Research, Innovation and Commercialisation - Research Publications

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    Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer
    Li, R ; Sant, S ; Brown, E ; Caramia, F ; Nikolic, B ; Clarke, K ; Byrne, A ; Gonzalez, LEL ; Savas, P ; Luen, SJ ; Teo, ZL ; Virassamy, B ; Neeson, PJ ; Darcy, PK ; Loi, S (OXFORD UNIV PRESS INC, 2023-07-06)
    BACKGROUND: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. METHODS: We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. RESULTS: In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. CONCLUSION: Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
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    G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes
    Isojima, T ; Walker, EC ; Poulton, IJ ; McGregor, NE ; Wicks, IP ; Gooi, JH ; Martin, TJ ; Sims, NA (WILEY, 2022-10)
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    Differential antigen requirements by diverse MR1-restricted T cells (vol 100, pg 112, 2022)
    Seneviratna, R ; Redmond, SJ ; McWilliam, HEG ; Reantragoon, R ; Villadangos, JA ; McCluskey, J ; Godfrey, D ; Gherardin, NA (WILEY, 2022-03)
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    Are NKT cells a useful predictor of COVID-19 severity?
    Koay, H-F ; Gherardin, NA ; Nguyen, THO ; Zhang, W ; Habel, JR ; Seneviratna, R ; James, F ; Holmes, NE ; Smibert, OC ; Gordon, CL ; Trubiano, JA ; Kedzierska, K ; Godfrey, DI (CELL PRESS, 2022-02-08)
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    Structural biology of cell surface receptors implicated in Alzheimer's disease
    Hermans, SJ ; Nero, TL ; Morton, CJ ; Gooi, JH ; Crespi, GAN ; Hancock, NC ; Gao, C ; Ishii, K ; Markulic, J ; Parker, MW (SPRINGERNATURE, 2022-02)
    Alzheimer's disease is a common and devastating age-related disease with no effective disease-modifying treatments. Human genetics has implicated a wide range of cell surface receptors as playing a role in the disease, many of which are involved in the production or clearance of neurotoxins in the brain. Amyloid precursor protein, a membrane-bound signaling molecule, is at the very heart of the disease: hereditary mutations in its gene are associated with a greatly increased risk of getting the disease. A proteolytic breakdown product of amyloid precursor protein, the neurotoxic Aβ peptide, has been the target for many drug discovery efforts. Antibodies have been designed to target Aβ production with some success, although they have not proved efficacious in clinical trials with regards to cognitive benefits to date. Many of the recently identified genes associated with late-onset Alzheimer's disease risk are integral to the innate immune system. Some of these genes code for microglial proteins, such as the strongest genetic risk factor for the disease, namely APOE, and the cell surface receptors CD33 and TREM2 which are involved in clearance of the Aβ peptide from the brain. In this review, we show how structural biology has provided key insights into the normal functioning of these cell surface receptors and provided a framework for developing novel treatments to combat Alzheimer's disease.
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    Anionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain
    Boland, MP ; Hatty, CR ; Separovic, F ; Hill, AF ; Tew, DJ ; Barnham, KJ ; Haigh, CL ; James, M ; Masters, CL ; Collins, SJ (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-10-15)
    Although the N terminus of the prion protein (PrP(C)) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP(C) and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.
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    Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2
    Pymm, P ; Redmond, SJ ; Dolezal, O ; Mordant, F ; Lopez, E ; Cooney, JP ; Davidson, KC ; Haycroft, ER ; Tan, CW ; Seneviratna, R ; Grimley, SL ; Purcell, DFJ ; Kent, SJ ; Wheatley, AK ; Wang, L-F ; Leis, A ; Glukhova, A ; Pellegrini, M ; Chung, AW ; Subbarao, K ; Uldrich, AP ; Tham, W-H ; Godfrey, DI ; Gherardin, NA (CELL PRESS, 2022-11-18)
    The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.
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    Rising to the challenge of teaching Chinese students
    Cooney-O'Donoghue, D ( 2020-05-23)
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    Basic income: trade-offs and bottom lines
    Bowman, D ; Mallett, S ; Cooney-O'Donoghue, D (Brotherhood of St Laurence, 2017-11-01)
    In 2016, Professor Brian Howe, University of Melbourne academic and former Deputy Prime Minister and Minister for Social Security in the Hawke Labor Government, recognised the opportunity to celebrate the 50 plus year legacy of Professor Ronald Henderson, the inaugural director of the Melbourne Institute of Applied Economic and Social Research at the University of Melbourne. Professor Henderson led the National Poverty Inquiry (1972–1975), which resulted in the Henderson Poverty Line as well as a proposal for a Basic Income. The crucial role of social security in mitigating the negative impact of poverty was also considered in the poverty inquiry. Professor Howe, together with Professor Shelley Mallett, General Manager of the Brotherhood of St Laurence’s Research and Policy Centre, and the Melbourne Institute have partnered in a program of activities throughout 2016 and 2017 that honour Professor Henderson’s work on poverty, social security and basic income. This working paper was commissioned by the partners to review existing proposals and trials of basic income and inform discussion of the strengths and weaknesses of basic income approaches, especially in relation to income adequacy. Further papers on basic income will be developed by a range of authors as part of the Henderson Program.
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