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Semsarian C.,Centenary Institute | Semsarian C.,University of Sydney | Semsarian C.,Royal Prince Alfred Hospital | Ingles J.,Centenary Institute | And 3 more authors.
Journal of the American College of Cardiology | Year: 2015

Hypertrophic cardiomyopathy (HCM) is an important genetic heart muscle disease for which prevalence in the general population has not been completely resolved. For the past 20 years, most data have supported the occurrence of HCM at about 1 in 500. However, the authors have interrogated a number of relevant advances in cardiovascular medicine, including widespread fee-for-service genetic testing, population genetic studies, and contemporary diagnostic imaging, as well as a greater index of suspicion and recognition for both the clinically expressed disease and the gene-positive-phenotype-negative subset (at risk for developing the disease). Accounting for the potential impact of these initiatives on disease occurrence, the authors have revisited the prevalence of HCM in the general population. They suggest that HCM is more common than previously estimated, which may enhance its recognition in the practicing cardiovascular community, allowing more timely diagnosis and the implementation of appropriate treatment options for many patients. © 2015 American College of Cardiology Foundation.

Semsarian C.,Centenary Institute | Semsarian C.,University of Sydney | Semsarian C.,Royal Prince Alfred Hospital | Hamilton R.M.,University of Toronto
Heart Rhythm | Year: 2012

Sudden Cardiac Death (SCD) is a major and tragic complication of a number of cardiovascular diseases. While in the older populations, SCD is most frequently caused by underlying coronary artery disease and heart failure, in those aged under 40 years, the causes of SCD commonly include genetic disorders, such as inherited cardiomyopathies and primary arrhythmogenic diseases. As part of the evaluation of families in which SCD has occurred, the role of genetic testing has evolved as an important feature in both establishing an underlying diagnosis and in screening at-risk family relatives. Specifically, in cases where no definitive cause is identified at postmortem, i.e. Sudden Unexpected Death (SUD), the "molecular autopsy" has emerged as a key process in the investigation of the cause of death. The combination of clinical and genetic evaluation of families in which SUD has occurred provides a platform for early initiation of therapeutic and prevention strategies, with the ultimate goal to reduce sudden death among the young in our communities.

Jain R.,Centenary Institute | Weninger W.,Centenary Institute | Weninger W.,Royal Prince Alfred Hospital
Immunology and Cell Biology | Year: 2013

The skin is under constant assault by environmental factors and microbes. Innate immune cells in epidermis and dermis regulate immune responses against pathogens while maintaining tolerance against commensal bacteria and autoantigens. The introduction of intravital imaging approaches, in particular multiphoton microscopy, has enabled studying the cellular and molecular regulation of cutaneous immunity in real time within intact skin. Here, we discuss recent advances in our understanding of innate immune cell behaviour in the skin, as unravelled by intravital microscopy, with emphasis on the function of myeloid cells, including dendritic cells, neutrophils and monocytes. © 2013 Australasian Society for Immunology Inc.

Ingles J.,Centenary Institute | Ingles J.,University of Sydney | Semsarian C.,Centenary Institute | Semsarian C.,University of Sydney | Semsarian C.,Royal Prince Alfred Hospital
Heart Rhythm | Year: 2014

The evolution of genetic testing in the past few years has been astounding. In a matter of only a few years, we now have comprehensive gene tests comprising vast panels of "cardiac" genes, whole exome sequencing (the entire coding region) and even whole genome sequencing (the entire genome). Making the call as to whether a DNA variant is causative or benign is difficult and the focus of intense research efforts. In most cases, the final answer will not be a simple yes/no outcome but rather a graded continuum of pathogenicity. This allows classification of variants in a more probabilistic way. How we convey this to a patient is the challenge, and certainly shines a spotlight on the important skills of the cardiac genetic counselor. This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. The multidisciplinary specialized clinic model, incorporating genetic counselors, cardiologists and geneticists, provides the ideal framework for ensuring the best possible care for genetic heart disease families. © 2014 Heart Rhythm Society.

News Article | March 1, 2017

Antibacterial compounds found in soil could spell the beginnings of a new treatment for tuberculosis, new research led by the University of Sydney has found. Believed by many to be a relic of past centuries, tuberculosis (TB) causes more deaths than any other infectious disease including HIV/AIDs. In 2015 there were an estimated 10.4 million new cases of TB and 1.4 million deaths from the disease. The bacterium causing TB (Mycobacterium tuberculosis) is becoming increasingly resistant to current therapies, meaning there is an urgent need to develop new TB drugs. In 2015 an estimated 480,000 cases were unresponsive to the two major drugs used to treat TB. It is estimated more than 250,000 TB deaths were from drug-resistant infections. An international collaboration led by University Professors Richard Payne, from the School of Chemistry, and Warwick Britton, from the Sydney Medical School and the Centenary Institute, has discovered a new compound which could translate into a new drug lead for TB. Its findings were published in Nature Communications today. The group was drawn to soil bacteria compounds known to effectively prevent other bacteria growing around them. Using synthetic chemistry the researchers were able to recreate these compounds with structural variations, turning them into more potent compounds called analogues. When tested in a containment laboratory these analogues proved to be effective killers of Mycobacterium tuberculosis. "These analogues inhibit the action of a key protein needed to build a protective cell wall around the bacterium," said Professor Payne. "Without a cell wall, the bacterium dies. This wall-building protein is not targeted by currently available drugs. "The analogues also effectively killed TB-causing bacteria inside macrophages, the cells in which the bacteria live in human lungs." Professor Payne said the findings are the starting point for a new TB drug. Planning for further testing and safety studies is underway. The research was done in collaboration with Colorado State University in the USA, Simon Fraser University in Canada, Warwick University in the UK, Monash University and the University of Queensland. It was funded by Australia's National Health and Medical Research Centre (NHMRC). Professors Payne and Britton also belong to the University's Marie Bashir Institute for Infectious Diseases and Biosecurity. Professor Payne won the Malcolm McIntosh Prize for Physical Scientist of the Year at the 2016 Prime Minister's Science Prizes.

Brandner J.M.,University of Hamburg | Haass N.K.,University of Queensland | Haass N.K.,Centenary Institute | Haass N.K.,University of Sydney
Pathology | Year: 2013

Melanoma cells interact with and depend on seemingly normal cells in their tumour microenvironment to allow the acquisition of the hallmarks of solid cancer. In general, there are three types of interaction of melanoma cells with their microenvironment. First, there is bilateral communication between melanoma cells and the stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix. Second, while under normal conditions keratinocytes control localisation and proliferative behaviour of melanocytes in the epidermis, once this balance is disturbed and a melanoma has developed, melanoma cells may take over the control of their epidermal tumour microenvironment. Finally, there are subcompartments within tumours with different microenvironmental milieu defined by their access to oxygen and nutrients. Therefore, different melanoma cells within a tumour face different microenvironments. Interactions between melanoma cells among each other and with the cell types in their microenvironment happen through endocrine and paracrine communication and/or through direct contact via cell-cell and cell-matrix adhesion, and gap junctional intercellular communication (GJIC). Connexins have been identified as key molecules for direct cell-cell communication and are also thought to be important for the release of signalling molecules from cells to the microenvironment. In this review we provide an update of the alterations in cell-cell communication in melanoma and the tumour microenvironment associated with melanoma development and progression. © 2013 Royal College of Pathologists of Australasia.

Levesque J.-P.,Materials Medical Research Institute | Winkler I.G.,Materials Medical Research Institute | Rasko J.E.J.,Centenary Institute | Rasko J.E.J.,University of Sydney
BioEssays | Year: 2013

Stem cells and their malignant counterparts require the support of a specific microenvironment or "niche". While various anti-cancer therapies have been broadly successful, there are growing opportunities to target the environment in which these cells reside to further improve therapeutic efficacy and outcome. This is particularly true when the aim is to target normal or malignant stem cells. The field aiming to target or use the niches that harbor, protect, and support stem cells could be designated as "nichotherapy". In this essay, we provide a few examples of nichotherapies. Some have been employed for decades, such as hematopoietic stem cell mobilization, whereas others are emerging, such as chemosensitization of leukemia stem cells by targeting their niche. © 2013 WILEY Periodicals, Inc.

Liu R.,Centenary Institute | Liu R.,University of Sydney | Leslie K.L.,Yale University | Martin K.A.,Yale University
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2015

Smooth muscle cells (SMC) are the major cell type in blood vessels. Their principal function in the body is to regulate blood flow and pressure through vessel wall contraction and relaxation. Unlike many other mature cell types in the adult body, SMC do not terminally differentiate but retain a remarkable plasticity. They have the unique ability to toggle between a differentiated and quiescent "contractile" state and a highly proliferative and migratory "synthetic" phenotype in response to environmental stresses.While there have been major advances in our understanding of SMC plasticity through the identification of growth factors and signals that can influence the SMC phenotype, how these regulate SMC plasticity remains unknown. To date, several key transcription factors and regulatory cis elements have been identified that play a role in modulating SMC state. The frontier in understanding the molecular mechanisms underlying SMC plasticity has now advanced to the level of epigenetics. This review will summarize the epigenetic regulation of SMC, highlighting the role of histone modification, DNA methylation, and our most recent identification of a DNA demethylation pathway in SMC that is pivotal in the regulation of the SMC phenotypic state.Many disorders are associated with smooth muscle dysfunction, including atherosclerosis, the major underlying cause of stroke and coronary heart disease, as well as transplant vasculopathy, aneurysm, asthma, hypertension, and cancer. An increased understanding of the major regulators of SMC plasticity will lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of these diseases. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. © 2014 Elsevier B.V.

Bonham K.S.,Harvard University | Orzalli M.H.,Harvard University | Hayashi K.,Yale University | Wolf A.I.,Wistar Institute | And 6 more authors.
Cell | Year: 2014

The Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction. © 2014 Elsevier Inc.

Power C.,Centenary Institute | Rasko J.E.J.,Centenary Institute
Annals of Internal Medicine | Year: 2011

In recent years, stem cells have generated increasing excitement, with frequent claims that they are revolutionizing medicine. For those not directly involved in stem cell research, however, it can be difficult to separate fact from fiction or realistic expectation from wishful thinking. This article aims to provide internists with a clear and concise introduction to the field. While recounting some scientific and medical milestones, the authors discuss the 3 main varieties of stem cells-adult, embryonic, and induced pluripotent- comparing their advantages and disadvantages for clinical medicine. The authors have sought to avoid the moral and political debates surrounding stem cell research, focusing instead on scientific and medical issues. © 2011 American College of Physicians.

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