Melbourne Medical School Collected Works - Research Publications
Now showing items 1-12 of 296
Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior
(BMC Cancer, 2012)
BACKGROUND: Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival. METHODS: Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed. RESULTS: Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear β-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes. CONCLUSIONS: We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.
Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer's Disease Amyloid Precursor Protein
(PUBLIC LIBRARY SCIENCE, 2013-04-17)
BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents the first step in the production of amyloid β (Aβ) peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer's disease (AD). The association between oxidative stress (OS) and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10-40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS), as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H2O2 concentration (100 µM) caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, β-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis.
Behavioural activation in nursing homes to treat depression (BAN-Dep): study protocol for a pragmatic randomised controlled trial
(BMJ PUBLISHING GROUP, 2019-10-01)
INTRODUCTION: Depression is a common disorder among older people living in residential aged care facilities. Several trials have demonstrated the effectiveness of behavioural therapies in treating depressive symptoms in older adults living in the community and in residential aged care. Behavioural Activation is demonstrably effective even when delivered by non-specialists (staff without formal psychological training), although strategies for adapting its use in residential aged care facilities are yet to be explored. This study will determine whether training residential care staff in the use of a structured Behavioural Activation programme is more effective at decreasing depressive symptoms among older residents than internet-based training about depression recognition and management alone. METHOD AND ANALYSIS: The behavioural activation in nursing homes to treat depression (BAN-Dep) trial is a pragmatic two-arm parallel clustered randomised controlled trial. It will recruit 666 residents aged 60 or older from 100 residential aged care facilities, which will be randomly assigned to the Behavioural Activation or control intervention. Staff in both treatment groups will be encouraged to complete the Beyondblue Professional Education to Aged Care e-learning programme to improve their recognition of and ability to respond to depression in older adults. Selected staff from intervention facilities will undergo additional training to deliver an 8-module Behavioural Activation programme to residents with subthreshold symptoms of depression-they will receive ongoing Mental support from trained Behavioural Activation therapists. Outcome measures will be collected by blind research officer at baseline and after 3, 6 and 12 months. The Patient Health Questionnaire-9 is the primary outcome measure of the study. ETHICS AND DISSEMINATION: The trial will comply with the principles of the Declaration of Helsinki for Human Rights and is overseen by the University of Western Australia (reference RA/4/20/4234) and Melbourne Health (reference number HREC/18/MH/47) Ethics Committees. The results of this research project will be disseminated through publications and/or presentations in a variety of media to health professionals, academics, clinicians and the public. Only de-identified group data will be presented. TRIAL REGISTRATION: ACTRN12618000634279.
Research data management in health and biomedical citizen science: practices and prospects
(Oxford University Press (OUP), 2019)
Background: Public engagement in health and biomedical research is being influenced by the paradigm of citizen science. However, conventional health and biomedical research relies on sophisticated research data management tools and methods. Considering these, what contribution can citizen science make in this field of research? How can it follow research protocols and produce reliable results? Objective: The aim of this article is to analyze research data management practices in existing biomedical citizen science studies, so as to provide insights for members of the public and of the research community considering this approach to research. Methods: A scoping review was conducted on this topic to determine data management characteristics of health and bio medical citizen science research. From this review and related web searching, we chose five online platforms and a specific research project associated with each, to understand their research data management approaches and enablers. Results: Health and biomedical citizen science platforms and projects are diverse in terms of types of work with data and data management activities that in themselves may have scientific merit. However, consistent approaches in the use of research data management models or practices seem lacking, or at least are not prevalent in the review. Conclusions: There is potential for important data collection and analysis activities to be opaque or irreproducible in health and biomedical citizen science initiatives without the implementation of a research data management model that is transparent and accessible to team members and to external audiences. This situation might be improved with participatory development of standards that can be applied to diverse projects and platforms, across the research data life cycle.
Implementing dementia risk reduction in primary care: a preliminary conceptual model based on a scoping review of practitioners' views.
(Cambridge University Press (CUP), 2019-10-23)
Primary care practitioners (PCPs) do not routinely promote dementia risk reduction. The purpose of this study was to map the published literature on the views of PCPs about dementia risk reduction, in order to identify implementation constructs and strategies crucial to the development of an implementation intervention to support dementia risk reduction in primary care. We undertook a scoping review of the PCPs' views about promoting brain health for reducing dementia risk. We searched MEDLINE, PsycINFO, CINAHL, and Embase for English-language articles published between 1995 and December 2017. We then applied the Consolidated Framework for Implementation Research (CFIR) and matched Expert Recommendations for Implementing Change to the scoping review findings in order to develop a preliminary implementation model. Eight articles reported views of PCPs about dementia prevention. Study findings were mapped to 5 of the 39 CFIR constructs: (i) knowledge and beliefs about dementia risk reduction, (ii) evidence strength and quality, (iii) relative priority, (iv) available resources, and (v) external policy and incentives. The findings suggest implementation strategies to consider in our preliminary model include (i) educational meetings, (ii) identifying and preparing champions, (iii) conducting local consensus discussions, (iv) altering incentive structures, and (v) capturing and sharing local knowledge. There have been few studies about the views of PCPs about dementia risk reduction. Implementation in the primary care setting is fundamental to early identification of risk and supporting preventive practices, but it needs to focus on more than just education for PCPs. We need more up-to-date and in-depth data on the views of PCPs about dementia risk reduction and context-specific analyses of implementation needs. Further research into effective primary care interventions to reduce dementia risk is expected to support implementation efforts.
Microwave Synthesis of Prion Protein Fragments up to 111 Amino Acids in Length Generates Biologically Active Peptides
(Springer Verlag, 2012)
Misfolded conformers of the prion protein are aetiologically implicated in neurodegenerative conditions termed prion diseases (also known as transmissible spongiform encephalopathies). Two constitutively expressed N-terminal peptides corresponding to human residues 23–90 and 23–111 are thought to serve normal physiological roles related to neuronal protection with membrane binding possibly playing a part in their mechanism of action. These peptides, along with several derivatives up to 111 residues in length, have been produced by microwave assisted peptide synthesis. HPLC and MS characterisation showed that the peptides were manufactured in good yields at high purity. Peptides were assayed by fluorescence spectroscopy for synthetic lipid-membrane binding activity and by dichlorodihydrofluorescein diacetate assay for the amelioration of reactive oxygen species production. Results of these assays were similar to those reported for the wild type recombinant PrP, demonstrating that these synthetic peptides are useful for biological and chemical assays of PrP activity. Further, the longest peptide 1–111 was dimerised via a single internal cystine residue with good yield. The high yields and low purification burden of the microwave assisted synthesis method lends itself to the production of difficult to produce peptides for such studies.
Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity
Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP-/- mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration.
Improving access to and participation in medical research for Culturally and Linguistically Diverse background patients: A bilingual, digital communication approach.
(Routledge Studies in Empirical Translation and Multilingual Communication, 2019)
Chapters in this book aim to fill in a persistent knowledge gap in current multicultural health research, that is, culturally effective and user-oriented healthcare translation.
Ghosts in the Machine: Identifying the Digital Health Information Workforce.
(IOS Press, 2019)
In descriptions of digital health the role of human agency and the work of managing and governing health information and communication technology is often invisible. This paper reports preliminary results of a scoping review of the literature and a national workforce census, undertaken as part of a research program to shed light on the responsibilities and the contributions of the health information workforce. The global literature is not a good indicator of the actual proportion of health informaticians, health information managers, health librarians or other health professionals who are engaged in health information work in Australia. While the research interest in health information work of all descriptions is increasing, the practice of health information work is neither highly skilled nor easily identifiable in findings of an Australian census. Reforming this workforce may be a key to translating digital health rhetoric into measurable improvements in health system performance.
Health information work - a scoping review protocol
(PeerJ Preprints, 2019-02-15)
Background: The work of managing health data, health information or health knowledge is a vital, yet unacknowledged, function in our current health system. This protocol is for a literature review which explores the evolution and development of the concept of health information work. Methodology: A scoping review of published literature in the domains of health sciences, information technology and information sciences has been carried out. A thematic and bibliometric analysis of the resulting set of publications is currently being undertaken. Results: The review results will shed light on the responsibilities and the contribution of the health information workforce, with a synthesis of themes identified in the literature, and analysis of publication year spans, prominent authors, institutions and source journals.
Measuring the outcomes of using person-generated health data: a case study of developing a PROM item bank
(BMJ Publishing Group, 2019-08)
INTRODUCTION: Patient-reported outcome measures (PROMs) allow patients to self-report the status of their health condition or experience independently. A key area for PROMs to contribute in building the evidence base is in understanding the effects of using person-generated health data (PGHD), and using PROMs to measure outcomes of using PGHD has been suggested in the literature. Key considerations inherent in the stroke rehabilitation context makes the measurement of PGHD outcomes in home-based poststroke rehabilitation, which uses body-tracking technologies, an important use case. OBJECTIVE: This paper describes the development of a preliminary item bank of a PROM-PGHD for Kinect-based stroke rehabilitation systems (K-SRS), or PROM-PGHD for K-SRS. METHODS: The authors designed a method to develop PROMs of using PGHD, or PROM-PGHD. The PROM-PGHD Development Method was designed by augmenting a key PROM development process, the Qualitative Item Review, and follows PROM development best practice. It has five steps, namely, literature review; binning and winnowing; initial item revision; eliciting patient input and final item Revision. RESULTS: A preliminary item bank of the PROM-PGHD for K-SRS is presented. This is the result of implementing the first three steps of the PROM-PGHD Development Method within the domains of interest, that is, stroke and Kinect-based simulated rehabilitation. CONCLUSIONS: This paper has set out a case study of our method, showing what needs to be done to ensure that the PROM-PGHD items are suited to the health condition and technology category. We described it as a case study because we argue that it is possible for the PROM-PGHD method to be used by others to measure effects of PGHD utilisation in other cases of health conditions and technology categories. Hence, it offers generalisability and has broader clinical relevance for evidence-based practice with PGHD. This paper is the first to offer a case study of developing a PROM-PGHD.