Melbourne Medical School Collected Works - Research Publications
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ItemNo Preview AvailableAn Ultrasound‐Responsive Theranostic Cyclodextrin‐Loaded Nanoparticle for Multimodal Imaging and Therapy for Atherosclerosis (Small 31/2022)(Wiley, 2022-08)In article number 2200967, Xiaowei Wang, Karlheinz Peter, and co-workers show that theranostic nanoparticles made of air can deliver a near-infrared fluorescence dye, cyclodextrin, to be used as a contrast agent for ultrasound and fluorescence imaging and as ultrasound-responsive anti-atherosclerotic drug, achieving reduction of cholesterol in plaques after ingestion of nanoparticle by monocytes/macrophages.
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ItemNo Preview Available3D‐Printed Micro Lens‐in‐Lens for In Vivo Multimodal Microendoscopy (Small 17/2022)(Wiley, 2022-04)In article number 2107032, Jiawen Li and co-workers use two-photon 3D printing to develop a 330 micron diameter lens optimized for both fluorescence imaging and optical coherence tomography. This lens-in-lens design is incorporated in an intravascular imaging catheter offering improved performance for heart disease detection.
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ItemAssociation between frailty, delirium, and mortality in older critically ill patients: a binational registry study(SPRINGER, 2022-11-17)BACKGROUND: Frailty and delirium are prevalent among older adults admitted to the intensive care unit (ICU) and associated with adverse outcomes; however, their relationships have not been extensively explored. This study examined the association between frailty and mortality and length of hospital stay (LOS) in ICU patients, and whether the associations are mediated or modified by an episode of delirium. METHODS: Retrospective analysis of data from the Australian New Zealand Intensive Care Society Adult Patient Database. A total of 149,320 patients aged 65 years or older admitted to 203 participating ICUs between 1 January 2017 and 31 December 2020 who had data for frailty and delirium were included in the analysis. RESULTS: A total of 41,719 (27.9%) older ICU patients were frail on admission, and 9,179 patients (6.1%) developed delirium during ICU admission. Frail patients had significantly higher odds of in-hospital mortality (OR: 2.15, 95% CI 2.05-2.25), episodes of delirium (OR: 1.86, 95% CI 1.77-1.95), and longer LOS (log-transformed mean difference (MD): 0.24, 95% CI 0.23-0.25). Acute delirium was associated with 32% increased odds of in-hospital mortality (OR: 1.32, 95% CI 1.23-1.43) and longer LOS (MD: 0.54, 95% CI 0.50-0.54). The odds ratios (95% CI) for in-hospital mortality were 1.37 (1.23-1.52), 2.14 (2.04-2.24) and 2.77 (2.51-3.05) for non-frail who developed delirium, frail without delirium, and frail and developed delirium during ICU admission, respectively. There was very small but statistically significant effect of frailty on in-hospital mortality (b for indirect effect: 0.00037, P < 0.001) and LOS (b for indirect effect: 0.019, P < 0.001) mediated through delirium. CONCLUSION: Both frailty and delirium independently increase the risk of in-hospital mortality and LOS. Acute delirium is more common in frail patients; however, it does not mediate or modify a clinically meaningful amount of the association between frailty and in-hospital mortality and LOS.
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ItemIn vivo fluorescence imaging: success in preclinical imaging paves the way for clinical applications(BMC, 2022-10-15)Advances in diagnostic imaging have provided unprecedented opportunities to detect diseases at early stages and with high reliability. Diagnostic imaging is also crucial to monitoring the progress or remission of disease and thus is often the central basis of therapeutic decision-making. Currently, several diagnostic imaging modalities (computed tomography, magnetic resonance imaging, and positron emission tomography, among others) are routinely used in clinics and present their own advantages and limitations. In vivo near-infrared (NIR) fluorescence imaging has recently emerged as an attractive imaging modality combining low cost, high sensitivity, and relative safety. As a preclinical tool, it can be used to investigate disease mechanisms and for testing novel diagnostics and therapeutics prior to their clinical use. However, the limited depth of tissue penetration is a major challenge to efficient clinical use. Therefore, the current clinical use of fluorescence imaging is limited to a few applications such as image-guided surgery on tumors and retinal angiography, using FDA-approved dyes. Progress in fluorophore development and NIR imaging technologies holds promise to extend their clinical application to oncology, cardiovascular diseases, plastic surgery, and brain imaging, among others. Nanotechnology is expected to revolutionize diagnostic in vivo fluorescence imaging through targeted delivery of NIR fluorescent probes using antibody conjugation. In this review, we discuss the latest advances in in vivo fluorescence imaging technologies, NIR fluorescent probes, and current and future clinical applications.
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ItemCrosstalk between cytotoxic CD8+T cells and stressed cardiomyocytes triggers development of interstitial cardiac fibrosis in hypertensive mouse hearts(FRONTIERS MEDIA SA, 2022-11-22)AIMS: Cardiac fibrosis is central to heart failure (HF), especially HF with preserved ejection fraction (HFpEF), often caused by hypertension. Despite fibrosis causing diastolic dysfunction and impaired electrical conduction, responsible for arrhythmia-induced sudden cardiac death, the mechanisms are poorly defined and effective therapies are lacking. Here we show that crosstalk between cardiac cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is essential for development of non-ischemic hypertensive cardiac fibrosis. METHODS AND RESULTS: CD8 T cell depletion in hypertensive mice, strongly attenuated CF, reduced cardiac apoptosis and improved ventricular relaxation. Interaction between cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is highly dependent on the CD8+ T cells expressing the innate stress-sensing receptor NKG2D and stressed cardiomyocytes expressing the NKG2D activating ligand RAE-1. The interaction between NKG2D and RAE-1 results in CD8+ T cell activation, release of perforin, cardiomyocyte apoptosis, increased numbers of TGF-β1 expressing macrophages and fibrosis. Deleting NKG2D or perforin from CD8+ T cells greatly attenuates these effects. Activation of the cytoplasmic DNA-STING-TBK1-IRF3 signaling pathway in overly stressed cardiomyocytes is responsible for elevating RAE-1 and MCP-1, a macrophage attracting chemokine. Inhibiting STING activation greatly attenuates cardiomyocyte RAE-1 expression, the cardiomyocyte apoptosis, TGF-β1 and fibrosis. CONCLUSION: Our data highlight a novel pathway by which CD8 T cells contribute to an early triggering mechanism in CF development; preventing CD8+ T cell activation by inhibiting the cardiomyocyte RAE-1-CD8+ T cell-NKG2D axis holds promise for novel therapeutic strategies to limit hypertensive cardiac fibrosis.
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ItemC-reactive protein, immunothrombosis and venous thromboembolism(FRONTIERS MEDIA SA, 2022-09-13)C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP). with the latter two being destabilized isoforms possessing highly pro-inflammatory features. pCRP* and mCRP have significant biological effects in regulating many of the aspects central to pathogenesis of atherothrombosis and venous thromboembolism (VTE), by directly activating platelets and triggering the classical complement pathway. Importantly, it is now well appreciated that VTE is a consequence of thromboinflammation. Accordingly, acute VTE is known to be associated with classical inflammatory responses and elevations of CRP, and indeed VTE risk is elevated in conditions associated with inflammation, such as inflammatory bowel disease, COVID-19 and sepsis. Although the clinical data regarding the utility of CRP as a biomarker in predicting VTE remains modest, and in some cases conflicting, the clinical utility of CRP appears to be improved in subsets of the population such as in predicting VTE recurrence, in cancer-associated thrombosis and in those with COVID-19. Therefore, given the known biological function of CRP in amplifying inflammation and tissue damage, this raises the prospect that CRP may play a role in promoting VTE formation in the context of concurrent inflammation. However, further investigation is required to unravel whether CRP plays a direct role in the pathogenesis of VTE, the utility of which will be in developing novel prophylactic or therapeutic strategies to target thromboinflammation.
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ItemMacrophage polarization as a potential therapeutic target for atherosclerosis: a dynamic stochastic modelling study(ROYAL SOC, 2022-08-03)We proposed a dynamic stochastic mathematical model to evaluate the role of macrophage polarization in plaque development. The dynamic process of macrophages from proliferation to death was simulated under different lipid microenvironments. The probability of macrophage phenotypic switching was described using a Bernoulli distribution where the stochastic variable was determined by the local lipid level. Moreover, the interactions between macrophages and microenvironmental factors vary with macrophage phenotype. We investigated the distribution of key microenvironmental factors, the dynamics of macrophage polarization and its influence on foam cell formation. M1 macrophages were found to predominate in advanced plaque corresponding to the exacerbated inflammation observed in mice experiments. The imbalance between the deposition of oxidized low-density lipoprotein and phagocytic effects of macrophages governed the formation of foam cells. Furthermore, we simulated targeted therapies by either directly inhibiting the polarization probability to M1 macrophages or indirectly regulating macrophage polarization due to high-density lipoprotein levels. Comparison of simulation results with experimental findings in both therapies indicated that the intervention and regulation of macrophage polarization could influence plaque microenvironment and subsequently induce plaque regression, especially in the early stage. The proposed modelling system can facilitate the evaluation of novel therapies targeting macrophage polarization.
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Item18F Site-Specific Labelling of a Single-Chain Antibody against Activated Platelets for the Detection of Acute Thrombosis in Positron Emission Tomography(MDPI, 2022-07)Positron emission tomography is the imaging modality of choice when it comes to the high sensitivity detection of key markers of thrombosis and inflammation, such as activated platelets. We, previously, generated a fluorine-18 labelled single-chain antibody (scFv) against ligand-induced binding sites (LIBS) on activated platelets, binding it to the highly abundant platelet glycoprotein integrin receptor IIb/IIIa. We used a non-site-specific bio conjugation approach with N-succinimidyl-4-[18F]fluorobenzoate (S[18F]FB), leading to a mixture of products with reduced antigen binding. In the present study, we have developed and characterised a novel fluorine-18 PET radiotracer, based on this antibody, using site-specific bio conjugation to engineer cysteine residues with N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM). ScFvanti-LIBS and control antibody mut-scFv, with engineered C-terminal cysteine, were reduced, and then, they reacted with N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM). Radiolabelled scFv was injected into mice with FeCl3-induced thrombus in the left carotid artery. Clots were imaged in a PET MR imaging system, and the amount of radioactivity in major organs was measured using an ionisation chamber and image analysis. Assessment of vessel injury, as well as the biodistribution of the radiolabelled scFv, was studied. In the in vivo experiments, we found uptake of the targeted tracer in the injured vessel, compared with the non-injured vessel, as well as a high uptake of both tracers in the kidney, lung, and muscle. As expected, both tracers cleared rapidly via the kidney. Surprisingly, a large quantity of both tracers was taken up by organs with a high glutathione content, such as the muscle and lung, due to the instability of the maleimide cysteine bond in vivo, which warrants further investigations. This limits the ability of the novel antibody radiotracer 18F-scFvanti-LIBS to bind to the target in vivo and, therefore, as a useful agent for the sensitive detection of activated platelets. We describe the first fluorine-18 variant of the scFvanti-LIBS against activated platelets using site-specific bio conjugation.
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ItemNo Preview AvailableUltrasonic particles: An approach for targeted gene delivery(ELSEVIER, 2021-12)Gene therapy has been widely investigated for the treatment of genetic, acquired, and infectious diseases. Pioneering work utilized viral vectors; however, these are suspected of causing serious adverse events, resulting in the termination of several clinical trials. Non-viral vectors, such as lipid nanoparticles, have attracted significant interest, mainly due to their successful use in vaccines in the current COVID-19 pandemic. Although they allow safe delivery, they come with the disadvantage of off-target delivery. The application of ultrasound to ultrasound-sensitive particles allows for a direct, site-specific transfer of genetic materials into the organ/site of interest. This process, termed ultrasound-targeted gene delivery (UTGD), also increases cell membrane permeability and enhances gene uptake. This review focuses on the advances in ultrasound and the development of ultrasonic particles for UTGD across a range of diseases. Furthermore, we discuss the limitations and future perspectives of UTGD.
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ItemP2Y12 Antagonists in Cardiovascular Disease-Finding the Best Balance Between Preventing Ischemic Events and Causing Bleeding(FRONTIERS MEDIA SA, 2022-05-12)Dual antiplatelet therapy comprising of aspirin and oral P2Y12 receptor antagonists are an established cornerstone of therapy in acute coronary syndromes and percutaneous coronary intervention. As a result, the platelet P2Y12 receptor remains a key therapeutic target in cardiovascular medicine since pharmacological antagonists were first developed in the 1990's. With a greater understanding of platelet biology and the role played by the P2Y12 receptor in the amplification of platelet activation and thrombus formation, there has been progressive refinement in the development of P2Y12 receptor antagonists with greater potency and consistency of antiplatelet effect. However, challenges remain in the utilization of these agents particularly in balancing the need for greater protection from ischemic events whilst minimizing the bleeding risk and present a real opportunity for the institution of individualized medicine. Future drug developments will provide clinicians with greater avenues to achieve this.
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