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Haass N.K.,University of Queensland | Haass N.K.,The Centenary Institute | Haass N.K.,University of Sydney | Schumacher U.,University of Hamburg
Experimental Dermatology | Year: 2014

Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Targeting apoptosis regulators is thus considered a promising approach to sensitizing melanoma to therapy. In the previous issue of Experimental Dermatology, Plötz and Eberle discuss the role that apoptosis plays in melanoma progression and drug resistance and the utility of apoptosis-inducing BH3-mimetics as targeted therapy. There are a number of compounds in clinical development and the field seems close to translating recent findings into benefits for patients with melanoma. Thus, this viewpoint is timely and achieves a valuable summary of the current state of apoptosis-inducing therapy of melanoma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source


Ma J.Z.-I.,Malaghan Institute of Medical Research | Ma J.Z.-I.,Victoria University of Wellington | Ma J.Z.-I.,University of Melbourne | Lim S.N.,Malaghan Institute of Medical Research | And 9 more authors.
PLoS ONE | Year: 2012

Cytotoxic T lymphocytes (CTL) provide protection against pathogens and tumors. In addition, experiments in mouse models have shown that CTL can also kill antigen-presenting dendritic cells (DC), reducing their ability to activate primary and secondary CD8+ T cell responses. In contrast, the effects of CTL-mediated killing on CD4+ T cell responses have not been fully investigated. Here we use adoptive transfer of TCR transgenic T cells and DC immunization to show that specific CTL significantly inhibited CD4+ T cell proliferation induced by DC loaded with peptide or low concentrations of protein antigen. In contrast, CTL had little effect on CD4+ T cell proliferation induced by DC loaded with high protein concentrations or expressing antigen endogenously, even if these DC were efficiently killed and failed to accumulate in the lymph node (LN). Residual CD4+ T cell proliferation was due to the transfer of antigen from carrier DC to host APC, and predominantly involved skin DC populations. Importantly, the proliferating CD4+ T cells also developed into IFN-γ producing memory cells, a property normally requiring direct presentation by activated DC. Thus, CTL-mediated DC killing can inhibit CD4+ T cell proliferation, with the extent of inhibition being determined by the form and amount of antigen used to load DC. In the presence of high antigen concentrations, antigen transfer to host DC enables the generation of CD4+ T cell responses regardless of DC killing, and suggests mechanisms whereby CD4+ T cell responses can be amplified. © 2012 Ma et al. Source


Beaumont K.A.,University of Queensland | Beaumont K.A.,The Centenary Institute | Smit D.J.,University of Queensland | Liu Y.Y.,University of Queensland | And 6 more authors.
Pigment Cell and Melanoma Research | Year: 2012

Binding of melanocortin peptide agonists to the melanocortin-1 receptor of melanocytes results in eumelanin production, whereas binding of the agouti signalling protein inverse agonist results in pheomelanin synthesis. Recently, a novel melanocortin-1 receptor ligand was reported. A β-defensin gene mutation was found to be responsible for black coat colour in domestic dogs. Notably, the human equivalent, β-defensin 3, was found to bind with high affinity to the melanocortin-1 receptor; however, the action of β-defensin as an agonist or antagonist was unknown. Here, we use in vitro assays to show that β-defensin 3 is able to act as a weak partial agonist for cAMP signalling in human embryonic kidney (HEK) cells expressing human melanocortin-1 receptor. β-defensin 3 is also able to activate MAPK signalling in HEK cells stably expressing either wild type or variant melanocortin-1 receptors. We suggest that β-defensin 3 may be a novel melanocortin-1 receptor agonist involved in regulating melanocyte responses in humans. © 2012 John Wiley & Sons A/S. Source


Mitchell A.J.,The Centenary Institute | Roediger B.,The Centenary Institute | Weninger W.,The Centenary Institute | Weninger W.,University of Sydney
Cellular Immunology | Year: 2014

Monocytes are mononuclear myeloid cells that develop in the bone marrow and circulate within the bloodstream. Although they have long been argued to play a role in the repopulation of tissue-resident macrophages, this has been questioned by numerous recent studies, which has forced a reappraisal of their biology. Here we discuss monocyte development, as well as the homeostatic control of monocyte subpopulations within the blood. We also outline the known functions of monocyte subsets. Finally, we highlight the plastic nature of monocytes, which are capable of a remarkable range of phenotypic and functional changes that depend on signals from local microenvironments. © 2014 Elsevier Inc. Source


Mohana-Kumaran N.,The Centenary Institute | Mohana-Kumaran N.,Universiti Sains Malaysia | Hill D.S.,The Centenary Institute | Hill D.S.,Northumbria University | And 4 more authors.
Pigment Cell and Melanoma Research | Year: 2014

Summary: Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL-2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3- or SMAC-mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3-mimetics indicate that the antiapoptotic BCL-2 protein MCL-1 and its antagonist NOXA are particularly important regulators of BCL-2 family signaling, while SMAC-mimetic studies show that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although most solid tumors, including melanoma, are insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF-inhibitors, which have already revolutionized melanoma treatment, are a clear priority. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

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