Surgery (St Vincent's) - Research Publications
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ItemNo Preview AvailableGata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14(AMER SOC MICROBIOLOGY, 2011-11)The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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ItemAAV-mediated gene delivery of the calreticulin anti-angiogenic domain inhibits ocular neovascularization(SPRINGER, 2018-02)Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. The expression of CAD180 and CAD112 was elevated in human umbilical vein endothelial cells transduced with scAAV2-CAD180 or scAAV2-CAD112, respectively, and both inhibited angiogenic activity in vitro. Intravitreal gene delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly inhibited ischemia-induced retinal neovascularization in rat eyes (CAD180: 52.7% reduction; CAD112: 49.2% reduction) compared to scAAV2-mCherry, as measured in retinal flatmounts stained with isolectin B4. Moreover, the retinal structure and function were unaffected by scAAV2-CAD180 or scAAV2-CAD112, as measured by optical coherence tomography and electroretinography. Moreover, subretinal delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly attenuated laser-induced choroidal neovascularization in mouse eyes compared to scAAV2-mCherry, as measured by fundus fluorescein angiography (CAD180: 62.4% reduction; CAD112: 57.5% reduction) and choroidal flatmounts (CAD180: 40.21% reduction; CAD112: 43.03% reduction). Gene delivery using scAAV2-CAD180 or scAAV2-CAD112 has significant potential as a therapeutic option for the management of ocular neovascularization.
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ItemThe delicate balance of melanoma immunotherapy(WILEY, 2013-08)The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted.
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ItemElectrical probing of cortical excitability in patients with epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011-12)Standard methods for seizure prediction involve passive monitoring of intracranial electroencephalography (iEEG) in order to track the 'state' of the brain. This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus. Electrical probing enables feature extraction in a more robust and controlled manner compared to passively tracking features of iEEG signals. The probing stimuli consist of 100 bi-phasic pulses, delivered every 10 min. Features representing neural excitability are estimated from the iEEG responses to the stimuli. These features include the amplitude of the electrically evoked potential, the mean phase variance (univariate), and the phase-locking value (bivariate). In one patient, it is shown how the features vary over time in relation to the sleep-wake cycle and an epileptic seizure. For a second patient, it is demonstrated how the features vary with the rate of interictal discharges. In addition, the spatial pattern of increases and decreases in phase synchrony is explored when comparing periods of low and high interictal discharge rates, or sleep and awake states. The results demonstrate a proof-of-principle for the method to be applied in a seizure anticipation framework. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.
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ItemTight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells(American Association for Cancer Research, 2018-06-01)Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer.
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ItemStatic force dependency of bone conduction transducer as sensory feedback for stump-socket based prosthesis(Australian Robotics and Automation Association, 2018-01-01)The dependency of a novel sensory feedback for stump-socket based prosthesis on the static force is presented using a bone conduction transducer as feedback source. The stimulation was induced onto the bony landmarks of the elbow, specifically the Ulna and presented in an interval halving method. The perception threshold in the range of tactile and auditory perception at three different force levels has been tested. The inter subject variability is bigger than the intra subject variation. The small static force variation suggests a similar approach as in bone conduction hearing aids and therefore a static force bigger than 6N should be applied to perceive a constant stimulation. A mechanical design to include such a novel feedback into a stump-socket needs to account for this requirement. The inter subject variability needs to be addressed by incorporate some kind of person to person calibration of the gain.
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ItemSham surgery: justified but practical? A systematic review of sham surgery trials in orthopaedics(Academy of Science of South Africa, 2018)BACKGROUND: An increasing trend for sham surgery trials in minor orthopaedic procedures has been observed. Trial outcomes have changed the practice landscape of these procedures. However, there has been no sham surgery trial in a major orthopaedic procedure. The aims of this systematic review were to consider the ethics of sham surgery trials; to describe orthopaedic sham surgery trials conducted to date; and to consider the challenges that will need to be overcome in order to conduct sham surgery trials for major orthopaedic procedures in the future. METHODS: A systematic review of the literature and clinical trial registries was undertaken. Trials with a published main findings paper underwent a risk of bias assessment using the Cochrane Collaboration risk of bias tool, in addition to an ethical assessment based on the work of Horng and Miller. RESULTS: We identified 22 sham surgery trials for minor orthopaedic procedures that have been completed, terminated, or are currently in process. Among the ten trials with a published main findings paper, only one was free from risk of bias; all others were at risk of bias. According to the ethical assessment, the benefits of a sham control were outweighed by the risks in all but two of the ten trials. Across the 22 trials with published and unpublished main findings, participant recruitment within reasonable timeframes, as well as the low threshold for crossover from the sham were recurring challenges. CONCLUSIONS: Researchers are obliged to carefully consider the feasibility of conducting a sham surgery trial in a major orthopaedic procedure, before drawing on limited research funds. Exploring the conditions under which patients and surgeons would find participation in a sham surgery trial acceptable, and simulating trial costs based on patient and surgeon preferences may assist funders, assessors and ethics boards to determine whether to support the conducting of future sham surgery trials in major orthopaedic procedures.
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ItemQualitative research and osteoarthritis of the knee(CRC Press (Taylor & Francis Group), 2019)
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ItemWhiplash Patients' Responses on the Impact of Events Scale-R Congruent With Pain or PTSD Symptoms?(LIPPINCOTT WILLIAMS & WILKINS, 2019-03)OBJECTIVES: Posttraumatic stress disorder (PTSD) symptoms are common among people with whiplash following a motor vehicle crash. The Impact of Events Scale-Revised (IES-R) screens for PTSD symptoms with psychologist referral recommended for above-threshold scores. Recent data indicate that PTSD symptoms post-whiplash may relate more to pain and disability than the crash itself. This study explored the interpretation of IES-R items by people with whiplash to establish whether responses relate to the crash or to whiplash pain and disability. METHODS: Adults with whiplash scoring >24 on the IES-R were eligible. The 3-step test-interview technique was used and responses analyzed using content analysis. A coding framework was developed, comprising 5 categories: "congruent"-responses related to the crash; "incongruent"-responses did not relate to the crash; "ambiguous"-responses were both congruent and incongruent; "confusion"-participants misunderstood the item content; "not applicable"-irrelevancy of items to participants' circumstances. RESULTS: The 15 participants (mean IES-R=37/88) were inclined to respond congruently to specific PTSD items and incongruently to nonspecific PTSD items. Participants were more inclined to rate nonspecific PTSD items in terms of pain and disability, for example, >60% responded incongruently to item 2: "I had trouble staying asleep"; item 4: "I felt irritable and angry"; item 15: "I had trouble falling asleep"; and item 18: "I had trouble concentrating." DISCUSSION: Incongruent responses on nonspecific PTSD items may inadvertently inflate levels of PTSD symptoms measured with the IES-R for some whiplash patients, raising implications for the assessment and treatment of the psychological sequelae of whiplash.
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ItemConductive Tough Hydrogel for Bioapplications(WILEY-V C H VERLAG GMBH, 2018-02)Biocompatible conductive tough hydrogels represent a new class of advanced materials combining the properties of tough hydrogels and biocompatible conductors. Here, a simple method, to achieve a self-assembled tough elastomeric composite structure that is biocompatible, conductive, and with high flexibility, is reported. The hydrogel comprises polyether-based liner polyurethane (PU), poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(4-styrenesulfonate) (PSS), and liquid crystal graphene oxide (LCGO). The polyurethane hybrid composite (PUHC) containing the PEDOT:PSS, LCGO, and PU has a higher electrical conductivity (10×), tensile modulus (>1.6×), and yield strength (>1.56×) compared to respective control samples. Furthermore, the PUHC is biocompatible and can support human neural stem cell (NSC) growth and differentiation to neurons and supporting neuroglia. Moreover, the stimulation of PUHC enhances NSC differentiation with enhanced neuritogenesis compared to unstimulated cultures. A model describing the synergistic effects of the PUHC components and their influence on the uniformity, biocompatibility, and electromechanical properties of the hydrogel is presented.