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    University of Melbourne Digital Preservation Strategy 2015-2025 - Vision Mandate and Principles
    Shadbolt, A ; Konstantelos, L ; McCarthy, G ; Dean, K ; O'Neil, O (University of Melbourne, 2013)
    University of Melbourne Digital Preservation Strategy 2015-2025 - Vision Mandate and Principles
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    Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers
    John, EM ; McGuire, V ; Thomas, D ; Haile, R ; Ozcelik, H ; Milne, RL ; Felberg, A ; West, DW ; Miron, A ; Knight, JA ; Terry, MB ; Daly, M ; Buys, SS ; Andrulis, IL ; Hopper, JL ; Southey, MC ; Giles, GG ; Apicella, C ; Thorne, H ; Whittemore, AS (AMER ASSOC CANCER RESEARCH, 2013-09)
    BACKGROUND: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. METHODS: We studied 454 BRCA1 and 273 BRCA2 mutation carriers ages younger than 50 years from three breast cancer family registries in the United States, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest X-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest X-rays was self-reported. Mammograms were not considered in the analysis. RESULTS: After adjusting for known risk factors for breast cancer, the ORs for a history of diagnostic chest X-rays, excluding those for tuberculosis or pneumonia, were 1.16 [95% confidence interval (CI), 0.64-2.11] for BRCA1 mutations carriers and 1.22 (95% CI, 0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with three to five diagnostic chest X-rays (P = 0.01) but not for those with six or more chest X-rays. Few women reported chest fluoroscopy for tuberculosis or chest X-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. CONCLUSIONS: Our findings do not support a positive association between diagnostic chest X-rays and breast cancer risk before the ages of 50 years for BRCA1 or BRCA2 mutation carriers. IMPACT: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.
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    The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-Myc Lymphoma by Restoring Oncogene-Induced Senescence
    Wall, M ; Poortinga, G ; Stanley, KL ; Lindemann, RK ; Bots, M ; Chan, CJ ; Bywater, MJ ; Kinross, KM ; Astle, MV ; Waldeck, K ; Hannan, KM ; Shortt, J ; Smyth, MJ ; Lowe, SW ; Hannan, RD ; Pearson, RB ; Johnstone, RW ; McArthur, GA (AMER ASSOC CANCER RESEARCH, 2013-01)
    UNLABELLED: MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes. SIGNIFICANCE: This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit
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    The BTB-zinc Finger Transcription Factor Abrupt Acts as an Epithelial Oncogene in Drosophila melanogaster through Maintaining a Progenitor-like Cell State
    Turkel, N ; Sahota, VK ; Bolden, JE ; Goulding, KR ; Doggett, K ; Willoughby, LF ; Blanco, E ; Martin-Blanco, E ; Corominas, M ; Ellul, J ; Aigaki, T ; Richardson, HE ; Brumby, AM ; Horwitz, MS (PUBLIC LIBRARY SCIENCE, 2013-07)
    The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.
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    In Drosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1-Rok-Myosin-II and JNK signalling
    Khoo, P ; Allan, K ; Willoughby, L ; Brumby, AM ; Richardson, HE (COMPANY BIOLOGISTS LTD, 2013-05)
    The Ras oncogene contributes to ≈ 30% of human cancers, but alone is not sufficient for tumorigenesis. In a Drosophila screen for oncogenes that cooperate with an activated allele of Ras (Ras(ACT)) to promote tissue overgrowth and invasion, we identified the GTP exchange factor RhoGEF2, an activator of Rho-family signalling. Here, we show that RhoGEF2 also cooperates with an activated allele of a downstream effector of Ras, Raf (Raf(GOF)). We dissect the downstream pathways through which RhoGEF2 cooperates with Ras(ACT) (and Raf(GOF)), and show that RhoGEF2 requires Rho1, but not Rac, for tumorigenesis. Furthermore, of the Rho1 effectors, we show that RhoGEF2 + Ras (Raf)-mediated tumorigenesis requires the Rho kinase (Rok)-Myosin-II pathway, but not Diaphanous, Lim kinase or protein kinase N. The Rho1-Rok-Myosin-II pathway leads to the activation of Jun kinase (JNK), in cooperation with Ras(ACT). Moreover, we show that activation of Rok or Myosin II, using constitutively active transgenes, is sufficient for cooperative tumorigenesis with Ras(ACT), and together with Ras(ACT) leads to strong activation of JNK. Our results show that Rok-Myosin-II activity is necessary and sufficient for Ras-mediated tumorigenesis. Our observation that activation of Myosin II, which regulates Filamentous actin (F-actin) contractility without affecting F-actin levels, cooperates with Ras(ACT) to promote JNK activation and tumorigenesis, suggests that increased cell contractility is a key factor in tumorigenesis. Furthermore, we show that signalling via the Tumour necrosis factor (TNF; also known as Egr)-ligand-JNK pathway is most likely the predominant pathway that activates JNK upon Rok activation. Overall, our analysis highlights the need for further analysis of the Rok-Myosin-II pathway in cooperation with Ras in human cancers.
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    An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery
    Willoughby, LF ; Schlosser, T ; Manning, SA ; Parisot, JP ; Street, IP ; Richardson, HE ; Humbert, PO ; Brumby, AM (COMPANY OF BIOLOGISTS LTD, 2013-03)
    Anti-cancer drug development involves enormous expenditure and risk. For rapid and economical identification of novel, bioavailable anti-tumour chemicals, the use of appropriate in vivo tumour models suitable for large-scale screening is key. Using a Drosophila Ras-driven tumour model, we demonstrate that tumour overgrowth can be curtailed by feeding larvae with chemicals that have the in vivo pharmacokinetics essential for drug development and known efficacy against human tumour cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumour model. In a proof-of-principle pilot screen of 2000 compounds, we identify the glutamine analogue, acivicin, a chemical with known activity against human tumour cells, as a potent and specific inhibitor of Drosophila tumour formation. RNAi-mediated knockdown of candidate acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible crucial target of acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumours are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economical tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering widespread applications in drug development.
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    Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors
    Nickels, S ; Truong, T ; Hein, R ; Stevens, K ; Buck, K ; Behrens, S ; Eilber, U ; Schmidt, M ; Haeberle, L ; Vrieling, A ; Gaudet, M ; Figueroa, J ; Schoof, N ; Spurdle, AB ; Rudolph, A ; Fasching, PA ; Hopper, JL ; Makalic, E ; Schmidt, DF ; Southey, MC ; Beckmann, MW ; Ekici, AB ; Fletcher, O ; Gibson, L ; Silva, IDS ; Peto, J ; Humphreys, MK ; Wang, J ; Cordina-Duverger, E ; Menegaux, F ; Nordestgaard, BG ; Bojesen, SE ; Lanng, C ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Clarke, CA ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Brauch, H ; Bruening, T ; Harth, V ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Lambrechts, D ; Smeets, D ; Neven, P ; Paridaens, R ; Flesch-Janys, D ; Obi, N ; Wang-Gohrke, S ; Couch, FJ ; Olson, JE ; Vachon, CM ; Giles, GG ; Severi, G ; Baglietto, L ; Offit, K ; John, EM ; Miron, A ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Chanock, SJ ; Lissowska, J ; Liu, J ; Cox, A ; Cramp, H ; Connley, D ; Balasubramanian, S ; Dunning, AM ; Shah, M ; Trentham-Dietz, A ; Newcomb, P ; Titus, L ; Egan, K ; Cahoon, EK ; Rajaraman, P ; Sigurdson, AJ ; Doody, MM ; Guenel, P ; Pharoah, PDP ; Schmidt, MK ; Hall, P ; Easton, DF ; Garcia-Closas, M ; Milne, RL ; Chang-Claude, J ; Horwitz, MS (PUBLIC LIBRARY SCIENCE, 2013-03)
    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
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    The Robert Menzies Collection at the University of Melbourne
    Stone, Caitlin ; Berryman, Jim (University of Melbourne Library, 2013-06)
    Sir Robert Gordon Menzies (1894–1978) is best remembered as the founder of the Liberal Party and Australia’s longest-serving prime minister, a role he occupied in two terms from 1939 to 1941 and 1949 to 1966. Menzies was also an alumnus of the University of Melbourne and, from 1967 to 1972, its chancellor. His long association with the university is reflected in many of its collections. This article focuses on just one of these, his personal library. Accumulated over his lifetime, the Robert Menzies Collection casts light on Menzies’ public and private worlds, his varied interests and tastes, and his vast political and social networks.
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    Cybraries in paradise: New technologies and ethnographic repositories
    Barwick, L ; Thieberger, N ; Kapitzke, C ; Bruce, BC (Routledge, 2013-01-01)
    Digital technologies have altered research practices surrounding creation and use of ethnographic field recordings, and the methodologies and paradigms of the disciplines centered around their interpretation. In this chapter we discuss some examples of our current research practices as fieldworkers documenting music and language in the Asia-Pacific region in active engagement with the cultural heritage communities, and as developers and curators of the digital repository PARADISEC (the Pacific and Regional Archive for Digital Sources in Endangered Cultures: ). We suggest a number of benefits that the use of digital technologies can bring to the recording of material from small and endangered cultures, and to its re-use by communities and researchers.
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