A5042674529- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Microtubule and mitosis dynamics
- Prostate Cancer Treatment and Research
- Cell Image Analysis Techniques
- Botulinum Toxin and Related Neurological Disorders
- Immunotherapy and Immune Responses
- Drug-Induced Hepatotoxicity and Protection
- Cancer Immunotherapy and Biomarkers
- Cancer Cells and Metastasis
- Chemical Reactions and Isotopes
- Drug Transport and Resistance Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Lung Cancer Treatments and Mutations
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- RNA Interference and Gene Delivery
- Cannabis and Cannabinoid Research
- Pharmacogenetics and Drug Metabolism
- Immune Response and Inflammation
- Cancer, Hypoxia, and Metabolism
- 3D Printing in Biomedical Research
- Heme Oxygenase-1 and Carbon Monoxide
- Sympathectomy and Hyperhidrosis Treatments
Peter MacCallum Cancer Centre
2020-2024
The University of Melbourne
2021-2024
Victorian Comprehensive Cancer Centre
2021
Harvard University
2015-2019
Center for Systems Biology
2016-2019
Brigham and Women's Hospital
2016-2019
University of Würzburg
2009-2016
Strathmann (Germany)
1996-1998
Roche Pharma AG (Germany)
1995
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX),...
We report the effects of a single bedtime dose L-dopa 100–200 mg on sleep quality, frequency periodic leg movements (PLM) and daily living in patients with idiopathic uremic restless legs syndrome (RLS). Seventeen 11 (on continuous hemodialysis) RLS were evaluated comparatively by polysomnography, actigraphy subjective ratings randomized, controlled double-blind crossover trial placebo for 4 weeks each. Neurophysiologic assessments showed significant reduction number (p = 0.003) PLM-index...
Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality morbidity, but there is no high throughput in vitro method predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated rendering them desirable use such systems. To identify a reliable biomarker nephrotoxicity, we conducted multiplexed gene expression profiling HPTECs after exposure six different...
<h3>OBJECTIVE</h3> Vitamin E, the most potent naturally occurring lipid soluble antioxidant has been suggested to possess both anti-inflammatory and analgesic activity in humans. This double blind randomised study used a broad spectrum of clinical laboratory parameters investigate whether there was any additional or effects, both, orally administered α-tocopherol rheumatoid arthritis patients who were already receiving anti-rheumatic drugs. <h3>METHODS</h3> Forty two enrolled treated with...
Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs chips" proposed to accelerate drug predict safety. Polymyxins potent antibiotics against multidrug-resistant microorganisms; however, remains restricted because high risk...
New treatments are required for advanced prostate cancer; however, there fewer preclinical models of cancer than other common tumor types to test candidate therapeutics. One opportunity increase the scope studies is grow tissue from patient-derived xenografts (PDXs) as organoid cultures. Here we report a scalable pipeline automated seeding, treatment and an analysis drug responses organoids. We established cultures 5 PDXs with diverse phenotypes cancer, including castrate-sensitive...
Abstract Background Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. Methods The activity of an orally bioavailable inhibitor, CDKI-73, was evaluated prostate cell lines, a xenograft mouse model, patient-derived tumor explants organoids. Expression clinical specimens by mining public datasets immunohistochemistry. Effects CDKI-73 on cells were determined cell-based assays, molecular...
The efficacy and safety of oral tolperisone hydrochloride (Mydocalm®) in the treatment painful reflex muscle spasm was assessed a prospective, randomized, double-blind, placebo-controlled trial. A total 138 patients, aged between 20 75 years, with associated diseases spinal column or proximal joints were enrolled eight rehabilitation centers. Patients randomized to receive either 300 mg placebo for period 21 days. Both groups recovered during 3 weeks program. However, proved be significantly...
The tumor suppressor gene TP53 is the most frequently mutated in cancer. compound APR-246 (PRIMA-1Met/Eprenetapopt) converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. currently tested a phase III clinical trial myelodysplastic syndrome (MDS). By vitro, ex vivo, vivo models, we show combined treatment with inhibitors of efflux pump MRP1/ABCC1 results synergistic cell death, which more pronounced cells. This associated altered...
Abstract There are diverse phenotypes of castration‐resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy BET and CBP/p300 inhibitors cancer is attributed, at least part, ability decrease androgen receptor (AR) signalling. However, the activity cancers lack AR unclear. In this study, we showed BRD4, CBP, p300 were co‐expressed AR‐positive AR‐null cancer. A combined inhibitor these three proteins, NEO2734, reduced growth...
Sedative effects of single and repeated doses 50 mg 150 tolperisone hydrochloride (Mydocalm®), a centrally active muscle-relaxing agent, were evaluated in placebo-controlled double-blind clinical trial. A total 72 healthy young adults balanced by sex randomized to receive or placebo t.i.d. for period 8 days. Control examinations performed the mornings days 1 before intake morning dose at 1.5, 4 6 hours postdose. The psychomotoric test battery used this trial revealed no sedative given any...
To study the efficacy and safety of tolperisone – a centrally acting muscle relaxant with membrane stabilizing activity in treatment stroke‐related spasticity. This was randomized, double‐blind, placebo‐controlled, multicenter parallel groups. Treatment lasted 12 weeks started titration period variable length (dose range 300–900 mg daily). The degree spasticity determined on Ashworth Scale most severely affected joint area defined as primary target parameter. Hundred twenty patients (43...
Introduction: Surgery and radiotherapy are key cancer treatments the leading causes of damage to lymphatics, a vascular network critical fluid homeostasis immunity. The clinical manifestation this constitutes devastating side-effect treatment, known as lymphoedema. Lymphoedema is chronic condition evolving from accumulation interstitial due impaired drainage via lymphatics recognised contribute significant morbidity patients who survive their cancer. Nevertheless, molecular mechanisms...
The failure to predict kidney toxicity of new chemical entities early in the development process before they reach humans remains a critical issue. Here, we used primary human cells and applied systems biology approach that combines multidimensional datasets machine learning identify biomarkers not only nephrotoxic compounds but also provide hints toward their mechanism toxicity. Gene expression high-content imaging-derived phenotypical data from 46 diverse toxicants were analyzed using...
Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) defects in homologous recombination (HR) DNA repair. New treatments are required remaining tumors, and an emerging strategy to combine other therapies that induce damage. Here we tested whether HR-proficient CRPC, including androgen receptor (AR)-null when used combination CX-5461, a small molecule inhibits RNA polymerase I transcription activates damage response, has antitumor activity...
<div>Abstract<p>Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring <i>CCNE1</i> amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using...
Abstract Mucinous ovarian carcinoma (MOC) is a subtype of cancer that distinct from all other subtypes and currently has no targeted therapies. To identify novel therapeutic targets, we developed applied new method differential network analysis comparing MOC to benign mucinous tumours (in the absence known normal tissue origin). This mapped protein-protein in then utilised structural bioinformatics prioritise proteins identified as upregulated for their likelihood being successfully drugged....
Abstract Kidney toxicity due to drugs and chemicals poses a significant health burden for patients financial risk pharmaceutical companies. However, currently no sensitive high‐throughput in vitro method exists predictive nephrotoxicity assessment. Primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated cells, making them desirable model use screening systems. Additionally, heme oxygenase 1 (HO‐1) protein expression is upregulated as protective...
Abstract CYP3A5 is the primary CYP3A subfamily enzyme expressed in human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between hypertension, however, most investigators considered CYP3A5*1 as active CYP3A5*3 an inactive allele. Observations gender specific differences CYP3A5*3/*3 protein suggest additional complexity gene regulation that underpin environmentally responsive role for...
Background The death of epithelial cells in the proximal tubules is thought to be primary cause AKI, but that survive kidney injury have a remarkable ability proliferate. Because tubular play predominant role regeneration after damage, potential approach treat AKI discover regenerative therapeutics capable stimulating proliferation these cells. Methods We conducted high-throughput phenotypic screen using 1902 biologically active compounds identify new molecules promote human vitro . Results...
<p>Description of methods to synthesize INX-315</p>