Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Studies on the target conditioning for deposition of $LiCoO_{2}$ films

Deposition of good quality thin films of Lithium Cobalt Oxide (LiCoO2), by sputtering is preceded by target conditioning, which dictates the surface composition, morphology and electrochemical performance of the deposited film. Sputtering from a Virgin target surface, results in films with excess of the more reactive elements. The concentration of these reactive elements in the films decreases until the system reaches a steady state after sufficient sputtering from the target. This paper discusses the deposition kinetics in terms of target conditioning of LiCoO2. The composition, morphology and texturing of deposited film during various hours of sputtering were analyzed using X-ray photoelectron Spectroscopy (XPS) and Field Emission Scanning electron microscopy (FESEM). The compositional stability is not observed in the films formed during the initial hours or Sputtering from the fresh target, which becomes stable after several hours of sputtering. The Li and Co concentration in the Films deposited subsequently is found to be varying and possible causes are discussed. After the compositional stability is reached, electrochemical analysis of LiCoO2 thin films was performed, which shows a discharge capacity of 129 mu Ah/cm(2).

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

An Algorithm for Tracking a Maneuvering Target in Clutter

We consider the problem of tracking a maneuvering target in clutter. In such an environment, missed detections and false alarms make it impossible to decide, with certainty, the origin of received echoes. Processing radar returns in cluttered environments consists of three functions: 1) target detection and plot formation, 2) plot-to-track association, and 3) track updating. Two inadequacies of the present approaches are 1) Optimization of detection characteristics have not been considered and 2) features that can be used in the plot-to-track correlation process are restricted to a specific class. This paper presents a new approach to overcome these limitations. This approach facilitates tracking of a maneuvering target in clutter and improves tracking performance for weak targets.

Effect of the Queensland Shark Control Program on non target species : whale, dugong, turtle and dolphin : a review

The Queensland Shark Control Program (QSCP) aims to protect swimmers at ten beach areas on the east coast of Queensland between Cairns (17°S) and the Gold coast (28°S). Since its inception in 1962 it has deployed shark nets and baited drumlines in a `mixed gear strategy' that adapts the type of gear to the characteristics of a site (e .g . extreme tidal range, high energy wave action, or proximity of turtle breeding areas) . The policy has provided swimmer protection, and the incidental capture of non-target species has been lower than that resulting from deployment of nets alone (Dudley 1997; Gribble et al. 1998b). The QSCP is the only major public-safety shark-control program to routinely use mixed gear. Both the New South Wales (Holt 1998) and KwaZulu-Natal (Dudley 1998) programs use nets exclusively, although the KwaZulu-Natal program has recently tested drumlines on an experimental basis (Dudley 1998; Dudley, personal communication).

Non-target impacts of poison baiting for predator control in Australia

1. Mammalian predators are controlled by poison baiting in many parts of the world, often to alleviate their impacts on agriculture or the environment. Although predator control can have substantial benefits, the poisons used may also be potentially harmful to other wildlife. 2. Impacts on non-target species must be minimized, but can be difficult to predict or quantify. Species and individuals vary in their sensitivity to toxins and their propensity to consume poison baits, while populations vary in their resilience. Wildlife populations can accrue benefits from predator control, which outweigh the occasional deaths of non-target animals. We review recent advances in Australia, providing a framework for assessing non-target effects of poisoning operations and for developing techniques to minimize such effects. We also emphasize that weak or circumstantial evidence of non-target effects can be misleading. 3. Weak evidence that poison baiting presents a potential risk to non-target species comes from measuring the sensitivity of species to the toxin in the laboratory. More convincing evidence may be obtained by quantifying susceptibility in the field. This requires detailed information on the propensity of animals to locate and consume poison baits, as well as the likelihood of mortality if baits are consumed. Still stronger evidence may be obtained if predator baiting causes non-target mortality in the field (with toxin detected by post-mortem examination). Conclusive proof of a negative impact on populations of non-target species can be obtained only if any observed non-target mortality is followed by sustained reductions in population density. 4. Such proof is difficult to obtain and the possibility of a population-level impact cannot be reliably confirmed or dismissed without rigorous trials. In the absence of conclusive evidence, wildlife managers should adopt a precautionary approach which seeks to minimize potential risk to non-target individuals, while clarifying population-level effects through continued research.

The suitability of non-target native mangroves for the survival and development of the lantana bug Aconophora compressa, an introduced weed biological control agent

Aconophora compressa (Hemiptera: Membracidae), a biological control agent introduced against the weed Lantana camara (Verbenaceae) in Australia, has since been observed on several non-target plant species, including native mangrove Avicennia marina (Acanthaceae). In this study we evaluated the suitability of two native mangroves, A. marina and Aegiceras corniculatum (Myrsinaceae), for the survival and development of A. compressa through no-choice field cage studies. The longevity of females was significantly higher on L. camara (57.7 ± 3.8 days) than on A. marina (43.3 ± 3.3 days) and A. corniculatum (45.7 ± 3.8 days). The proportion of females laying eggs was highest on L. camara (72%) followed by A. marina (36%) and A. corniculatum (17%). More egg batches per female were laid on L. camara than on A. marina and A. corniculatum. Though more nymphs per shoot emerged on L. camara (29.9 ± 2.8) than on A. marina (13 ± 4.8) and A. corniculatum (10 ± 5.3), the number of nymphs that developed through to adults was not significantly different. The duration of nymphal development was longer on A. marina (67 ± 5.8 days) than on L. camara (48 ± 4 days) and A. corniculatum (43 ± 4.6 days). The results, which are in contrast to those from previous glasshouse and quarantine trials, provide evidence that A. compressa adults can survive, lay eggs and complete nymphal development on the two non-target native mangroves in the field under no-choice condition.

Temporal patterns in incidence and abundance of Aconophora compressa (Hemiptera: Membracidae), a biological control agent for Lantana camara, on target and nontarget plants

The membracid Aconophora compressa Walker, a biological control agent released in 1995 to control Lantana camara (Verbenaceae) in Australia, has since been collected on several nontarget plant species. Our survey suggests that sustained populations of A. compressa are found only on the introduced nontarget ornamental Citharexylum spinosum (Verbenaceae) and the target weed L. camara. It is found on other nontarget plant species only when populations on C. spinosum and L. camara are high, suggesting that the presence of populations on nontarget species may be a spill-over effect. Some of the incidence and abundance on nontarget plants could have been anticipated from host specificity studies done on this agent before release, whereas others could not. This raises important issues about predicting risks posed by weed biological control agents and the need for long-term postintroduction monitoring on nontarget species.

Portrait of unidentified man wearing medals and holding rifle, standing in front of shooting target Portraits Men

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Regional development, commercialisation and target adoption of new integrated management techniques for Sheep industry

This Sheep CRC2 project is directed towards regional development of, support for, commercialisation and target adoption of, new integrated management techniques, which will lift productivity and better match product with market specification. The outputs and benefits will help support and improve the productivity and profitability of producers remaining in the industry, and support industry in the current move towards one in which both meat and wool will be joint drivers of industry productivity.

MT10049 Pheromone component of a multi target approach to fruitspotting bug management

A pheromone-based trapping system will be developed for both A. lutescens and A. nitida to improve insecticide timing and to rationalise use.

Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis

Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3'UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4-60.7, P = 9.03 x 10(-5)). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3'UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.

Gene expression evidence for off-target effects caused by RNA interference-mediated gene silencing of Ubiquitin-63E in the cattle tick Rhipicephalus microplus.

Knowledge of cattle tick (Rhipicephalus (Boophilus) microplus; Acari: Ixodidae) molecular and cellular pathways has been hampered by the lack of an annotated genome. In addition, most of the tick expressed sequence tags (ESTs) available to date consist of similar to 50% unassigned sequences without predicted functions. The most common approach to address this has been the application of RNA interference (RNAi) methods to investigate genes and their pathways. This approach has been widely adopted in tick research despite minimal knowledge of the tick RNAi pathway and double-stranded RNA (dsRNA) uptake mechanisms. A strong knockdown phenotype of adult female ticks had previously been observed using a 594 bp dsRNA targeting the cattle tick homologue for the Drosophila Ubiquitin-63E gene leading to nil or deformed eggs. A NimbleGen cattle tick custom microarray based on the BmiGI.V2 database of R. microplus ESTs was used to evaluate the expression of mRNAs harvested from ticks treated with the tick Ubiquitin-63E 594 bp dsRNA compared with controls. A total of 144 ESTs including TC6372 (Ubiquitin-63E) were down-regulated with 136 ESTs up-regulated following treatment. The results obtained substantiated the knockdown phenotype with ESTs identified as being associated with ubiquitin proteolysis as well as oogenesis, embryogenesis, fatty acid synthesis and stress responses. A bioinformatics analysis was undertaken to predict off-target effects (OTE) resulting from the in silico dicing of the 594 bp Ubiquitin-63E dsRNA which identified 10 down-regulated ESTs (including TC6372) within the list of differentially expressed probes on the microarrays. Subsequent knockdown experiments utilising 196 and 109 bp dsRNAs, and a cocktail of short hairpin RNAs (shRNA) targeting Ubiquitin-63E, demonstrated similar phenotypes for the dsRNAs but nil effect following shRNA treatment. Quantitative reverse transcriptase PCR analysis confirmed differential expression of TC6372 and selected ESTs. Our study demonstrated the minimisation of predicted OTEs in the shorter dsRNA treatments (similar to 100-200 bp) and the usefulness of microarrays to study knockdown phenotypes.

Target Cell Topography and Cytoskeletal Reorganization in Natural Killer Cell Activity

The immune system has to recognize and destroy abnormal or infected cells to maintain homeostasis. Natural killer (NK) cells directly recognize and kill transformed or virus-infected cells without prior sensitization. We have studied both virus-infected and tumor cells in order to identify the target structures involved in triggering NK activity. Mouse/human cell hybrids containing various human chromosomes were used as targets. The human chromosome responsible for activating NK cell killing was identified to chromosome number 6. The results suggest that activated NK cells recognize ligands that are encoded on human chromosome 6. We showed that the ligand on the target cell side was intercellular adhesion molecule 2 (ICAM-2). There was no difference in the level of expression of ICAM-2, however, but a drastic difference was seen in the distribution of the molecule: ICAM-2 was evenly distributed on the surface of the NK-resistant cells, but almost totally redistributed to the tip of uropods, bud-like extensions, which were absent from the parental cells. Interestingly, the gene coding for cytoskeletal linker protein ezrin has been localized to human chromosome 6, and there was a colocalization of ezrin and ICAM-2 in the uropods. Furthermore, the transfected human ezrin into NK cell-resistant cells induced uropod formation, ICAM-2 and ezrin redistribution to newly formed uropods, and sensitized target cells to NK cell killing. These data reveal a novel form of NK cell recognition: target structures are already present on normal cells; they become detectable only after abnormal redistribution into hot spots on the target cell membrane. NK cells are central players in the defence against virus infections. They inhibit the spread of infection, allowing time for specific immune responses to develop. The virus-proteins that directly activate human NK cell killing are largely unknown. We studied the sensitivity of virus-specific early proteins of Semliki Forest virus (SFV) to NK killing. The viral non-structural proteins (nsP1-4) translated early in the virus cycle were transfected in NK-resistant cells. Viral early gene nsP1 alone efficiently sensitized target cells to NK activity, and the tight membrane association of nsP1 seems to be critical in the triggering of NK killing. NsP1 protein colocalized with (redistributed) ezrin in filopodia-like structures to which the NK cells were bound. The results suggest that also in viral infections NK cells react to rapid changes in membrane topography. Based on the results of this thesis, a new model of target cell recognition of NK cells can be suggested: reorganization of the cytoskeleton induces alterations in cell surface topography, and this new pattern of surface molecules is recognized as "altered-self".

Soil seed bank longevity information for weed eradication target species

The longevity of seed in the soil is a key determinant of the cost and length of weed eradication programs. Soil seed bank information and ongoing research have input into the planning and reporting of two nationally cost shared weed eradication programs based in tropical north Queensland. These eradication programs are targeting serious weeds such as Chromoleana odorata, Mikania micrantha, Miconia calvescens, Clidemia hirta and Limnocharis flava. Various methods are available for estimating soil seed persistence. Field methods to estimate the total and germinable soil seed densities include seed packet burial trials, extracting seed from field soil samples, germinating seed in field soil samples and observations from native range seed bank studies. Interrogating field control records can also indicate the length of the control and monitoring periods needed to exhaust the seed bank. Recently, laboratory tests which rapidly age seed have provided an additional indicator of relative seed persistence. Each method has its advantages, drawbacks and logistical constraints.