Surgery (RMH) - Research Publications
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ItemCurated MicroRNAs in Urine and Blood Fail to Validate as Predictive Biomarkers for High-Risk Prostate Cancer(PUBLIC LIBRARY SCIENCE, 2014-04-04)PURPOSE: The purpose of this study was to determine if microRNA profiling of urine and plasma at radical prostatectomy can distinguish potentially lethal from indolent prostate cancer. MATERIALS AND METHODS: A panel of microRNAs was profiled in the plasma of 70 patients and the urine of 33 patients collected prior to radical prostatectomy. Expression of microRNAs was correlated to the clinical endpoints at a follow-up time of 3.9 years to identify microRNAs that may predict clinical response after radical prostatectomy. A machine learning approach was applied to test the predictive ability of all microRNAs profiled in urine, plasma, and a combination of both, and global performance assessed using the area under the receiver operator characteristic curve (AUC). Validation of urinary expression of miRNAs was performed on a further independent cohort of 36 patients. RESULTS: The best predictor in plasma using eight miRs yielded only moderate predictive performance (AUC = 0.62). The best predictor of high-risk disease was achieved using miR-16, miR-21 and miR-222 measured in urine (AUC = 0.75). This combination of three microRNAs in urine was a better predictor of high-risk disease than any individual microRNA. Using a different methodology we found that this set of miRNAs was unable to predict high-volume, high-grade disease. CONCLUSIONS: Our initial findings suggested that plasma and urinary profiling of microRNAs at radical prostatectomy may allow prognostication of prostate cancer behaviour. However we found that the microRNA expression signature failed to validate in an independent cohort of patients using a different platform for PCR. This highlights the need for independent validation patient cohorts and suggests that urinary microRNA signatures at radical prostatectomy may not be a robust way to predict the course of clinical disease after definitive treatment for prostate cancer.
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ItemPercutaneous image-guided biopsy of prostate cancer metastases yields samples suitable for genomics and personalised oncology(SPRINGER, 2014-02)Personalised oncology through mutational profiling of cancers requires the procurement of fresh frozen tumour samples for genomics applications. While primary cancers are often surgically excised and therefore yield such tissue, metastases in the setting of a known cancer diagnosis are not routinely sampled prior to systemic therapy. Our study aimed to determine the suitability of extracted nucleic acids for genomics applications using distant metastatic prostate cancer samples obtained via percutaneous or surgical biopsy. Patients with metastatic prostate cancer were recruited for image-guided biopsy of metastases. Patients undergoing surgical procedures for the complications of metastases were also recruited. Tissue samples were flash frozen and cryosectioned for histological examination. DNA and RNA were simultaneously extracted and genomic DNA hybridised onto SNP arrays for genome-wide copy number analysis. 37 samples of metastatic tissue from seven patients with prostate cancer were obtained. Five of these underwent image-guided biopsies whilst two had therapeutic surgical procedures performed. 22 biopsy samples were obtained across the image-guided biopsy patients with 80 % of samples being successfully processed for downstream analysis. Nucleic acid yield from these samples were satisfactory for genomics applications. Copy number analysis revealed a median estimated tumour purity of 53 % and all samples showed chromosomal abnormalities suggestive of malignancy. The procurement of osseous metastatic prostate cancer from live patients, including the use of image-guided biopsy, is safe and feasible. Sufficient tissue can be obtained in a manner such that extracted nucleic acids are suitable for genomics research.
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ItemHyperphosphorylated Tau is Implicated in Acquired Epilepsy and Neuropsychiatric Comorbidities(SPRINGER, 2014-06)Epilepsy is a common group of neurological diseases. Acquired epilepsy can be caused by brain insults, such as trauma, infection or tumour, and followed by a latent period from several months to years before the emergence of recurrent spontaneous seizures. More than 50% of epilepsy cases will develop chronic neurodegenerative, neurocognitive and neuropsychiatric comorbidities. It is important to understand the mechanisms by which a brain insult results in acquired epilepsy and comorbidities in order to identify targets for novel therapeutic interventions that may mitigate these outcomes. Recent studies have implicated the hyperphosphorylated tubulin-associated protein (tau) in rodent models of epilepsy and Alzheimer's disease, and in experimental and clinical studies of traumatic brain injury. This potentially represents a novel target to mitigate epilepsy and associated neurocognitive and psychiatric disorders post-brain injury. This article reviews the potential role of tau-based mechanisms in the pathophysiology of acquired epilepsy and its neurocognitive and neuropsychiatric comorbidities, and the potential to target these for novel disease-modifying treatments.
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ItemReducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array(BMC, 2014-01-22)BACKGROUND: The Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues. RESULTS: We comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation. CONCLUSIONS: Our method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.