A5101516540- Porphyrin Metabolism and Disorders
- Acute Myeloid Leukemia Research
- Hormonal and reproductive studies
- Neonatal Health and Biochemistry
- Chronic Myeloid Leukemia Treatments
- Heme Oxygenase-1 and Carbon Monoxide
- Bone Metabolism and Diseases
- Metabolism and Genetic Disorders
- Growth Hormone and Insulin-like Growth Factors
- Sexual Differentiation and Disorders
- Folate and B Vitamins Research
- Histone Deacetylase Inhibitors Research
- Bone health and osteoporosis research
- Signaling Pathways in Disease
- Neuropeptides and Animal Physiology
- Hematopoietic Stem Cell Transplantation
- Multiple Myeloma Research and Treatments
- Animal Genetics and Reproduction
- Genetic Neurodegenerative Diseases
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Acute Ischemic Stroke Management
- Ovarian function and disorders
- Peroxisome Proliferator-Activated Receptors
Royal Alexandra Hospital
2019-2022
Monash University
1999-2020
Alfred Health
2020
The Alfred Hospital
2015-2019
The University of Melbourne
2004-2008
Austin Health
2004-2008
The Royal Melbourne Hospital
1988-1999
Walter and Eliza Hall Institute of Medical Research
1999
Neurosciences Institute
1998
To identify mechanisms of anabolic androgen action in muscle, we generated male and female genomic receptor (AR) knockout (ARKO) mice, characterized muscle mass, contractile function, gene expression. Muscle mass is decreased ARKO males, but normal females. The levator ani which fails to develop females, also absent males. Force production from fast-twitch slow-twitch has increased fatigue resistance. Microarray analysis shows up-regulation genes encoding proteins. Real-time PCR confirms...
The mechanism of androgen action on bone was studied in male mice with the AR deleted mature osteoblasts. These had decreased trabecular volume associated a decrease number, suggesting that androgens may act directly osteoblasts to maintain bone.Androgens modulate cell activity and are important for maintenance mass. However, mechanisms by which they exert these actions remain poorly defined. aim this study investigate role acting through classical receptor (AR) signaling pathways (i.e.,...
Androgens play a key role in skeletal growth and bone maintenance; however, their mechanism of action remains unclear. To address this, we selectively deleted the androgen receptor (AR) terminally differentiated, mineralizing osteoblasts using Cre/loxP system mice (osteocalcin-Cre AR knockouts [mOBL-ARKOs]). Male mOBL-ARKOs had decreased femoral trabecular volume compared with littermate controls because reduction number at 6, 12, 24 wk age, indicative increased resorption. The effects...
Abstract To study the physiological control of osteoclasts, bone resorbing cells, we generated transgenic mice carrying Cre recombinase gene driven by either tartrate‐resistant acid phosphatase (TRAP) or cathepsin K (Ctsk) promoters. TRAP‐Cre and Ctsk‐Cre mouse lines were characterized breeding with LacZ ROSA 26 (R26R) reporter immunohistochemistry for recombinase. The transgene was functional in all lines, Cre‐mediated recombination occurring primarily long bones, vertebrae, ribs, calvaria....
It is well established that calcitonin a potent inhibitor of bone resorption; however, physiological role for acting through its cognate receptor, the receptor (CTR), has not been identified. Data from previous genetically modified animal models have recognized possible and CTR in controlling formation; interpretation these data are complicated, part because their mixed genetic background. Therefore, to elucidate calcium metabolism, we generated viable global knockout (KO) mouse model using...
The prognosis of older patients with acute myelogenous leukemia is generally poor. interleukin-3 receptor α-chain (CD123) highly expressed on the surface cells compared normal hematopoietic stem cells. CSL362 a fully humanized, CD123-neutralizing monoclonal antibody containing modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous xenografts established from patient explants and characterized by molecular criteria,...
Summary In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0–25 mg, days 5–25) in combination with azacitidine (50–75 mg/m 2 , 1–5) every 28 d, was explored 40 patients acute myeloid leukaemia ( AML ) complete remission after chemotherapy. Eligibility included first CR 1) adverse risk karyotype n = 8), fms‐related tyrosine kinase 3‐internal tandem duplication FLT 3 ‐ ITD 5), age ≥60 years 31) or second 2) 14). Dose‐limiting toxicity not...
Idiopathic Parkinson's disease involves the loss of midbrain dopaminergic neurons, resulting in presynaptic breakdown transmission striatum. Huntington's and some neurodegenerative diseases with Parkinsonian features have postsynaptic defects caused by striatal cell death. Mice were generated which an attenuated form diphtheria toxin gene (tox-176) was expressed exclusively D1 dopamine receptor (D1R)-positive cells aim determining effect this mutation on development basal ganglia locomotor...
We previously generated a conditional floxed mouse line to study androgen action, in which exon 3 of the receptor ( AR) gene is flanked by loxP sites, with neomycin resistance present intron 3. Deletion global AR knockout mice causes insensitivity syndrome, characterized genotypic males lacking normal masculinization. now report that male carrying allele (AR lox ) have reverse phenotype, termed hyperandrogenization. increased mass androgen-dependent tissues, including kidney, P < 0.001),...
Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target rapamycin (mTOR) inhibitor, everolimus (days 5-21) combination with azacitidine 75 mg/m2 subcutaneously 1-5 8-9 every 28 days) 40 patients relapsed (n = 27), primary refractory 11) or elderly unfit for intensive chemotherapy 2). MTD was not reached following escalation (2.5, 5 10 mg; n 19) to mg level which expanded...
To see whether the fecal coproporphyrin III:coproporphyrin I (CIII:CI) ratio (determined by HPLC) would be suitable for screening patients at risk of hereditary coproporphyria (HC), we compared such ratios with lymphocyte coproporphyrinogen oxidase (EC 1.3.3.3) activities (COOX) in 38 subjects from one large family and two smaller families HC. The CIII:CI was normal (less than 1.3) adults COOX (greater 180 nmol/g protein per hour) high 2) those low COOX. Results were difficult to interpret...
Measurement of uroporphyrinogen decarboxylase (UROD; EC 4.1.1.37) activity in erythrocytes is useful distinguishing between familial porphyria cutanea tarda (PCT), which UROD activities are low, and acquired PCT, normal. In this method for measuring UROD, pentacarboxylic acid porphyrinogen I (PPI) used as substrate. A sample the patient's whole blood incubated with PPI at 37 degrees C 30 min pH 6.0. The reaction stopped by adding trichloroacetic acid/dimethyl sulfoxide containing...
Spermatogenesis requires androgen but, paradoxically, oestradiol (E2) treatment stimulates spermatogenic development in gonadotrophin- and androgen-deficient hypogonadal (hpg) mice. The mechanisms of E2-induced spermatogenesis were investigated by determining intratesticular E2 levels testis cell populations E2-treated hpg male mice, actions determined receptor-knockout (ARKO) Despite increased serum concentrations (150–300 pmol L–1), declined fivefold (P < 0.001) v. untreated Serum FSH...
Abstract Background Androgens function through DNA and non‐DNA binding‐dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood. Design methods To identify pathway, we treated male mice lacking second zinc finger DNA‐binding domain AR (AR ΔZF2 ) with non‐aromatizable 5α‐dihydrotestosterone (5α‐DHT) or aromatizable testosterone. distinguish direct hematopoietic non‐hematopoietic mechanisms, performed bone marrow reconstitution...
Abstract We report an unusual case of variegate porphyria in a young girl with epilepsy, mental retardation and premature adrenarche. Symptoms commenced about the age 12 years death occurred 18 months later. The patient had very low protoporphyrinogen oxidase activity her cultured fibro‐blasts. Both parents half normal this enzyme lymphocytes are heterozygous for abnormal gene porphyria. Therefore, it is possible that was homozygous variant. Anticonvulsant therapy hepatic 5α reductase were...
We describe multiple alternative transcripts of uroporphyrinogen decarboxylase mRNA in normal individuals and patients with familial porphyria cutanea tarda. was reverse-transcribed, subjected to the polymerase chain reaction, analyzed for nucleotide sequence. Seven different were characterized, a cryptic splice acceptor site identified intron 1. In all mRNAs exons abutted at previously defined exon boundaries. Characterization junctions genomic DNA showed that donor sequences complied...
We have characterised three new mutations in the uroporphyrinogen decarboxylase gene familial porphyria cutanea tarda. The first of these was a G to A substitution 5′ splice junction exon 4 which generated an mRNA that lacked 4. second nonsense mutation 5 changed arginine residue at position 142 stop codon, and third mutation, also 5, triple base from nucleotide 417 419. This encompassed two codons but only amino acid predicted resulting replacement valine with glutamine 134. missense has...
A 55 year old man presented with a 2 week history of headache, right sided ptosis, ipsilateral facial sensitivity, and anisocoria. He underwent computed tomography angiography (fig 1). Fig 1 (Image courtesy MA …
Abstract Acute myeloid leukaemia (AML) is an aggressive blood cancer that usually fatal within weeks without effective therapy. Treatment currently involves standard chemotherapy agents such as cytarabine (Ara-C) and anthracyclines but these drugs fail to elicit complete clinical responses in 20-30% of cases. An understanding the mechanisms AML mediating resistance may uncover new oncoproteins amenable medicinal targeting. Activation phosphoinositide 3-kinase (PI3-K)/AKT pathway prevalent...