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  • (2006) Hitchins, Megan; Suter, C; Wong, Jenny; Cheong, Kay; Hawkins, Nicholas; Leggett, B; Scott, R; Spigelman, Allan; Tomlinson, Ian; Martin, David; Ward, Robyn
    Journal Article

  • (2003) Welsh, John; Sapinoso, Lisa; Kern, Suzanne; Brown, David; Liu, Tao; Bauskin, Asne; Ward, Robyn; Hawkins, Nicholas; Quinn, David; Russell, Pamela; Sutherland, Robert; Breit, Samuel; Moskaluk, Christopher; Frierson Jr, Henry; Hampton, Garret
    Journal Article
    Genetic alterations in tumor cells often lead to the emergence of growth-stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited for cancer diagnosis and management or as points of therapeutic intervention. Here, we combined the use of controlled vocabulary terms and sequence-based algorithms to predict genes encoding secreted proteins from among ≈12,500 sequences represented on oligonucleotide microarrays. Expression of these genes was queried in 150 carcinomas from 10 anatomic sites of origin and compared with 46 normal tissues derived from the corresponding sites of tumor origin and other body tissues and organs. Of 74 different genes identified as overexpressed in cancer tissues, several encode proteins with demonstrated clinical diagnostic application, such as α-fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or therapeutic utility, such as gastrin-releasing peptide/bombesin in lung carcinomas. We show that several of the other candidate genes encode proteins with high levels of tumor-associated expression by immunohistochemistry on tissue microarrays and further demonstrate significantly elevated levels of another novel candidate protein, macrophage inhibitory cytokine 1, a distant member of the tranforming growth factor-β superfamily, in the serum of patients with metastatic prostate, breast, and colorectal carcinomas. Our results suggest that the combination of annotation/protein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to other human diseases.

  • (2003) Brown, David; Ward, Robyn; Buckhaults, Philip; Liu, Tao; Romans, Katherine; Hawkins, Nicholas; Bauskin, Asne; Kinzler, Kenneth; Vogelstein, Bert; Breit, Samuel
    Journal Article
    Purpose: Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor ß (TGF-ß) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia. Experimental Design: We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures. Results: MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes. Conclusions: This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.

  • (2009) Lim, Wee Han; Huebl, Hans; Willems van Beveren, Laurens; Rubanov, Sergey; Spizzirri, Paul; Angus, Susan; Clark, Robert; Dzurak, Andrew
    Journal Article
    A few-electron double quantum dot was fabricated using metal-oxide-semiconductor-compatible technology and low-temperature transport measurements were performed to study the energy spectrum of the device. The double dot structure is electrically tunable, enabling the inter-dot coupling to be adjusted over a wide range, as observed in the charge stability diagram. Resonant single-electron tunneling through ground and excited states of the double dot was clearly observed in bias spectroscopy measurements.

  • (2007) Garner, James; Harding, Margaret
    Journal Article
    The á-helix is the most abundant secondary structural element in proteins and is an important structural domain for mediating protein-protein and protein-nucleic acid interactions. Strategies for the rational design and synthesis of á-helix mimetics have not matured as well as other secondary structure mimetics such as strands and turns. This perspective will focus on developments in the design, synthesis and applications of á-helices and mimetics, particularly in the last 5 years. Examples where synthetic compounds have delivered promising biological results will be highlighted as well as opportunities for the design of mimetics of the type I á-helical antifreeze proteins. © The Royal Society of Chemistry.

  • (2007) Abeysinghe, Priyanthi; Harding, Margaret
    Journal Article
    This Perspective will focus on recent developments in the field of antitumour metallocenes structurally related to titanocene dichloride. Despite extensive testing of titanocene dichloride which culminated in phase I and II clinical trials, further trials have been abandoned. While DNA has been implicated as the major target related to anticancer activity, identification of the active species and mechanism of action has been poorly understood and hence the design of second generation titanocene derivatives has not been possible. Recent mechanistic studies have provided a plausible mechanism for delivery of Ti to cancer cells via transferrin mediated endocytosis. This mechanism requires the presence of labile Cp-Ti bonds that hydrolyse on a time scale to deliver Ti to transferrin. A large range of titanocene derivatives in which the cyclopentadienyl rings have been substituted by both electron withdrawing and donating groups, including aromatic, alkyl and cyclic amines, have been prepared and tested for activity in the last 5 years. These results have shown that subtle structural effects can have a significant effect on biological activity and that biological activity is highly cell line dependent. However, the biological chemistry and cellular studies required to determine the mechanism of action of these new titanocenes have not been reported. In contrast, the bioorganometallic chemistry and cellular studies of molybdocene dichloride have implicated interaction with cellular thiols as the key reaction related to biological activity. Tailoring of the pseudohalide ligands by tuning the strength of the Mo-S bonds provides the opportunity to enhance cell uptake. Further research is required to establish the origin of antitumour activity. © The Royal Society of Chemistry.

  • (2007) Harding, Margaret; Campbell, Kate; Dillon, Carolyn; Smith, S
    Journal Article
    Neutron irradiation Of Cp2MoCl2 for 24 h afforded the radiotracer (CP2MoCl2)-Mo-99 which was characterised by UV-Vis spectroscopy and thin layer chromatography. Binding experiments with the thiol containing protein human serum albumin (HSA) or calf thymus DNA, were monitored for Mo-99 using a gamma counter. Under the conditions investigated, molar ratios of binding of 0.2:1 (Cp2MoCl2:DNA) and 9.4:1 (Cp2MoCl2:HSA) were calculated. The results are consistent with in vitro coordination studies that have shown strong preferential interaction Of Cp2MoCl2 with thiols versus other donor sites in biomolecules including DNA. (c) 2006 Elsevier Ltd. All rights reserved.

  • (2006) Dillon, Carolyn; Harding, Margaret; Campbell, Kate; Foster, Amalanie
    Journal Article
    The cytotoxic effects of molybdocene dichloride (Cp2MoCl2) were investigated in V79 Chinese hamster lung cells using the micronucleus assay. Cp2MoCl2 produced significant genotoxic damage whereby 0.2 micronuclei/1000 binucleated cells were induced per μM of Cp2MoCl2. Transmission electron microscopic analysis of thin-sectioned cells treated with Cp2MoCl2 (300 μM) showed distinct morphological alterations of the nuclei, condensation of chromatin, and a high incidence of polynucleated cells. Implications for the mechanism of antitumor action of molybdocene dichloride are discussed.

  • (2006) Inglis, Steven; Turner, J; Harding, Margaret
    Journal Article
    Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs), found in the body fluids of many species of polar fish allow them to survive in waters colder than the equilibrium freezing point of their blood and other internal fluids. Despite their structural diversity, all AF(G)Ps kinetically depress the temperature at which ice grows in a noncolligative manner and hence exhibit thermal hysteresis. AF(G)Ps also share the ability to interact with and protect mammalian cells and tissues from hypothermic damage (e.g., improved storage of human blood platelets at low temperatures), and are able to stabilize or disrupt membrane composition during low temperature and freezing stress (e.g., cryoprotectant properties in stabilization of sperm and oocytes). This review will summarize studies of AFPs with phospholipids and plant lipids, proposed mechanisms for inhibition of leakage from membranes, and cryoprotectant studies with biological samples. The major focus will be on the alpha-helical type I antifreeze proteins, and synthetic mutants, that have been most widely studied. For completeness, data on glycoproteins will also be presented. While a number of models to explain stabilization and destabilization of different lipid systems have been proposed, it is currently not possible to predict whether a particular AFP will stabilize or destabilize a given lipid system. Furthermore the relationship between the antifreeze property of thermal hysteresis and membrane stabilization is unknown. This lack of detailed knowledge about how AFPs function in the presence of different types of materials has hampered progress toward the development of antifreezes for cold storage of cells, tissues, and organs.

  • (2006) Rendina, L; Harding, Margaret; Lee, Chun-Cheng; Groneman, J; Turner, Peter
    Journal Article
    Ditopic symmetrical bis(pyridyl) ligands incorporating the chiral dibenzobicyclo[b,f][3.3.1]nona-5a,6a-dieiie-6,12-dione cleft have been synthesised and characterised by NMR spectroscopy, mass spectrometry and X-ray crystallography. The ligands, which incorporate pyridyl groups directly connected to the carbocyclic cleft core or via alkyne or phenyl linkers were accessed from palladium-catalysed coupling reactions of 2,8-dibromodibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione. X-ray crystal analyses show the interplanar angles between the two cleft aromatic rings in these molecules, which range from 97.80(3) to 109.80(4)degrees. (c) 2006 Elsevier Ltd. All rights reserved.