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Centenary Institute Of Cancer Medicine And Cell Biology, Wenkart Foundation, Medvet Science Pty Ltd. and University of Sydney | Date: 2010-06-04

The present invention relates to methods for modulating angiogenesis, comprising administering to a subject, or cells or tissue derived therefrom: (i) one or more miRNA, or precursors or variants thereof, wherein at least one of said miRNA comprises a seed region comprising the sequence UCACAGU (SEQ ID NO:37) to inhibit angiogenesis; or (ii) one or more antagonists of a miRNA, wherein said miRNA comprises a seed region comprising the sequence UCACAGU (SEQ ID NO:37) to promote or induce angiogenesis. Also provided are methods of diagnosis of conditions associated with abnormal angiogenesis, or determining predisposition thereto. Suitable pharmaceutical compositions are also provided.


Munoz M.A.,Centenary Institute of Cancer Medicine and Cell Biology | Biro M.,Centenary Institute of Cancer Medicine and Cell Biology | Biro M.,University of Sydney | Weninger W.,Centenary Institute of Cancer Medicine and Cell Biology | And 2 more authors.
Current Opinion in Cell Biology | Year: 2014

In the lymph node, T cells migrate rapidly and with striking versatility in a continuous scan for antigen presenting dendritic cells. The scanning process is greatly facilitated by the lymph node structure and composition. In vivo imaging has been instrumental in deciphering the spatiotemporal dynamics of intranodal T cell migration in both health and disease. Here we review recent developments in uncovering the migration modes employed by T cells in the lymph node, the underlying molecular mechanisms, and the scanning strategies utilised by T cells to ensure a timely response to antigenic stimuli. © 2014 The Authors.


De Zwaan S.E.,Royal Prince Alfred Hospital | Haass N.K.,Royal Prince Alfred Hospital | Haass N.K.,University of Sydney | Haass N.K.,Centenary Institute of Cancer Medicine and Cell Biology
Australasian Journal of Dermatology | Year: 2010

Basal cell carcinoma is the most common human malignancy in populations of European origin, and Australia has the highest incidence of basal cell carcinoma in the world. Great advances in the understanding of the genetics of this cancer have occurred in recent years. Mutations of the patched 1 gene (PTCH1) lead to basal cell carcinoma predisposition in Gorlin syndrome. PTCH1 is part of the hedgehog signalling pathway, and derangements within this pathway are now known to be important in the carcinogenesis of many different cancers including sporadic basal cell carcinoma. The molecular biology of the hedgehog pathway is discussed, and mouse models of basal cell carcinoma based on this pathway are explored. New developments in non-surgical treatment of basal cell carcinoma are based on this knowledge. Other genes of importance to basal cell carcinoma development include the tumour suppressor gene P53 and the melanocortin-1 receptor gene. In addition, we discuss molecules of possible importance such as the glutathione-S-transferases, DNA repair genes, cyclin-dependent kinase inhibitor 2A, Brahma and connexins. Evidence of familial aggregation of this cancer is explored and supports the possibility of genetic predisposition to this common malignancy. © 2009 The Australasian College of Dermatologists.


Biro M.,Centenary Institute of Cancer Medicine and Cell Biology | Biro M.,University of Sydney | Munoz M.A.,Centenary Institute of Cancer Medicine and Cell Biology | Weninger W.,Centenary Institute of Cancer Medicine and Cell Biology | And 2 more authors.
British Journal of Pharmacology | Year: 2014

Leukocytes are unmatched migrators capable of traversing barriers and tissues of remarkably varied structural composition. An effective immune response relies on the ability of its constituent cells to infiltrate target sites. Yet, unwarranted mobilization of immune cells can lead to inflammatory diseases and tissue damage ranging in severity from mild to life-threatening. The efficacy and plasticity of leukocyte migration is driven by the precise spatiotemporal regulation of the actin cytoskeleton. The small GTPases of the Rho family (Rho-GTPases), and their immediate downstream effector kinases, are key regulators of cellular actomyosin dynamics and are therefore considered prime pharmacological targets for stemming leukocyte motility in inflammatory disorders. This review describes advances in the development of small-molecule inhibitors aimed at modulating the Rho-GTPase-centric regulatory pathways governing motility, many of which stem from studies of cancer invasiveness. These inhibitors promise the advent of novel treatment options with high selectivity and potency against immune-mediated pathologies. © 2014 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.


Roediger B.,Centenary Institute of Cancer Medicine and Cell Biology | Roediger B.,University of Sydney | Weninger W.,Centenary Institute of Cancer Medicine and Cell Biology | Weninger W.,University of Sydney | Weninger W.,Royal Prince Alfred Hospital
Advances in Immunology | Year: 2015

Type 2 cytokine-driven immune responses are important against parasite infections but also underlie the development of inflammatory allergic diseases. Type 2 CD4+ T (Th2) cells have long been believed to act as central regulators of allergic conditions via the production of the signature cytokines IL-4, IL-5, and IL-13. However, the more recent identification of group 2 innate lymphoid cells ILC (ILC2) cells, which also produce the same cytokines, necessitates a reevaluation of the relative roles these two populations play during type 2 inflammation. ILC2 cells preferentially localize to the interface between the host and the environment (lung, intestine, skin) and respond to epithelium-derived cytokines associated with barrier disruption, such as IL-25, IL-33, and thymic stromal lymphopoietin. ILC2 cells are a major source of IL-5 and IL-13 in vivo but may also produce IL-4 and IL-9 under more defined conditions. ILC2 cells regulate local inflammatory responses to environmental challenges, and this in turn enables them to influence downstream adaptive immune responses. Here, we discuss our current understanding of ILC2 cell phenotype, development and function, and detail the expanding array of cell surface receptor and signaling pathways that enable ILC2 cells to perform a variety of biological functions in vivo. We give special attention to the most recently described and poorly understood member of the ILC2 cell family, the dermal ILC2 cells, and discuss their role in regulating skin inflammation. © 2015 Elsevier Inc.


Gardam S.,Garvan Institute of Medical Research | Turner V.M.,Garvan Institute of Medical Research | Anderton H.,La Trobe University | Limaye S.,Centenary Institute of Cancer Medicine and Cell Biology | And 7 more authors.
Blood | Year: 2011

B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma. © 2011 by The American Society of Hematology.


Patent
Centenary Institute Of Cancer Medicine And Cell Biology, Mirrx Therapeutics A S and University of Sydney | Date: 2013-10-02

The present invention provides oligonucleotides that inhibit the binding of miR-27a to VE-cadherin mRNA, particularly in the form of blockmirs. The invention also provides compositions comprising such oligonucleotides and methods of use of such oligonucleotides to modulate the activity of VE-cadherin, inhibit or reduce vascular permeability, treat or prevent a vascular permeability-associated disease or condition, inhibit tumour growth, treat ischaemic injury, enhance recovery from ischaemic injury, treat surgical wounds and/or promotes post-operative recovery, and promote or induce angiogenesis.


Patent
Centenary Institute Of Cancer Medicine And Cell Biology, University of Sydney and Wenkart Foundation | Date: 2016-03-22

The present invention relates to methods for modulating angiogenesis, comprising administering to a subject, or cells or tissue derived therefrom: (i) one or more miRNA, or precursors or variants thereof, wherein at least one of said miRNA comprises a seed region comprising the sequence UCACAGU (SEQ ID NO:37) to inhibit angiogenesis; or (ii) one or more antagonists of a miRNA, wherein said miRNA comprises a seed region comprising the sequence UCACAGU (SEQ ID NO:37) to promote or induce angiogenesis. Also provided are methods of diagnosis of conditions associated with abnormal angiogenesis, or determining predisposition thereto. Suitable pharmaceutical compositions are also provided.


West N.P.,Centenary Institute of Cancer Medicine and Cell Biology | Cergol K.M.,University of Sydney | Xue M.,University of Sydney | Randall E.J.,Centenary Institute of Cancer Medicine and Cell Biology | And 3 more authors.
Chemical Communications | Year: 2011

The first targeted inhibitors of an essential M. tuberculosis cell wall lipase, Rv3802c, are described. Lead compounds exhibited nanomolar inhibition of the enzyme, and encouraging antibacterial activity against M. tuberculosis in vitro, supporting Rv3802c as a novel TB drug target. © 2011 The Royal Society of Chemistry.


Patent
Centenary Institute Of Cancer Medicine And Cell Biology | Date: 2011-04-15

The present invention relates to methods and kits for identifying, quantifying and isolating regulatory T cells, to methods and kits for diagnosing or monitoring autoimmune diseases, immunoinflammatory diseases, allergic diseases, predispositions thereto, infectious diseases, cancer, cancer treatment and/or organ transplantation based on regulatory T cell quantity, to methods and kits for predicting responses to therapy for autoimmune diseases, immunoinflammatory diseases, allergic diseases, predispositions thereto, infectious diseases, cancer and/or organ transplantation based on regulatory T cell quantity, and to methods and kits for therapy using isolated regulatory T cells.

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