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Best G.,Kolling Institute | Thompson P.,St. Vincents Hospital | Tam C.S.,St. Vincents Hospital | Tam C.S.,University of Melbourne
Leukemia and Lymphoma | Year: 2012

Aberrations of the TP53 pathway, whether by deletion or mutation, are increasingly recognized as one of the most important biological risk factors in chronic lymphocytic leukemia. Yet, there is little consensus on how to assess for TP53 defects in the clinic, and very few clinical studies to guide optimal management of such patients. In this review, we discuss the state-of-the-art in the assessment of the TP53 pathway, and review the evidence-base for therapeutic recommendations. © 2012 Informa UK, Ltd.


Malhi G.S.,Kolling Institute | Malhi G.S.,University of Sydney
Evidence-Based Mental Health | Year: 2015

Antidepressants are widely used in the treatment of bipolar depression despite relatively meagre evidence for their efficacy and significant concerns that their prescription can precipitate an acute affective switch into mania/hypomania and that long-term administration can lead to mood instability. Therefore, the use of antidepressants to treat bipolar depression is an important but contentious issue that two recent studies, which provide important new evidence, attempt to inform. One study suggests that long-term continuation of antidepressants in patients with rapid-cycling bipolar disorder leads to a threefold increase in mood episodes during the first year of follow-up—supporting the notion that antidepressants can cause more harm than good, and that they should be used sparingly. However, this is countered by findings from the other study, which suggests that continuation antidepressant monotherapy provides patients with bipolar II disorder reasonable prophylaxis, and that the risk of switching into mania/ hypomania is actually quite low. In addition to contrary findings both studies are modest in sample sizes and have significant design limitations and hence the debate remains unresolved. This brief perspective presents both views in the context of evidence and provides some key insights into the complexity of this challenging but common clinical issue. © 2015, BMJ Publishing Group. All rights reserved.


Jaiswal R.,University of Sydney | Jaiswal R.,University of Technology, Sydney | Gong J.,University of Sydney | Gong J.,University of Technology, Sydney | And 6 more authors.
FASEB Journal | Year: 2012

Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids; MPs change recipient cells'transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells'ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating"the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology. © FASEB.


Harkness L.M.,University of Sydney | Ashton A.W.,Kolling Institute | Burgess J.K.,University of Sydney
Pharmacology and Therapeutics | Year: 2015

Multiple studies have identified an expansion and morphological dysregulation of the bronchial vascular network in the airways of asthmatics. Increased number, size and density of blood vessels, as well as vascular leakage and plasma engorgement, have been reported in the airways of patients with all grades of asthma from mild to fatal. This neovascularisation is an increasingly commonly reported feature of airway remodelling; however, the pathophysiological impact of the increased vasculature in the bronchial wall and its significance to pulmonary function in asthma are unrecognised at this time. Multiple factors capable of influencing the development and persistence of the vascular network exist within asthmatic airway tissue. These include structural components of the altered extracellular matrix (ECM), imbalance of proteases and their endogenous inhibitors, release of active matrikines and the dysregulated levels of both soluble and matrix sequestered growth factors. This review will explore the features of the asthmatic airway which influence the development and persistence of the increased vascular network, as well as the effect of enhanced tissue perfusion on chronic inflammation and airway dynamics. The response of cells of the airways to the altered vascular profile and the subsequent influence on the features of airway remodelling will also be highlighted. We will explore the failure of current asthma therapeutics in "normalising" this vascular remodelling. Finally, we will summarize the outcomes of recent clinical trials which provide hope that anti-angiogenic therapies may be a potent asthma-resolving class of drugs and provide a new approach to asthma management in the future. © 2014 Elsevier Inc.


Sambrook P.,Kolling Institute | Cranney A.,Ottawa Health Research Institute | Adachi J.D.,McMaster University
Current Medical Research and Opinion | Year: 2010

In the BONE study (3 years duration), daily oral ibandronate 2.5mg reduced vertebral fracture risk by 62 (vs. placebo; pCombining double low line0.0001). In the DIVA study (2 years duration), i.v. ibandronate 2mg every 2 months (q2mo) or 3mg every 3 months (q3mo) was superior to daily oral ibandronate in terms of BMD gains (p<0.001) and normalisation of bone turnover markers, suggesting potential antifracture efficacy with the licensed i.v. regimen (3mg q3mo). To evaluate this, a post-hoc analysis of non-vertebral fracture incidence was performed using DIVA study individual patient data. Both i.v. doses had the same annual cumulative exposure (ACE)-12mg. Therefore, data for these two regimens were pooled. This higher dose was compared with 2.5mg daily oral ibandronate (ACE 5.5mg) to maintain trial randomisation. Osteoporotic non-vertebral fractures were captured as a secondary endpoint. Time-to-event analysis was conducted using Kaplan-Meier methodology; hazard ratios (HRs) were derived from a Cox model with adjustments for clinical fracture, age and BMD. The DIVA trial was not primarily designed to assess fracture efficacy. The rate of non-vertebral fractures was significantly reduced when ibandronate ACE 12mg (3mg q3mo and 2mg q2mo i.v.) was compared with ACE 5.5mg (2.5mg daily oral). The non-vertebral fracture incidence was 3.1 versus 4.8, respectively, representing a 43 relative risk reduction with i.v. ibandronate (pCombining double low line0.0489; adjusted HR 0.569 [95 confidence interval: 0.324, 0.997]). Time to non-vertebral fracture was also extended for high-versus low-dose ibandronate (pCombining double low line0.048). A significant effect on non-vertebral fracture risk reduction was seen when high i.v. ibandronate doses were compared with a lower oral dose. This post-hoc analysis indicates greater antifracture efficacy for the licensed quarterly i.v. regimen versus daily oral dosing. © 2010 Informa UK Ltd.

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