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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.

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.

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.

Semsarian C.,Centenary Institute | Semsarian C.,University of Sydney | 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.

Gordon J.E.A.,Centenary Institute | Wong J.J.-L.,Centenary Institute | Rasko J.E.J.,Centenary Institute | Rasko J.E.J.,University of Sydney
British Journal of Haematology | Year: 2013

MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberrant miRNA expression, have consistently underpinned our understanding of the role that miRNAs play in cancer development. Here, we review the expanding roles attributed to miRNAs in the pathogenesis of different types of myeloid malignancies and highlight key findings. © 2013 John Wiley & Sons Ltd.

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