1,721,231 research outputs found
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
Exploring Breast Cancer Drug Targets in the Third Dimension with Imaging
No full textThis project utilises innovative methodology to evaluate the suitability of novel three-dimensional (3D) cell culture models for investigating anti-cancer drug activity. 3D cell culture methodology was utilised as this in vitro approach is considered to recapitulate the in vivo conditions more accurately than two-dimensional (2D) monolayer cell culture. Two separate 3D cell culture model formats were developed which are amenable to automated liquid handling systems, and a variety of instruments for total well fluorescence and confocal imaging. The first 3D cell culture assay developed was in a 384-well format, and was validated as suitable for use for drug discovery. The second 3D cell culture assay was optimised for 1536-well format, specifically created for extensive drug combination studies.
The 3D breast cancer cell culture assay developed for drug discovery utilised the breast cancer cell lines of MDA-MB-231 (endocrine receptor- and ErbB2 receptor-negative), MCF-7 (endocrine receptor-positive) and BT-474 (ErBb2 receptor over-expression). This 3D cell culture assay was miniaturised to a 384-well format, developed to be semi-automated and was thoroughly characterised for sensitivity and reproducibility. In addition, measurements of metabolic activity or spheroid morphology can be utilised for determination of drug activity. To validate the 3D breast cancer cell culture assay for use in high-throughput applications, a pilot screen comprising of 741 clinically relevant drugs was completed. Results from the pilot screen identified a number of drugs with anti-breast cancer activity that warranted further investigation. The drugs of interest were a mixture of drugs with both novel and demonstrated anti-cancer activity.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Biomolecular and Physical SciencesScience, Environment, Engineering and TechnologyFull Tex
Anti-malarial Drug Discovery from Australian Flora
No full textMalaria is a mosquito-borne disease caused by the parasitic protozoan Plasmodium that is
responsible for approximately half a million deaths every year. The vast majority of these
deaths are caused by P. falciparum in Sub-Saharan Africa (SSA). Although most cases of P.
falciparum malaria can currently be treated effectively using artemisinin-based combination
therapies (ACTs), resistance to ACTs is beginning to emerge in South-East Asia. This resistance
is likely to proliferate and spread into SSA, after which a public health catastrophe is likely to
follow. There is currently no drug poised to replace ACTs as the front-line treatment for
malaria and there is a need for the discovery of new drugs. Historically, natural products from
plants have been our best source of anti-malarial drugs: the alkaloid quinine (from the bark of
the Cinchona tree) and the sesquiterpene lactone artemisinin (from the leaves of Artemisia
annua) have formed the backbone of anti-malarial chemotherapeutics for centuries.
The primary goal of this thesis was to respond to the need for new anti-plasmodial
compounds. This was achieved by collecting and screening a library of Australian Rutaceae
species against P. falciparum, selecting species that showed high bioactivity and performing
large-scale natural product purification. Isolated natural products were screened against
chloroquine-resistant and sensitive P. falciparum and human embryonic kidney (HEK-293) cells
to evaluate bioactivity and parasite selectivity. This forms the majority of the thesis (Chapters
2-6).
Chapter 2 reports the initial collection, screening and fingerprinting of a library of 30 Australian
Rutaceae species. Chemical fingerprinting using LC-MS was used to identify species that were
most likely to contain new natural products. From these results, four species were selected for
investigation: Clausena brevistyla (Chapter 2) Flindersia pimenteliana (Chapters 3-4),
Acronychia pubescens (Chapter 5) and Pitaviaster haplophyllus (Chapter 6). This chapter also
reports the isolation of two known pyranocoumarins from C. brevistyla. One of the
pyranocoumarins showed potent and selective activity against P. falciparum, with IC50 values
between 466 – 822 nM.
Chapter 3 reports the chemical investigation of F. pimenteliana leaf material. From this plant, a
new class of ascorbic-acid adduct indole alkaloids, pimentelamines A-C, were isolated along
with one new indole alkaloid, 2-isoprenyl-N,N-dimethyltryptamine. Five known compounds
were also isolated. Although the new natural products did not show strong bioactivity, three of
the isolated bis-indole alkaloids, borreverine, 4-methylborreverine and
dimethylisoborreverine, showed potent activity with IC50 values between 190 – 670 nM against
P. falciparum
Chapter 4 reports the isolation of three new isoborreverine-type alkaloids, 10,10’-
dimethoxydimethylisoborreverine, 10-methoxydimethylisoborreverine and 10’-
methoxydimethylisoborreverine from the bark of F. pimenteliana. Two known borreverinetype alkaloids were also isolated. The moderate anti-plasmodial activity of these alkaloids is
reported, with IC50 values ranging from 959 – 2407 ng/mL. Further insights into structureactivity relationships of borreverine-type alkaloids are also discussed.
Chapter 5 reports the chemical investigation of the roots of A. pubescens, from which a highly
unusual oxidized furo[2,3-c]xanthene, acrotrione, was isolated along with two known
acetophenones. Acrotrione is the first natural product of its class to be isolated. Moderate
anti-plasmodial activity for the natural products is reported, with IC50 values ranging from 1.7
to 4.7 µM.
Chapter 6 reports the isolation of one new quinoline alkaloid, leptanoine D, from P.
haplophyllus. Nine known alkaloids were also isolated. The chemotaxonomic relationships
between the monotypic Pitaviaster genus and the related Australian genera Euodia, Melicope
and Acronychia are discussed.
The secondary goal of this thesis was to investigate the factors that influence diversity of
natural products in Australian plants. In recent years, natural product-driven drug discovery
has seen a decrease in popularity in the pharmaceutical industry, part of which has been
caused by the repeated isolation of known natural products. In response to this, there is a
requirement for the development of new ideas that expedite the discovery of new natural
products. Some recent publications have noted that natural product diversity is positively
correlated with diversity of plant-herbivore communities. This may suggest that plants in
regions of high biotic stress (i.e. rainforests) should be the focal point of terrestrial plant
natural product drug discovery. We aimed to validate this hypothesis by using the Australian
Rutaceae genus Flindersia as a case study. Contrary to expectations, our results showed that
Flindersia species growing in arid regions of central Australia produced a significantly higher
number of structurally unique alkaloids than rainforest species. These unexpected results
highlight the potential of the Australian arid zone as a source of new natural products.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Environment and ScScience, Environment, Engineering and TechnologyFull Tex
Regulation of the Chemokine Receptors CXCR4, CXCR7 , and the Androgen Receptor in Prostate Cancer
No full textThe chemokine receptor CXCR4 contributes to tumour cell migration and invasion during the progression of prostate cancer. In particular, this pathway is central to the metastasis of prostate cancer to the bone marrow. Limited therapeutic options exist for prostate cancer patients who have progressed to advanced metastatic disease, and pharmacological interference of the chemokine network may serve to control tumour cell dissemination and the establishment of metastasis. A more detailed knowledge of the mechanisms regulating chemokine receptors is required, in order to further characterise and explore the capacity and effectiveness of targeting these pathways for therapeutic intervention in prostate cancer.
Here, the regulation of CXCR4 protein expression and function was investigated in relation to androgens and the extracellular matrix. Accumulating evidence of CXCR4 regulation by androgens and the androgen receptor have indicated that androgens not only promote the growth and development of prostate cancer, but may actively contribute to the metastatic progression of prostate through modulation of the chemokine network. In the current study, the endogenous protein expression and functionality of the androgen receptor were firstly characterised in the androgen-insensitive prostate cancer cell lines DU145 and PC3, using the androgen-sensitive LNCaP cells as a basis for comparison. Investigations were performed using two-dimensional culture in conjunction with the more physiologically relevant three-dimensional in vitro culture model.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Eskitis Institute for Cell and Molecular TherapiesScience, Environment, Engineering and TechnologyFull Tex
Exploring Morphology and Drug Interactions in Pancreatic Cancer with 3D Cell Culture
No full textPancreatic cancer continues to have one of the poorest prognoses amongst all cancers, with a 95% mortality rate. Standard of care chemotherapy has failed to provide significant clinical benefits, which has led to the development of targeted agents against validated signalling pathways. However, to date the approach of targeted agents alone, or in combination with traditional chemotherapeutics, has failed to significantly improve the prognosis for pancreatic cancer patients. The current standard of care chemotherapy for advanced pancreatic cancer provides only a modest increase in survival of several months. Models that improve the predictive potential of drug discovery programs and gain greater insights into the complexity of tumour biology are therefore urgently required. To better understand the mechanisms influencing the anti-cancer activities of current and novel therapies, we have developed a 3D in vitro micro-tumour cell culture model. Current in vitro models utilising cell monolayer cultures are unable to recapitulate the biological and physiological complexities of the in vivo pancreatic tumour microenvironment and may be poor predictors of drug efficacy. Pancreatic adenocarcinomas are characterised as having a highly dense and poorly vascularised stroma that is made up of extracellular matrix (ECM) components and host cells. This complex tumour microenvironment has been implicated in the chemoresistance profiles observed in pancreatic tumours.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Eskitis Institute for Cell and Molecular TherapiesScience, Environment, Engineering and TechnologyFull Tex
Investigation of Anti-infective Compounds within the Flowers of Myrtaceae
No full textThis thesis reports on the chemistry and anti-infective activity of the flowering plant family Myrtaceae (a family whose members dominate the Australian landscape). To understand the significance and importance of the Myrtaceae family from a phytochemical and medical perspective, a systematic literature review was carried out. The conclusion from this review was that the family is a major source of [beta]-triketone, phloroglucinol, and volatile terpene natural products with the [beta]-triketones in particular being a major focus of recent research. Over hundred new compounds from this class, many of which possess novel ring systems, have been reported in the last ten years. Furthermore their chemical diversity is matched with their high biological activity, most notably anti-infective activities including antiplasmodial, antibacterial and antiviral being reported for these compounds. All the findings of the literature review are documented in Chapter 2 of this thesis. As a result of this review the experimental research carried out in this dissertation focused on the antiplasmodial and antibacterial activity of natural product constituents isolated from the flowers of three Australian Myrtaceae plant species, Corymbia intermedia, C. torelliana, and Angophora woodsiana collected from South East Queensland. These plants were chosen because of the literature precedent for Corymbia species to be a major source of bioactive [beta]-triketones and although Angophora species have not previously been investigated their close taxonomic relationship to the Corymbia suggested that they would likely be an additional source of [beta]-triketone constituents. A total of 24 [beta]-triketone compounds, 14 of which are new, were isolated from methanol extracts of flowers of these three species. [...]Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Griffith School of EnvironmentScience, Environment, Engineering and TechnologyFull Tex
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
Identification of Novel Natural Product Antimalarial Compounds
No full textMalaria, caused by infection with the Plasmodium parasite, contributes to a significant global health burden that disproportionally affects those living in developing nations. The majority of cases are caused by infection with the species P. falciparum and P. vivax with P. falciparum being responsible for most of the ~ 1 million deaths that occur each year. There is currently no licensed malaria vaccine and while antimalarial drugs are available, the prevention and treatment of this disease has been increasingly hampered by the emergence of multidrug resistant parasites. Derivatives of the natural product artemisinin, in combination with a second antimalarial, now form the basis of antimalarial chemotherapy. Unfortunately, treatment failures of artemisinin ]based combination therapies are now emerging underscoring the need for the next generation of antimalarial compounds. Compounds derived from natural sources have the potential to provide novel antimalarial compounds as demonstrated by the isolation of artemisinin and quinine from plant species. A unique natural product extract library was, therefore, screened for antimalarial activity to identify compounds that inhibit the growth of P. falciparum. Using a standard [3H]hypoxanthine growth inhibition assay, 1773 plant and marine extracts from Australia and Papua New Guinea (PNG) were initially screened against a drug ]sensitive P. falciparum laboratory strain (3D7) at a concentration of 312.5 .ge/mL. The 210 extracts that showed >40% inhibition were then re ]screened in dose response against 3D7 and the drug ]resistant strain, Dd2, to reconfirm their activity. Extracts that showed at least 40% inhibition at the lowest dose for either strain were then tested for cytotoxicity against HeLa mammalian cells. This identified 25 plant and 30 marine extracts with selective antimalarial activity. For over 90% of these extracts, this was the first report of antimalarial activity in the literature. From these extracts the PNG plant species Flindersia amboinensis (Rutaceae), Stephania zippeliana (Menispermaceae) and Voacanga papuana (Apocynaceae) were selected for further analysis and compound isolation. Using bioassay guided fractionation, the extracts were separated over multiple steps of high ]performance liquid chromatography until pure compounds were isolated. Chemical structures were then assigned using mass spectrometry and nuclear magnetic resonance spectroscopy. The extract from F. amboinensis yielded the indole alkaloids, flinderole B, flinderole C and dimethylisoborreverine. These were structural analogues of flinderole A and isoborreverine previously isolated from F. acuminata. The flinderole indole alkaloids were also shown to be novel structures. The remaining extracts yielded known antimalarial compounds, specifically liriodenine and xylopine from S. zippeliana and voacamine from V. papuana. Antimalarial activity had not been previously reported for the Flindersia indole alkaloids. To elucidate the potency and selectivity of these isolated compounds, they were then screened against a panel of P. falciparum strains exhibiting different levels of drug sensitivity, along with the mammalian cell lines, HeLa and HEK ]293. The indole alkaloids isolated from Flindersia showed the most selectivity and potency, with IC50 values between 0.02 . 1.61 .M. In particular the compounds containing a dimethylated ethylamine side chains also showed greater activity against the chloroquine resistant strains. The remaining compounds all showed IC50 values > 1 .M, however, xylopine did show comparable selectivity to the flinderole class of compounds. The antiparasitic activity of these compounds was also further explored by screening for inhibitory activity against Trypanosoma brucei brucei. All compounds, however, were less active against this organism. To further understand the effect of the Flindersia alkaloids on P. falciparum, in vitro growth inhibition studies were carried out using parasite cultures at the different asexual growth stages, which are associated with different molecular targets. Treatment of ring, trophozoite or schizont ]stage parasites with dimethylisoborrevine or flinderole B for 6 h, showed that over a growth period of 24 h, trophozoite stages were more susceptible to these compounds than ring or schizont stages. Morphological analysis by light and electron microscopy of compound treated parasites showed abnormalities of the food vacuole, the organelle used for the storage of haemozoin, a by ]product of haemoglobin degradation. The disruption of haemoglobin degradation and the subsequent detoxification of the toxic haem moiety to the inert haemozoin is a well characterised molecular target. However, using an in vitro assay the latter process was found to be not affected by either dimethylisoborreverine or flinderole B, suggesting another target is involved. Isobologram analysis also showed antagonistic interactions between dimethylisoborreverine and flinderole B when used in combination with mefloquine and artemisinin. Overall the novel activity of the Flindersia alkaloids warrants further work to explore the potential of these compounds as antimalarial agents.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Eskitis Institute for Cell and Molecular TherapiesScience, Environment, Engineering and TechnologyFull Tex
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
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