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Dive into the research topics where A. William Musk is active.

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Featured researches published by A. William Musk.


The Lancet | 2003

Mesothelin-family proteins and diagnosis of mesothelioma

Bruce W. S. Robinson; Jenette Creaney; Richard A. Lake; Anna K. Nowak; A. William Musk; Nicholas de Klerk; Pernilla Winzell; Karl Erik Hellström; Ingegerd Hellström

BACKGROUND Mesothelioma is a highly aggressive tumour for which there are no reliable serum tumour markers. Identification of such a marker would be useful in diagnosis of mesothelioma and for monitoring responses to treatment and screening at-risk individuals. METHODS We assayed serum concentrations of soluble mesothelin-related proteins (SMR) using a double determinant (sandwich) ELISA in a blinded study of serum samples from 44 patients with histologically proven mesothelioma; 68 matched healthy controls, 40 of whom had been exposed to asbestos; and 160 patients with other inflammatory or malignant lung and pleural diseases. FINDINGS 37 (84%) of 44 patients with mesothelioma had raised concentrations of SMR at a serum dilution of 1/80, compared with three (2%) of 160 patients with other cancers or other inflammatory lung or pleural diseases, and with none of 28 controls who had not been exposed to asbestos. SMR concentrations correlated with tumour size and increased during tumour progression. Seven of the 40 asbestos-exposed individuals had increased serum concentrations of SMR; three of those seven developed mesothelioma and one developed lung carcinoma within 1-5 years. None of the 33 asbestos-exposed participants whose serum samples had normal concentrations of SMR and who were followed up over 8 years developed mesothelioma. INTERPRETATION Determination of SMR in serum could be a useful marker for diagnosis of mesothelioma and to monitor disease progression. It might also prove helpful for screening asbestos-exposed individuals for early evidence of mesothelioma.


The Journal of Nuclear Medicine | 2007

Early Prediction of Response to Chemotherapy and Survival in Malignant Pleural Mesothelioma Using a Novel Semiautomated 3-Dimensional Volume-Based Analysis of Serial 18F-FDG PET Scans

Roslyn J. Francis; Michael J. Byrne; Agatha A. van der Schaaf; Jan Boucek; Anna K. Nowak; Michael Phillips; Richard W. Price; Andrew P. Patrikeos; A. William Musk; Michael Millward

The aim of chemotherapy for mesothelioma is to palliate symptoms and improve survival. Measuring response using CT is challenging because of the circumferential tumor growth pattern. This study aims to evaluate the role of serial 18F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma. Methods: Patients were prospectively recruited and underwent both 18F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based 18F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured. Results: Twenty-three patients were suitable for both radiological and 18F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30% of baseline (range, 11%–71%). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (P = 0.015). Neither a reduction in the maximum standardized uptake value (P = 0.097) nor CT (P = 0.131) demonstrated a statistically significant association with patient survival. Conclusion: Semiquantitative 18F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma.


Genetic Epidemiology | 1999

Genetic variance components analysis for binary phenotypes using generalized linear mixed models (GLMMs) and Gibbs sampling

Paul R. Burton; Katrina J. Tiller; Lyle C. Gurrin; William Cookson; A. William Musk; Lyle J. Palmer

The common complex diseases such as asthma are an important focus of genetic research, and studies based on large numbers of simple pedigrees ascertained from population‐based sampling frames are becoming commonplace. Many of the genetic and environmental factors causing these diseases are unknown and there is often a strong residual covariance between relatives even after all known determinants are taken into account. This must be modelled correctly whether scientific interest is focused on fixed effects, as in an association analysis, or on the covariances themselves. Analysis is straightforward for multivariate Normal phenotypes, but difficulties arise with other types of trait. Generalized linear mixed models (GLMMs) offer a potentially unifying approach to analysis for many classes of phenotype including multivariate Normal traits, binary traits, and censored survival times. Markov Chain Monte Carlo methods, including Gibbs sampling, provide a convenient framework within which such models may be fitted. In this paper, Bayesian inference Using Gibbs Sampling (a generic Gibbs sampler; BUGS) is used to fit GLMMs for multivariate Normal and binary phenotypes in nuclear families. BUGS is easy to use and readily available. We motivate a suitable model structure for Normal phenotypes and show how the model extends to binary traits. We discuss parameter interpretation and statistical inference and show how to circumvent a number of important theoretical and practical problems that we encountered. Using simulated data we show that model parameters seem consistent and appear unbiased in smaller data sets. We illustrate our methods using data from an ongoing cohort study. Genet. Epidemiol. 17:118–140, 1999.


Journal of Thoracic Disease | 2013

Guidelines for the diagnosis and treatment of malignant pleural mesothelioma

Nico van Zandwijk; C.A. Clarke; Douglas W. Henderson; A. William Musk; Kwun M. Fong; Anna K. Nowak; Robert Loneragan; Brian C. McCaughan; Michael Boyer; Malcolm Feigen; Penelope Schofield; Beth Ivimey Nick Pavlakis; Jocelyn McLean; Henry M. Marshall; Steven C. Leong; Victoria Keena; Andrew Penman

Malignant Pleural Mesothelioma (MPM), the asbestos-induced neoplasm originating in the mesothelial lining of the lung cavities represents significant diagnostic and therapeutic challenges for clinicians in Australia. Very seldom diagnosed prior to the advent of widespread asbestos mining in the early to midtwentieth century, it has sharply risen in incidence over the last five decades. According to the most recent Australian Institute of Health and Welfare data, there were 666 cases of malignant mesothelioma diagnosed in Australia in 2009 and around 90% of them originated in the pleura.


International Journal of Cancer | 1998

Vitamin A and cancer prevention II: Comparison of the effects of retinol and β-carotene

Nicholas de Klerk; A. William Musk; G L Ambrosini; J.L. Eccles; Janice Hansen; N. Olsen; V. Lynne Watts; Helen G. Lund; S.C. Pang; John Beilby; Michael Hobbs

Former blue asbestos workers known to be at high risk of asbestos‐related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo‐prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to β‐carotene or retinol. Subjects were assigned randomly to take 30 mg/day β‐carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention‐to‐treat analyses and efficacy analyses based on treatment actually taken. Median follow‐up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to β‐carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on β‐carotene was 0.24 (95% CI 0.07–0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic β‐carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation. Int. J. Cancer 75:362–367, 1998.


European Journal of Human Genetics | 2001

Association between quantitative traits underlying asthma and the HLA-DRB1 locus in a family-based population sample

Miriam F. Moffatt; Carsten Schou; Jennifer A. Faux; Gonçalo R. Abecasis; Alan James; A. William Musk; William Cookson

The region of human chromosome 6 containing the MHC has been identified as influencing asthma and atopy (allergy) by several genome-wide searches. The MHC contains many genes with potential effects on innate and specific immunity. As a first step in dissecting MHC influences on asthma and its underlying quantitative phenotypes, we have examined the HLA-DRB1 locus in a population sample consisting of 1004 individuals from 230 families from the rural Australian town of Busselton. The locus was strongly associated with the (loge) total serum IgE concentration, accounting for 4.0% of the σ2 (variance) in that trait (multi-allelic test, P=0.00001). The locus also influenced specific IgE titres to common allergens (multi-allelic tests, 2.8% σ2 for the house dust mite allergen Der p I, P=0.0013; 3.0% of σ2 for Der p II, P=0.0007; and 2.1% of σ2 for the cat allergen Fel d I, P=0.014). No associations were found to the categorical phenotype of asthma, or to the quantitative traits of peripheral blood eosinophil counts and bronchial hyper-responsiveness. Transmission disequilibrium tests excluded genetic admixture as a cause of false-positive findings. The results indicate that HLA-DRB1 alleles modulate the total serum IgE concentration and IgE responses to allergens, but do not account for the previous observations of linkage of asthma to the MHC.


International Journal of Cancer | 1998

Vitamin A and cancer prevention I: Observations in workers previously exposed to asbestos at Wittenoom, Western Australia

A. William Musk; Nicholas de Klerk; G L Ambrosini; J.L. Eccles; Janice Hansen; N. Olsen; V. Lynne Watts; Helen G. Lund; S.C. Pang; John Beilby; Michael Hobbs

Our aim was to describe a vitamin A‐based cancer prevention program for former asbestos workers and to check for possible harmful effects by comparing rates of disease and death in study subjects with subjects who chose not to join. All subjects had been occupationally exposed to crocidolite at Wittenoom Gorge between 1943 and 1966; 1,677 subjects indicated interest in the program and 1,203 joined between June 1990 and May 1995. Comparison subjects consisted of 996 former workers known to be alive in Western Australia in 1990 who did not join the program. Program subjects were provided with annual supplies of vitamin A (either synthetic β‐carotene or retinol), help in quitting smoking and dietary advice. The comparison group received only mail contact. Both groups were followed up to December 1994 for vital status and cancer information, and rates of cancer and death from various causes were compared. Mortality in both groups was higher than expected (standardised mortality ratio 1.23 in program subjects and 1.67 in comparison subjects). After adjustment for age, smoking and asbestos exposure, the relative rates in participants compared with non‐participants was below 1 for all examined cancers and causes of death. For mesothelioma and lung cancer, group differences increased with time from entry, whereas other differences dissipated with time. No significant side effects were reported. In conclusion, program participants had significantly lower mortality than non‐participants, but the rates of the 2 groups converged with time. Int. J. Cancer 75:355–361, 1998.


Pharmacogenetics | 2001

Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in aborigines from western Australia.

Ernst-Ulricha Griese; Kenneth F. Ilett; Neil R. Kitteringham; Michela Eichelbaum; Helend Powell; Randolph M. Spargo; Peter N. LeSouef; A. William Musk; Rodney F. Minchin

The polymorphisms of the important xenobiotic metabolizing enzymes CYP2D6, CYP2C19 and CYP2E1 have been studied extensively in a large number of populations and show significant heterogeneity in the frequency of different alleles/genotypes and in the prevalence of the extensive and poor metabolizer phenotypes. Understanding of inter-ethnic differences in genotypes is important in prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics. Since no data were available for Australian Aborigines, we investigated the frequencies of alleles and genotypes for CYP2D6, CYP2C19 and CYP2E1 in a population living in the far north of Western Australia. Because of its geographical isolation, this population can serve as a model to study the impact of evolutionary forces on the distribution of different alleles for xenobiotic metabolizing enzymes. Twelve CYP2D6 alleles were analysed. The wild-type allele *1 was the most frequent (85.81%) and the non-functional alleles (*4, * 5, * 16) had an overall frequency of less than 10%. Only one subject (0.4%) was a poor metabolizer for CYP2D6 because of the genotype *5/*5. For CYP2C19, the frequencies of the *1 (wild-type) and the non-functional (*2 and *3) alleles were 50.2%, 35.5% and 14.3%, respectively. The combined CYP2C19 genotypes (*2/*2, *2/*3 or *3/*3) correspond to a predicted frequency of 25.6% for the CYP2C19 poor metabolizer phenotype. For CYP2EI, only one subject had the rare c2 allele giving an overall allele frequency of 0.2%. For CYP2D6 and CYP2C19, allele frequencies and predicted phenotypes differed significantly from those for Caucasians but were similar to those for Orientals indicating a close relationship to East Asian populations. Differences between Aborigines and Orientals in allele frequencies for CYP2D6* 10 and CYP2E1 c2 may have arisen through natural selection, or genetic drift, respectively.


American Journal of Industrial Medicine | 1996

Comparison of measures of exposure to asbestos in former crocidolite workers from Wittenoom Gorge, W. Australia

Nicholas de Klerk; A. William Musk; V.M. Williams; P.R. Filion; Darrel Whitaker; Keith B. Shilkin

Determinations of exposure-response relationships between crocidolite and the major asbestos-related diseases in the Wittenoom cohort have previously depended on the validity of estimates of airborne exposure to asbestos. This work aims to validate the airborne exposure measurements by obtaining measurements of the concentrations of uncoated crocidolite fibers and asbestos bodies retained in the lungs of individual workers, and to estimate the half-life of crocidolite fibers in the lungs. Samples of lung tissue, excluding tumor, of all former Wittenoom workers known to have died in Western Australia (WA) were sought from teaching hospitals, pathology departments, and the Coroners pathologist. The lung specimens were processed using Pooleys method with TEM for counts of fibers of all types and using Smith and Naylors method with conventional light microscopy for asbestos bodies (AB). Multiple linear regression was utilized to examine the associations between crocidolite concentrations in the lung and duration of employment at Wittenoom, time since last employed at Wittenoom, nature of job, estimated average fiber concentration at the worksite, and estimated cumulative crocidolite exposure (CCE) in fiber-years/ml for each subject. Lung tissue from 90 cases was processed and there was good agreement between counts of crocidolite fibers, asbestos bodies, and CCE. Correlations were 0.77 for AB and fibers, 0.54 for AB and CCE, and 0.58 for CCE and fibers, after log transformation. The half-life of crocidolite fibers in the lung was estimated at 92 months (95% CI 55-277 months). Previous estimates of airborne exposure to Wittenoom crocidolite have been reasonably reliable. The relatively simple technique of light microscopy for counting ABs in lung tissue also provides a useful and reliable indication of the level of past occupational exposure to crocidolite in subjects whose exposure has been only to crocidolite. The half-life of crocidolite fibers in the lungs of former Wittenoom workers is about 7-8 years.


Clinical & Experimental Allergy | 2013

Genome-wide association study of body mass index in 23 000 individuals with and without asthma

Erik Melén; Raquel Granell; Manolis Kogevinas; David P. Strachan; Juan R. González; Matthias Wjst; Deborah Jarvis; Markus Ege; Charlotte Braun-Fahrländer; Jon Genuneit; Elisabeth Horak; Emmanuelle Bouzigon; Florence Demenais; Francine Kauffmann; Siroux; Sven Michel; A. von Berg; Andrea Heinzmann; Michael Kabesch; Nicole Probst-Hensch; Ivan Curjuric; Medea Imboden; Thierry Rochat; John Henderson; Jonathan A C Sterne; Wendy L. McArdle; Jennie Hui; Alan James; A. William Musk; Lyle J. Palmer

Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co‐morbidity between these conditions.

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Nicholas de Klerk

University of Western Australia

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Alan James

Sir Charles Gairdner Hospital

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Janice Hansen

Sir Charles Gairdner Hospital

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William Cookson

National Institutes of Health

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Nola Olsen

University of Western Australia

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Y. C. Gary Lee

University of Western Australia

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Gina L. Ambrosini

University of Western Australia

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Michael Hobbs

University of Western Australia

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