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1.  Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation 
The standard of care in Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC) is chemotherapy and radiation; however, Radiation-Induced Lung Injury (RILI), which may be prevented by the anti-inflammatory and anti-oxidant properties of Flaxseed (FS), impedes its maximum benefit.
Materials and Methods
Patients with LA-NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12-iso-iPF2a-VI (isoprostane) and 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxo-dGuo). Tolerability was defined as consuming ≥ 75% of the intended muffins and no ≥ grade 3 gastrointestinal toxicities.
Fourteen patients (control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37% versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS.
This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS.
PMCID: PMC3932620  PMID: 24575360
Flaxseed; Lignan; Radiation; Isoprostane; 8-oxo dGuo; Non-small cell lung cancer; Radiation induced lung injury; RILI; Pneumonitis; Fibrosis; Esophagitis
2.  Descriptive epidemiology of upper respiratory disease and associated risk factors in cats in an animal shelter in coastal western Canada 
The Canadian Veterinary Journal  2013;54(2):132-138.
We examined 250 cats at an animal shelter in the coastal temperate region of Canada to determine whether age, source, gender, and sterilization status influenced risk of shedding at intake, transmission of infection, and development of clinical upper respiratory disease (URD). On admission, 28% of the cats were positive for 1 or more infectious agent related to URD; 21% were carriers of Mycoplasma felis and < 3% were carriers of feline calicivirus (FCV), feline herpesvirus-1 (FHV-1) or Bordetella bronchiseptica. Chlamydophila felis and H1N1 influenza virus were not detected. Carrier status was not affected by source, gender, sterilization status, or age (P > 0.05). Viral and bacterial shedding increased by 9% and 11%, respectively, over 3 sampling times (days 1, 4, and 10). Over 40 days after admission, the cumulative probability of developing URD was 2.2 times greater for stray than owner-surrendered cats (P = 0.02) and 0.5 times as great for neutered cats as for intact cats (P = 0.03). Cats that were shedding at intake were 2.6 times more likely to develop URD than were non-carriers (P < 0.002). Cats with FHV-1 and B. bronchiseptica infections were most at risk compared with non-shedding cats (P < 0.01).
PMCID: PMC3552587  PMID: 23904635
3.  Epstein-Barr Virus, Human Papillomavirus and Mouse Mammary Tumour Virus as Multiple Viruses in Breast Cancer 
PLoS ONE  2012;7(11):e48788.
The purpose of this investigation is to determine if Epstein Barr virus (EBV), high risk human papillomavirus (HPV), and mouse mammary tumour viruses (MMTV) co-exist in some breast cancers.
Materials and Methods
All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis) and 14 were predominantly invasive ductal carcinomas (idc).
EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk – EBV (35%), HPV, 20%) and MMTV (32%) of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples.
We conclude that (i) EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii) the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer.
PMCID: PMC3501510  PMID: 23183846
4.  Differential expression of miRNAs in the serum of patients with high-risk oral lesions 
Cancer Medicine  2012;1(2):268-274.
Oral cancer is one of the most commonly diagnosed cancers worldwide. Disease is often diagnosed at later stages, which is associated with a poor 5-year survival rate and a high rate of local recurrence. MicroRNAs (miRNAs), a group of small, noncoding RNAs, can be isolated from blood serum samples and have demonstrated utility as biomarkers in multiple cancer types. The aim of this study was to examine the expression profiles of circulating miRNAs in the serum of patients with high-risk oral lesions (HRLs; oral cancer or carcinoma in situ) and to explore their utility as potential oral cancer biomarkers. Global serum miRNA profiles were generated using quantitative PCR method from 1) patients diagnosed with HRLs and undergoing intent-to-cure surgical treatment (N = 30) and 2) a demographically matched, noncancer control group (N = 26). We next honed our list of serum miRNAs associated with disease by reducing the effects of interpatient variability; we compared serum miRNA profiles from samples taken both before and after tumor resections (N = 10). Based on these analyses, fifteen miRNAs were significantly upregulated and five were significantly downregulated based on presence of disease (minimum fold-change >2 in at least 50% of samples, P < 0.05, permutation). Five of these miRNAs (miR-16, let-7b, miR-338-3p, miR-223, and miR-29a) yielded an area under the ROC curve (AUC) >0.8, suggesting utility as noninvasive biomarkers for detection of oral cancer or high-grade lesions. Combining these serum miRNA profiles with other screening techniques could greatly improve the sensitivity in oral cancer detection.
PMCID: PMC3544450  PMID: 23342275
Biomarkers; circulating microRNAs; oral squamous cell carcinoma
5.  High risk human papillomavirus and Epstein Barr virus in human breast milk 
BMC Research Notes  2012;5:477.
Multiple viruses, including human immunodeficiency virus, Epstein Barr virus (EBV) and mouse mammary tumour virus have been identified in human milk. High risk human papillomavirus (HPV) sequences have been identified in breast cancer. The aim of this study is to determine if viral sequences are present in human milk from normal lactating women.
Standard (liquid) and in situ polymerase chain reaction (PCR) techniques were used to identify HPV and EBV in human milk samples from normal lactating Australian women who had no history of breast cancer.
High risk human papillomavirus was identified in milk samples of 6 of 40 (15%) from normal lactating women - sequencing on four samples showed three were HPV 16 and one was HPV 18. Epstein Barr virus was identified in fourteen samples (33%).
The presence of high risk HPV and EBV in human milk suggests the possibility of milk transmission of these viruses. However, given the rarity of viral associated malignancies in young people, it is possible but unlikely, that such transmission is associated with breast or other cancers.
PMCID: PMC3492016  PMID: 22937830
Human papillomavirus; Epstein barr virus; Human milk
6.  Controlled vocabularies and semantics in systems biology 
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. This Perspective discusses the development and use of ontologies that are designed to add semantic information to computational models and simulations.
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. Model structures, simulation descriptions and numerical results can be encoded in structured formats, but there is an increasing need to provide an additional semantic layer. Semantic information adds meaning to components of structured descriptions to help identify and interpret them unambiguously. Ontologies are one of the tools frequently used for this purpose. We describe here three ontologies created specifically to address the needs of the systems biology community. The Systems Biology Ontology (SBO) provides semantic information about the model components. The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of systems biology models, their characterization and interrelationships. The Terminology for the Description of Dynamics (TEDDY) categorizes dynamical features of the simulation results and general systems behavior. The provision of semantic information extends a model's longevity and facilitates its reuse. It provides useful insight into the biology of modeled processes, and may be used to make informed decisions on subsequent simulation experiments.
PMCID: PMC3261705  PMID: 22027554
dynamics; kinetics; model; ontology; simulation
7.  Model annotation for synthetic biology: automating model to nucleotide sequence conversion 
Bioinformatics  2011;27(7):973-979.
Motivation: The need for the automated computational design of genetic circuits is becoming increasingly apparent with the advent of ever more complex and ambitious synthetic biology projects. Currently, most circuits are designed through the assembly of models of individual parts such as promoters, ribosome binding sites and coding sequences. These low level models are combined to produce a dynamic model of a larger device that exhibits a desired behaviour. The larger model then acts as a blueprint for physical implementation at the DNA level. However, the conversion of models of complex genetic circuits into DNA sequences is a non-trivial undertaking due to the complexity of mapping the model parts to their physical manifestation. Automating this process is further hampered by the lack of computationally tractable information in most models.
Results: We describe a method for automatically generating DNA sequences from dynamic models implemented in CellML and Systems Biology Markup Language (SBML). We also identify the metadata needed to annotate models to facilitate automated conversion, and propose and demonstrate a method for the markup of these models using RDF. Our algorithm has been implemented in a software tool called MoSeC.
Availability: The software is available from the authors' web site
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3065685  PMID: 21296753
8.  Revision history aware repositories of computational models of biological systems 
BMC Bioinformatics  2011;12:22.
Building repositories of computational models of biological systems ensures that published models are available for both education and further research, and can provide a source of smaller, previously verified models to integrate into a larger model.
One problem with earlier repositories has been the limitations in facilities to record the revision history of models. Often, these facilities are limited to a linear series of versions which were deposited in the repository. This is problematic for several reasons. Firstly, there are many instances in the history of biological systems modelling where an 'ancestral' model is modified by different groups to create many different models. With a linear series of versions, if the changes made to one model are merged into another model, the merge appears as a single item in the history. This hides useful revision history information, and also makes further merges much more difficult, as there is no record of which changes have or have not already been merged. In addition, a long series of individual changes made outside of the repository are also all merged into a single revision when they are put back into the repository, making it difficult to separate out individual changes. Furthermore, many earlier repositories only retain the revision history of individual files, rather than of a group of files. This is an important limitation to overcome, because some types of models, such as CellML 1.1 models, can be developed as a collection of modules, each in a separate file.
The need for revision history is widely recognised for computer software, and a lot of work has gone into developing version control systems and distributed version control systems (DVCSs) for tracking the revision history. However, to date, there has been no published research on how DVCSs can be applied to repositories of computational models of biological systems.
We have extended the Physiome Model Repository software to be fully revision history aware, by building it on top of Mercurial, an existing DVCS. We have demonstrated the utility of this approach, when used in conjunction with the model composition facilities in CellML, to build and understand more complex models. We have also demonstrated the ability of the repository software to present version history to casual users over the web, and to highlight specific versions which are likely to be useful to users.
Providing facilities for maintaining and using revision history information is an important part of building a useful repository of computational models, as this information is useful both for understanding the source of and justification for parts of a model, and to facilitate automated processes such as merges. The availability of fully revision history aware repositories, and associated tools, will therefore be of significant benefit to the community.
PMCID: PMC3033326  PMID: 21235804
9.  Mouse mammary tumour‐like virus gene sequences and specific breast cancer morphology 
Journal of Clinical Pathology  2006;60(9):1071.
PMCID: PMC1972429  PMID: 17158634
mouse mammary tumour virus; breast cancer; histology
10.  Viruses and Breast Cancer 
Cancers  2010;2(2):752-772.
Viruses are the accepted cause of many important cancers including cancers of the cervix and anogenital area, the liver, some lymphomas, head and neck cancers and indirectly human immunodeficiency virus associated cancers. For over 50 years, there have been serious attempts to identify viruses which may have a role in breast cancer. Despite these efforts, the establishment of conclusive evidence for such a role has been elusive. However, the development of extremely sophisticated new experimental techniques has allowed the recent development of evidence that human papilloma virus, Epstein-Barr virus, mouse mammary tumor virus and bovine leukemia virus may each have a role in the causation of human breast cancers. This is potentially good news as effective vaccines are already available to prevent infections from carcinogenic strains of human papilloma virus, which causes cancer of the uterine cervix.
PMCID: PMC3835103  PMID: 24281093
breast cancer; viruses; etiology; human papilloma virus; mouse mammary tumor virus; Epstein-Barr virus; bovine leukemia virus
11.  Localised breast cancers may have systemic influences on skin and hair 
Journal of Clinical Pathology  2006;60(2):180-184.
Biomarkers, commonly expressed in breast cancer cells, may be correlated with their expression in breast skin of the same subjects.
The expression of biomarkers in specimens from 33 breast tumours and breast skin from the same subject and from 32 normal controls was studied using immunohistochemical techniques.
(1) In normal women, there are significant correlations between the levels of expression of cyclin D1, bcl‐2 and p53 in normal breast epithelial cells and breast skin epithelial cells. (2) These patterns of biomarker expression in normal women are similar in breast cancer and breast skin epithelial cells of women with invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS), but are at significantly higher levels in both breast cancer cells and skin from the same subjects. (3) In normal women, human epidermal growth factor receptor 2 (HER‐2) is not expressed in either breast epithelial cells or skin epithelial cells. (4) HER‐2 is expressed in the breast skin of some subjects with HER‐2‐positive breast cancer. (5) Positive oestrogen receptor alpha expression occurs significantly more frequently in the breast skin of women with IDC and DCIS than in normal controls.
The influence of localised breast cancer seems to be systemic, and leads to changes in skin and hair.
PMCID: PMC1860615  PMID: 16751301
12.  CellML metadata standards, associated tools and repositories 
The development of standards for encoding mathematical models is an important component of model building and model sharing among scientists interested in understanding multi-scale physiological processes. CellML provides such a standard, particularly for models based on biophysical mechanisms, and a substantial number of models are now available in the CellML Model Repository. However, there is an urgent need to extend the current CellML metadata standard to provide biological and biophysical annotation of the models in order to facilitate model sharing, automated model reduction and connection to biological databases. This paper gives a broad overview of a number of new developments on CellML metadata and provides links to further methodological details available from the CellML website.
PMCID: PMC3268215  PMID: 19380315
CellML; markup languages; metadata; modelling
13.  Breastfeeding, breast milk and viruses 
BMC Women's Health  2007;7:17.
There is seemingly consistent and compelling evidence that there is no association between breastfeeding and breast cancer. An assumption follows that milk borne viruses cannot be associated with human breast cancer.
We challenge this evidence because past breastfeeding studies did not determine "exposure" of newborn infants to colostrum and breast milk.
We conducted a prospective review of 100 consecutive births of infants in the same centre to determine the proportion of newborn infants who were "exposed" to colostrum or breast milk, as distinct from being fully breast fed. We also report a review of the breastfeeding practices of mothers of over 87,000 newborn infants in the Australian State of New South Wales.
This study was approved by the Human Research Ethics Committee of the University of New South Wales (Sydney, Australia). Approval 05063, 29 September 2005.
Virtually all (97 of 100) newborn infants in this centre were "exposed" to colostrum or breast milk whether or not they were fully breast fed. Between 82.2% to 98.7% of 87,000 newborn infants were "exposed" to colostrum or breast milk.
In some Western communities there is near universal exposure of new born infants to colostrum and breast milk. Accordingly it is possible for the transmission of human milk borne viruses. This is contrary to the widespread assumption that human milk borne viruses cannot be associated with breast cancer.
PMCID: PMC2148035  PMID: 17919341
14.  Hormone replacement therapy use dramatically increases breast oestrogen receptor expression in obese postmenopausal women 
Breast Cancer Research : BCR  2001;3(5):342-345.
It is known that use of hormone replacement therapy (HRT) by postmenopausal women increases the risk of breast cancer.
In this study, oestrogen receptor (ER)-α expression is examined using standard immunoperoxidase technique.
Normal breast samples of 11 Australian postmenopausal women have been included in the ER-α study; the result showed a strong correlation (r2 = 0.80) between ER-α expression in normal breast epithelial cells and body mass index (BMI) in normal women who currently use HRT.
This finding confirms that the possibility of increased risk of breast cancer associated with increased ER-α expression in normal breast epithelial cells, in turn associated with high BMI and the use of HRT.
PMCID: PMC57804  PMID: 11597325
breast cancer; hormone replacement therapy; oestrogen receptor (ER)-α expression; body mass index
15.  From Bittner to Barr: a viral, diet and hormone breast cancer aetiology hypothesis 
Breast Cancer Research  2000;3(2):81-85.
It is hypothesized that the human homologue of the mouse mammary tumour virus (HHMMTV) and other viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV), act as cofactors with diet, oestrogens and other hormones in the initiation and promotion of some types of breast cancer in genetically susceptible women. It is further hypothesized that diet influences the risk of breast cancer, through its influence on oestrogen metabolism and that of other hormones, in combination with genetic and infectious agents.
PMCID: PMC138675  PMID: 11250750
breast cancer; diet; Epstein-Barr virus; human papillomavirus; mouse mammary tumour virus; oestrogens
16.  Haloboration of Internal Alkynes with Boronium and Borenium Cations as a Route to Tetrasubstituted Alkenes** 
PMCID: PMC3749439  PMID: 23740843
borenium ions; boronate esters; haloboration; synthetic methods; tetrasubstituted alkenes
17.  Cervical Cytology 
British Medical Journal  1966;2(5524):1260.
PMCID: PMC1944768
18.  Meigs's Syndrome 
British Medical Journal  1958;1(5071):628.
PMCID: PMC2028086  PMID: 13510752

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