Design and Prototyping of a Novel Triple Lumen Photo-Angioplasty Device: Lumi-Solve-T.

Purpose: A triple lumen iteration of the novel photo-angioplasty drug eluting balloon catheter (DEBc) Lumi-Solve may be compromised by guidewire shadow (GWS)-mediated attenuation of balloon surface drug activation. The current study aimed to design and evaluate a novel triple lumen prototype, designated Lumi-Solve-T, to circumvent these issues.

Methods: Effects of guidewire shadowing (GWS) on vascular smooth muscle cell (VSMC) proliferation was evaluated using the MTT assay.

Fibromuscular Dysplasia: Three Cases to Highlight a Requirement for Surveillance Strategy Optimization.

Fibromuscular dysplasia (FMD) is a rare vascular disease with broad, potentially severe complications. We present three cases of FMD covering the spectrum of clinical presentations involving the abdominal and visceral vasculature, and highlight the potential role of high-risk genotype detection in assisting with the determination of which patients may benefit from a more aggressive surveillance strategy.

A pilot clinical study to Evaluate Liraglutide-mediated Anti-platelet activity in patients with type-2 Diabetes (ELAID study).

Background: Liraglutide is an effective treatment for the management of type 2 diabetes mellitus (T2DM). In addition to glycemic control and potential cardioprotective effects, recent studies suggest a possible role for liraglutide in the inhibition of platelet reactivity, further attenuating atherothrombotic risk in patients with T2DM. We evaluated the in-vivo antiplatelet effect of liraglutide in T2DM patients without macrovascular disease or concurrent anti-platelet therapy.

Point of care ankle pulse waveform: A biomarker for abdominal aortic aneurysm?

Objective: To explore the potential relationship between the presence of abdominal aortic aneurysm and point of care ankle brachial index acquired posterior tibial artery Doppler waveform to inform on a potential novel biomarker of abdominal aortic aneurysm presence.

Methods: Abdominal aortic aneurysm presence and posterior tibial artery waveform acquired at time of routine point of care ankle brachial index were determined in 182 patients from an abdominal aortic aneurysm evaluation vascular outpatient clinic. Multivariate technical random forest analysis and logistical regression analysis assessed the outcome of abdominal aortic aneurysm presence and included the independent variables of monophasic initial posterior tibial artery waveform and known abdominal aortic aneurysm risk factors.

Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: Lumi-Solve.

Purpose: Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class.

Synthesis and biological evaluation of a novel photo-activated histone deacetylase inhibitor.

Hydroxamic acid-based histone deacetylase inhibitors (HDACi) are a class of epigenetic agents with potentially broad therapeutic application to several disease states including post angioplasty mediated neointimal hyperplasia (NIH). Precise spatiotemporal control over the release of HDACi at the target blood vessel site is required for the safe and successful therapeutic use of HDACi in the setting of drug eluting balloon catheter (DEBc) angioplasty treatment of NIH. We aimed to develop and characterise a novel photoactive HDACi, as a potential coating agent for DEBc.

A Novel Epigenetic Drug-Eluting Balloon Angioplasty Device: Evaluation in a Large Animal Model of Neointimal Hyperplasia.

Purpose: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH).

Epigenetic treatment-mediated modulation of PD-L1 predicts potential therapy resistance over response markers in myeloid malignancies: A molecular mechanism involving effectors of PD-L1 reverse signaling.

Recent evidence suggests an association exists between resistance to epigenetic therapy (EGT) and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in myeloid malignancies. Biomarkers are required to predict resistance to EGT in myeloid malignancies, which together with the delineation of associated molecular mechanisms, may provide additional understanding for novel treatment strategies when investigating resistance to EGT. The present study aimed to investigate the effects of EGT on the expression of PD-1, PD-L1 and orphan nuclear receptor NUR77 with clinical responses in patients with myeloid malignancies.

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis.

Background: Sodium glucose transporter type 2 inhibitors may reduce cardiovascular events in type 2 diabetes. Our study aimed to determine the effect of the sodium glucose transporter type 2 inhibitor dapagliflozin on endothelial cell activation, vasoreactivity and atherogenesis using in vitro and in vivo models and identify associated molecular mechanisms.

Methods: In vitro studies utilised human vascular endothelial cells stimulated with tumour necrosis factor α or hyperglycaemic conditions.

Current and emerging pharmacotherapies for obesity in Australia.

Background: Obesity is a major issue in Australia and globally. Many individuals struggle to maintain weight loss with lifestyle modification, and adjunctive pharmacotherapy may help. Historically, there have been limited pharmacotherapies for managing obesity.

Epigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies.

Epigenetic regulation of microRNA (miRNA) expression has recently been implicated in the pathogenesis of myelodysplastic syndrome (MDS). Particular interest has focused on miRNA-124 expression, which is inhibited in MDS and has recently been demonstrated to be upregulated in response to epigenetic treatment (EGT). Previous studies have determined the and expression of miRNA-124 and several molecular targets, including cyclin-dependent kinase (CDK) 4, CDK6 and enhancer of zeste homolog 2 (EZH2), in order to elucidate the molecular mechanisms associated with the miRNA-124-mediated therapeutic response to EGT in MDS and identify additional potential biomarkers of early EGT treatment response in myeloid malignancies.

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis.

Background: Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms.

Methods: C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively.

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.

Background: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.

Methods/design: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis.

Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells.

Objectives: To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency.

Design: In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines.

Methods: Latently infected chemokine ligand 19 (CCL19)-treated CD4⁺ T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3.

The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model.

Liraglutide, a once-daily glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved as a new treatment for type 2 diabetes and is the subject of a clinical trial programme to evaluate the effects on cardiovascular disease and safety. The current study aimed to determine the in vivo effect of liraglutide on progression of atherosclerotic vascular disease in the apolipoprotein E-deficient (ApoE(-/-)) mouse model and identify underlying mechanisms responsible. Liraglutide treatment inhibited progression of early onset, low-burden atherosclerotic disease in a partially GLP-1R-dependent manner in the ApoE(-/-) mouse model.

The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation.

Previous studies have suggested that homocysteine (Hcy) has wide-ranging biological effects, including accelerating atherosclerosis, impairing post injury endothelial repair and function, deregulating lipid metabolism and inducing thrombosis. However, the biochemical basis by which hyperhomocysteinemia (HHcy) contributes to cardiovascular diseases (CVDs) remains largely unknown. Several case-control studies have reported an association between HHcy and the presence of abdominal aortic aneurysms (AAA) and there are supportive data from animal models.

GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells.

The potential atheroprotective effects of glucagon-like peptide-1 (GLP-1), long-acting GLP-1 analogues and inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4) are currently the subject of intense research. Recent evidence suggests the effects of DPP-IV inhibitors, may, in-part, be mediated by GLP-1 independent molecular mechanisms. In this report we demonstrate that treatment of human vascular endothelial cells with the DPP-IV inhibitor sitagliptin inhibited tumour necrosis factor alpha (TNFα) induction of plasminogen activator inhibitor type-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein expression and that this effect was observed to be both GLP-1-dependent and independent.

Derivation of endothelial cells from human embryonic stem cells in fully defined medium enables identification of lysophosphatidic acid and platelet activating factor as regulators of eNOS localization.

The limited availability of human vascular endothelial cells (ECs) hampers research into EC function whilst the lack of precisely defined culture conditions for this cell type presents problems for addressing basic questions surrounding EC physiology. We aimed to generate endothelial progenitors from human pluripotent stem cells to facilitate the study of human EC physiology, using a defined serum-free protocol. Human embryonic stem cells (hESC-ECs) differentiated under serum-free conditions generated CD34(+)KDR(+) endothelial progenitor cells after 6days that could be further expanded in the presence of vascular endothelial growth factor (VEGF).

A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model.

The glucagon like peptide-1 receptor (GLP-1R) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression in human vascular endothelial cells (hVECs) in vitro and may afford protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease. Our study aimed to establish the dependence of the in vitro effects of liraglutide on the GLP-1R and characterise its in vivo effects in a mouse model of ECD. In vitro studies utilised the human vascular endothelial cell line C11-STH and enzyme-linked immunosorbent assays (ELISA) for determination of PAI-1 and VAM expression.

Clopidogrel Resistance: case reports of CYP2C19 gene variants in suspected coronary stent thrombosis.

Clopidogrel is a widely used anti-platelet agent for the prevention of arterial thrombosis. Clopidogrel is administered as a pro-drug and metabolised to its active metabolite by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. The active metabolite is responsible for the anti-platelet activity of clopidogrel.