Melbourne Medical School Collected Works - Research Publications

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    Estimation of glucose disposal rate in type 1 diabetes using clinical and research biomarkers
    Jenkins, AJ ; Januszewski, AS ; Sachithanandan, N ; Ward, G ; Karschimkus, C ; O'Neal, DN (Springer, 2018-10)
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    Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression
    Peng, K-Y ; Watt, MJ ; Rensen, S ; Greve, JW ; Huynh, K ; Jayawardana, KS ; Meikle, PJ ; Meex, RCR (ELSEVIER, 2018-10)
    Nonalcoholic fatty liver disease (NAFLD) comprises fat-accumulating conditions within hepatocytes that can cause severe liver damage and metabolic comorbidities. Studies suggest that mitochondrial dysfunction contributes to its development and progression and that the hepatic lipidome changes extensively in obesity and in NAFLD. To gain insight into the relationship between lipid metabolism and disease progression through different stages of NAFLD, we performed lipidomic analysis of plasma and liver biopsy samples from obese patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) and from those without NAFLD. Congruent with earlier studies, hepatic lipid levels overall increased with NAFLD. Lipid species that differed with NAFLD severity were related to mitochondrial dysfunction; specifically, hepatic cardiolipin and ubiquinone accumulated in NAFL, and levels of acylcarnitine increased with NASH. We propose that increased levels of cardiolipin and ubiquinone may help to preserve mitochondrial function in early NAFLD, but that mitochondrial function eventually fails with progression to NASH, leading to increased acylcarnitine. We also found a negative association between hepatic odd-chain phosphatidylcholine and NAFLD, which may result from mitochondrial dysfunction-related impairment of branched-chain amino acid catabolism. Overall, these data suggest a close link between accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD.
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    CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma
    Li, Z ; Ju, X ; Lee, K ; Clarke, C ; Hsu, JL ; Abadir, E ; Bryant, CE ; Pears, S ; Sunderland, N ; Heffernan, S ; Hennessy, A ; Lo, T-H ; Pietersz, GA ; Kupresanin, F ; Fromm, PD ; Silveira, PA ; Tsonis, C ; Cooper, WA ; Cunningham, I ; Brown, C ; Clark, GJ ; Hart, DNJ (FERRATA STORTI FOUNDATION, 2018-03-23)
    Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83-T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.
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    Systems Medicine Disease: Disease Classification and Scalability Beyond Networks and Boundary Conditions
    Berlin, R ; Gruen, R ; Best, J (FRONTIERS MEDIA SA, 2018-08-07)
    In order to accommodate the forthcoming wealth of health and disease related information, from genome to body sensors to population and the environment, the approach to disease description and definition demands re-examination. Traditional classification methods remain trapped by history; to provide the descriptive features that are required for a comprehensive description of disease, systems science, which realizes dynamic processes, adaptive response, and asynchronous communication channels, must be applied (Wolkenhauer et al., 2013). When Disease is viewed beyond the thresholds of lines and threshold boundaries, disease definition is not only the result of reductionist, mechanistic categories which reluctantly face re-composition. Disease is process and synergy as the characteristics of Systems Biology and Systems Medicine are included. To capture the wealth of information and contribute meaningfully to medical practice and biology research, Disease classification goes beyond a single spatial biologic level or static time assignment to include the interface of Disease process and organism response (Bechtel, 2017a; Green et al., 2017).
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    Immunogenicity of a Tripartite Cell Penetrating Peptide Containing a MUC1 Variable Number of Tandem Repeat (VNTR) and A T Helper Epitope
    Brooks, N ; Hsu, J ; Esparon, S ; Pouniotis, D ; Pietersz, GA (MDPI, 2018-09)
    Peptide-based vaccines for cancer have many advantages however, for optimization these immunogens should incorporate peptide epitopes that induce CD8, as well as CD4 responses, antibody and long term immunity. Cell penetrating peptides (CPP) with a capacity of cytosolic delivery have been used to deliver antigenic peptides and proteins to antigen presenting cells to induce cytotoxic T cell, helper T cell and humoral responses in mice. For this study, a tripartite CPP including a mucin 1 (MUC1) variable number of tandem repeat (VNTR) containing multiple T cell epitopes and tetanus toxoid universal T helper epitope peptide (tetCD4) was synthesised (AntpMAPMUC1tet) and immune responses investigated in mice. Mice vaccinated with AntpMAPMUC1tet + CpG show enhanced antigen-specific interferon-gamma (IFN-γ) and IL-4 T cell responses compared with AntpMAPMUC1tet vaccination alone and induced a Th1 response, characterised by a higher ratio of IgG2a antibody/IgG1 antibodies. Furthermore, vaccination generated long term MUC1-specific antibody and T cell responses and delayed growth of MUC1+ve tumours in mice. This data demonstrates the efficient delivery of branched multiple antigen peptides incorporating CPP and that the addition of CpG augments immune responses.
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    Mild cognitive impairment impacts health outcomes of patients with atrial fibrillation undergoing a disease management intervention
    Ball, J ; Lochen, M-L ; Carrington, MJ ; Wiley, JF ; Stewart, S (BMJ PUBLISHING GROUP, 2018-03)
    OBJECTIVE: Mild cognitive impairment (MCI) is prevalent in atrial fibrillation (AF) and has the potential to contribute to poor outcomes. We investigated the influence of MCI on survival and rehospitalisation in patients with chronic forms of AF undergoing a home-based, AF-specific disease management intervention (home-based intervention (HBI)) or standard management (SM). METHODS: The Montreal Cognitive Assessment tool was administered at baseline (a score of <26/30 indicated MCI) in patients with AF randomised to HBI versus SM. Post hoc analyses of mortality and rehospitalisations during a minimum 24-month follow-up were conducted in the overall cohort and in each study group separately. RESULTS: Of 260 patients (mean age 72±11, 47% female), 65% demonstrated MCI on screening (34% in SM; 31% in HBI). Overall, the number of days spent alive and out-of-hospital during follow-up (P=0.012) and all-cause rehospitalisation were influenced by MCI during follow-up (OR 3.16 (95% CI 1.46 to 6.84)) but MCI did not influence any outcomes in the SM group. However, survival was negatively influenced by MCI in the HBI group (P=0.036); those with MCI in this group were 5.6 times more likely to die during follow-up (OR 5.57 (95% CI 1.10 to 28.1)). Those with MCI in the HBI group also spent less days alive and out-of-hospital than those with no MCI (P=0.022). MCI was also identified as a significant independent correlate of shortest duration of event-free survival (OR 3.48 (95% CI 1.06 to 11.4)), all-cause rehospitalisation (OR 3.30 (95% CI 1.25 to 8.69)) and cardiovascular disease (CVD)-related rehospitalisation (OR 2.35 (95% CI 1.12 to 4.91)) in this group. CONCLUSIONS: The effectiveness of home-based, disease management for patients with chronic forms of AF is negatively affected by comorbid MCI. The benefit of adjunctive support for patients with MCI on CVD-related health outcomes requires further investigation.
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    Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
    Moneghetti, KJ ; Skhiri, M ; Contrepois, K ; Kobayashi, Y ; Maecker, H ; Davis, M ; Snyder, M ; Haddad, F ; Montoya, JG (NATURE PUBLISHING GROUP, 2018-02-09)
    Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.
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    How to perform posterior wall isolation in catheter ablation for atrial fibrillation
    Sugumar, H ; Thomas, SP ; Prabhu, S ; Voskoboinik, A ; Kistler, PM (WILEY, 2018-02)
    Catheter ablation has become standard of care in patients with symptomatic atrial fibrillation (AF). Although there have been significant advances in our understanding and technology, a substantial proportion of patients have ongoing AF requiring repeat procedures. Pulmonary vein isolation (PVI) is the cornerstone of AF ablation; however, it is less effective in patients with persistent as opposed to paroxysmal atrial fibrillation. Left atrial posterior wall isolation (PWI) is commonly performed as an adjunct to PVI in patients with persistent AF with nonrandomized studies showing improved outcomes. Anatomical considerations and detailed outline of the various approaches and techniques to performing PWI are detailed, and advantages and pitfalls to assist the clinical electrophysiologist successfully and safely complete PWI are described.
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    Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib
    Wongchenko, MJ ; Ribas, A ; Dreno, B ; Ascierto, PA ; McArthur, GA ; Gallo, JD ; Rooney, IA ; Hsu, J ; Koeppen, H ; Yan, Y ; Larkin, J (WILEY, 2018-07)
    The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1+ melanoma, with hazard ratios (HRs; PD-L1+ vs. PD-L1- ) of 0.70 (95% CI, 0.46-1.07) and 0.69 (95% CI, 0.42-1.13) for PFS and OS, respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HRs (PD-L1+ versus PD-L1- ) of 1.04 (95% CI, 0.66-1.68) and 0.94 (95% CI, 0.57-1.57) for PFS and OS, respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD-L1 expression.
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    Targeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides: comment
    Flierl, U ; Nero, TL ; Lim, B ; Andrews, RK ; Parker, MW ; Gardiner, EE ; Peter, K (WILEY, 2018-01)