxic prodrugs
Full text linkConventional cancer chemotherapy often lacks specificity and is consequently associated with
significant normal tissue toxicities. Molecular chemotherapy offers the potential to target the
activation of inert prodrugs by utilising tumour-specific catalytic enzymes to restrict cytotoxicity to neoplastic tissues. Appropriate expression of therapeutic enzymes can be achieved by exploiting the genetic distinctions that exist between tumour and normal tissues through the use of tissue- or disease-specific promoters. Alternatively, the unique physiological differences that arise in solid tumour masses as a consequence of the abnormal vascular architecture might also be exploited to achieve therapeutic selectivity. The most conspicuous of these differences is the presence of areas of low oxygen tension (hypoxia) arising through both diffusion and perfusion-limited oxygen availability. Hypoxia is an
important cause of radioresistance and is a independent prognostic indicator for local recurrence, metastatic spread and overall survival. Evidence also implicates hypoxia in chemotherapeutic resistance and genetic instability, as well as the progression of and selection for an aggressive neoplastic phenotype.
Attempts to eliminate tumour hypoxia have met with some success, but the opportunity to utilise thisphenomenonfor therapeutic gain, through the exploitation of the unique reductive tissue environment have lead to the development of hypoxic-specific cytotoxins. These bioreductive prodrugs rely. on the natural complement of tumour enzymes to catalyse their activation under low tissue oxygen tensions. Levels of these reductases are potentially heterogeneous and are often down-regulated in the neoplastic state. The artificial reintroduction of high levels of reductive enzyme expression may be of significant therapeutic value, particularly if expression is restricted to the hypoxic tissue enviroment in which the
prodrugs will be activated. This might be achieved through the utilisation of the specific cisacting
sequences that are responsive to hypoxia-regulated transcription factors.
A diverse spectrum of genes are known to be induced as a consequence of oxygen deprivation, being involved in systemic oxygen supply, vascular tone, neovascularisation, iron homeostasis, glucose metabolism, drug detoxification and protein chaperoning. The details of the cis-acting sequences and transcription factors that mediate this oxygen-sensitive gene control are beginning to emerge. This provides the opportunity to exploit these defined sequences to regulate therapeutic genes in a hypoxia-responsive manner.
This thesis describes the evaluation of three potential prodruglenzyme paradigms that may have application in this context. Further, the potential of hypoxia-response-elements to specifically regulate heterologous genes in response to low oxygen tension is described. The application of such an oxygen-regulated gene-directed enzyme/prodrug therapy to solid tumours may provide chemotherapeutic specificity aimed at a clinically important tumour subpopulation
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
Patterson, A R, 422684
No full textThis record was harvested from a previous catalogue system and will be withdrawn in 2025. Information in this record may be superseded or incomplete. Visit this record in UMA's new catalogue at: https://archives.library.unimelb.edu.au/nodes/view/409803Surname: PATTERSON. Given Name(s) or Initials: A R. Military Service Number or Last Known Location: 422684. Missing, Wounded and Prisoner of War Enquiry Card Index Number: 54055.225440
Item: [2016.0049.42074] "Patterson, A R, 422684
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