A5002588324- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- Cancer-related Molecular Pathways
- Neuroinflammation and Neurodegeneration Mechanisms
- Chromatin Remodeling and Cancer
- Cancer Mechanisms and Therapy
- Genetic and Kidney Cyst Diseases
- Cytomegalovirus and herpesvirus research
- Nuclear Receptors and Signaling
- Lanthanide and Transition Metal Complexes
- Tumors and Oncological Cases
- Biotin and Related Studies
- Tryptophan and brain disorders
- HIV/AIDS drug development and treatment
- Renal and related cancers
- Mechanisms of cancer metastasis
- Glioma Diagnosis and Treatment
- Genetics and Neurodevelopmental Disorders
- Radioactive element chemistry and processing
The Royal Melbourne Hospital
2022-2023
RMIT University
2021-2023
Hudson Institute of Medical Research
2015-2023
The University of Melbourne
2022-2023
John Wiley & Sons (United States)
2022
Monash University
2015-2020
Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure possible cause of comorbid disease. However, size replication competent nature central nervous system (CNS) reservoir unclear. Here, we used intact proviral DNA assay (IPDA) provide first quantitative assessment defective brain people with (PWH).Total, intact, proviruses were measured autopsy frontal lobe from viremic (n = 18) or virologically suppressed 12) PWH....
Hedgehog (Hh) signaling regulates cell fate and self-renewal in development cancer. Canonical Hh is mediated by ligand binding to the receptor Patched (Ptch), which turn activates Gli-mediated transcription through Smoothened (Smo), molecular target of pathway inhibitors used as cancer therapeutics. Small lung (SCLC) a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that block capacity SCLC cells, lack activating mutations cast doubt...
Here, we provide the first regional analysis of intact and defective HIV reservoirs within brain. Brain tissue from both viremic virally suppressed people with (PWH) harbored pol DNA in all regions tested, lower levels present basal ganglia cerebellum relative to frontal white matter. Intact proviruses were primarily found matter but also detected other brain PWH, demonstrating as a major reservoir intact, potentially replication competent that persists despite antiretroviral therapy. ANN...
Quantification of intact proviruses is a critical measurement in HIV cure studies both vitro and vivo. The widely adopted 'intact proviral DNA assay' (IPDA), designed to discriminate quantify genetically based on detection two sequence-specific targets, was originally validated using Bio-Rad's droplet digital PCR technology (ddPCR). Despite its advantages, ddPCR limited multiplexing capability (two-channel) labor- time intensive. To overcome some these limitations, we utilized nanowell-based...
HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to brain are unclear. Here we characterized CNS reservoir immune environment SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic 12) or ART-suppressed SIV infection 11). Multiplex immunofluorescence for markers (vRNA/vDNA) activation was performed on frontal cortex matched colon tissue. SIV+ animals contained...
Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations canonical pathway genes. Consequently, the genetic basis Hh adult solid tumors, such as small-cell lung (SCLC), is unknown. Here we show that combined inactivation Trp53 and Rb1, a defining feature SCLC, leads to hypersensitivity ligand vitro, during neural tube development vivo. This response associated with aberrant formation primary cilia, an organelle essential for through smoothened, transmembrane...
Abstract Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer of the kidney and CNS that resistant to current treatment protocols. MRT genetically characterized by homozygous inactivation SMARCB1, critical subunit SWI/SNF chromatin-remodeling complex. Next-generation sequencing data suggests SMARCB1 primary driver mutation, implicating epigenetic deregulation in pathogenesis MRT. Recently, we showed sustained cell lines with low-dose Panobinostat (LBH589), inhibited tumor growth driving...
Abstract TP53 and RB1 loss-of-function mutations are common in osteosarcoma. During development, combined loss of function leads to downregulation autophagy the aberrant formation primary cilia, cellular organelles essential for transmission canonical Hedgehog (Hh) signaling. Excess cilia then hypersensitivity ligand In mouse human models, we now show that osteosarcomas with exhibit enhanced ligand-dependent Hh pathway activation through Smoothened (SMO), a transmembrane signaling molecule...
Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer predominant in the kidney and CNS that resistant to current treatment regimes. MRT genetically characterized by homozygous inactivation of SMARCB1, core subunit SWI/SNF chromatin-remodeling complex. Next-generation sequencing data demonstrates SMARCB1 loss primary driver mutation, implicating epigenetic dysregulation pathogenesis MRT. Recently, we showed sustained cell lines with low-dose Panobinostat (LBH589), inhibited tumor growth...
Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer predominantly occurring in the kidney and CNS that highly resistant to current treatment protocols. MRT almost exclusively characterized by homozygous inactivation of SMARCB1, critical subunit SWI/SNF chromatin-remodeling complex, implicating epigenetic deregulation pathogenesis disease. Recently, we showed sustained human cell lines with Histone deacetylase inhibitor, Panobinostat, at low-dose, inhibited tumor growth driving...
Medulloblastoma is the most common yet challenging paediatric brain tumour. No longer considered a single disease entity, medulloblastoma comprised of at least four distinct genetically and molecularly defined subgroups. Retrospectively assess performance outcomes all patients diagnosed with between 1990-2017 according to molecular After obtaining ethical approval, confirming sample adequacy, 76 samples (FFPE Fresh Frozen) were retrieved from two Victorian children’s oncology providers,...
Abstract The evolutionary conserved Hedgehog (Hh) signaling pathway plays fundamental morphogenic and mitogenic roles in tissue development homeostasis, as well the initiation progression of various cancers. Signaling is driven by binding Sonic hedgehog (Shh) ligand to receptor Patched (Ptch1), initiate primary cilia dependent Smoothened (Smo)-Gli activation. Although mutations Hh components are described some cancers, majority tumors exhibit ligand-dependent signaling, where produced stroma...
Abstract Hedgehog (Hh) signaling regulates patterning, cell-fate and self-renewal in development. Hh proteins signal via Smoothened (Smo), a G-protein coupled receptor whose activity is dependent on translocation to the primary cilium, single immotile tubulin-based structure present most mammalian cells. Activation of Smo results stabilization GLI activator transcription factors, which turn induce pathway gene expression. Aberrant activation implicated initiation progression wide range...
Hedgehog (Hh) signalling is evolutionarily conserved pathway that critical during development and maintenance of stem cells in adults. Activation the can occur through either ligand-dependent or ligand-independent mechanisms. While mutations key Hh components (PTCH1, SUFU, SMO, GLI1) result constitutive activation some cancers, vast majority cancers which implicated do not have are therefore driven upstream at level ligand. Despite this, there no biomarkers predict tumours dependent on...
Abstract Hedgehog (Hh) signalling is evolutionarily conserved pathway that critical during development and maintenance of stem cells in adults. Activation the can occur through either ligand-dependent or ligand-independent mechanisms. While mutations key Hh components (PTCH1, SUFU, SMO, GLI1) result constitutive activation some cancers, vast majority cancers which implicated do not have are therefore driven upstream at level ligand. Despite this, there no biomarkers predict tumours dependent...