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Belessis Y.,Sydney Childrens Hospital | Belessis Y.,University of New South Wales | Dixon B.,Sydney Childrens Hospital | Hawkins G.,South Eastern Area Laboratory Service | And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Unrecognized airway infection and inflammation in young children with cystic fibrosis (CF) may lead to irreversible lung disease; therefore early detection and treatment is highly desirable. Objectives: To determine whether the lung clearance index (LCI) is a sensitive and repeatable noninvasive measure of airway infection and inflammation in newborn-screened children with CF. Methods: Forty-seven well children with CF (mean age, 1.55 yr) and 25 healthy children (mean age, 1.26 yr) underwent multiple-breath washout testing. LCI within and between-test variability was assessed. Children with CF also had surveillance bronchoalveolar lavage performed. Measurements and Main Results: The mean (SD) LCI in healthy children was 6.45 (0.49). The LCI was higher in children with CF (7.21 [0.81]; P < 0.001). The upper limit of normal for the LCI was 7.41. Fifteen (32%) children with CF had an elevated LCI. LCI measurements were repeatable and reproducible. Airway infection was present in 17 (36%) children with CF, including 7 (15%) with Pseudomonas aeruginosa. Polymicrobial growth was associated with worse inflammation. The LCI was higher in children with Pseudomonas (7.92 [1.16]) than in children without Pseudomonas (7.02 [0.56]) (P = 0.038). The LCI correlated with bronchoalveolar lavage IL-8 (R 2=0.20, P=0.004) and neutrophil count (R 2 = 0.21, P = 0.001). An LCI below the upper limit of normality had a high negative predictive value (93%) in excluding Pseudomonas. Conclusions: The LCI is elevated early in CF, especially in the presence of Pseudomonas and airway inflammation. The LCI is a feasible, repeatable, and sensitive noninvasive marker of lung disease in young children with CF. Copyright © 2012 by the American Thoracic Society. Source

O'toole S.A.,Royalprince Alfred Hospital | O'toole S.A.,Garvan Institute of Medical Research | O'toole S.A.,University of Sydney | Selinger C.I.,Royalprince Alfred Hospital | And 9 more authors.
Pathology | Year: 2011

Recent advances in understanding the molecularpathology of breast cancer offer significantpotential to identifypatients who may benefit from adjuvant therapies. To date, few of these advances are utilised in a routine setting. We review molecular assays that are currently in use or are in the advanced stages of development, which may be used aspredictive orprognostic biomarkers in breast cancer. The only widely used breast cancer molecular assay is in situ hybridisation (ISH) for human epidermal growth factor receptor 2 (HER2) gene amplification and we highlight key issues with the interpretation of this assay, withparticular attention to the difficulties of the equivocal category. New molecular assays such as ISH for the topoisomerase II alpha (TOP2A) gene and for the aberrations in the copy number of the centromeric region of chromosome 17 are readilyperformed in a standard histopathology laboratory, but to date there are insufficient data to support their routine use.We also review the current data on two commercially available multigene expression assays, Oncotype DX and MammaPrint and discuss theirpotential use. Overall, while new molecular assays have significantpotential to improvepatient selection for therapy, well-performed histopathology with reliable interpretation of standard hormone and HER2 assaysprovides the most importantpredictive andprognostic information in early breast cancer. © 2011 Royal College ofpathologists of Australasia. Source

Schade B.,McGill University | Lesurf R.,McGill University | Sanguin-Gendreau V.,McGill University | Bui T.,McGill University | And 15 more authors.
Cancer Research | Year: 2013

Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2KI model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2KI mammary tumors and human ERBB2-positive breast cancers, we show that ErbB2KI tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin-dependent signaling in ErbB2KI-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2KI or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors. © 2013 AACR. Source

Roberts C.G.,Garvan Institute of Medical Research | Millar E.K.A.,Garvan Institute of Medical Research | Millar E.K.A.,South Eastern Area Laboratory Service | Millar E.K.A.,University of Western Sydney | And 15 more authors.
Oncogene | Year: 2011

Recognition of the pivotal role of estrogen in the aetiology of breast cancer has led to the development of antiestrogens (AE), such as tamoxifen (TAM) as effective therapies for the treatment and prevention of this disease. However, despite their widespread clinical efficacy, response to AEs is often short-lived, and acquired or innate therapeutic resistance remains a major obstacle in the successful treatment of breast cancer. Thus, delineating the intracellular pathways that mediate the cellular response to estrogen could potentially lead to new, more effective approaches to the treatment of breast cancer, particularly endocrine-resistant disease. Here, we have identified the BCL-2 homology 3 (BH3)-only, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of their p53 status. PUMA is transcriptionally upregulated following treatment with TAM, and knock down of PUMA expression in these cells attenuates the apoptotic response to TAM. Furthermore, low PUMA expression in breast carcinomas is significantly associated with breast cancer-specific death (P0.0014 and P0.0115, for mRNA and protein, respectively), and worse outcome in TAM-treated patients (mRNA, P1.49e-05). These findings suggest that the dysregulation of apoptotic signaling pathways such as those executed through PUMA, can significantly impact on both the progression and therapeutic responsiveness of breast cancer. Moreover, they provide a convincing rationale for exploring new therapeutic approaches involving endocrine and non-endocrine therapies that target apoptotic pathways as an effective strategy for tackling endocrine refractory disease. © 2011 Macmillan Publishers Limited All rights reserved. Source

Samaras K.,Garvan Institute of Medical Research | Crawford J.,University of New South Wales | Baune B.T.,University of Adelaide | Campbell L.V.,Garvan Institute of Medical Research | And 9 more authors.
Journal of the American Geriatrics Society | Year: 2012

Objectives To determine whether the metabolic syndrome (MetS) or its components were more closely associated with disease states and inflammation in elderly adults. Design Sydney Memory and Ageing Study. Cross-sectional, observational cohort. Setting Population-derived, community-dwelling elderly adults. Participants Nine hundred thirty individuals aged 70 to 90. Measurements Age- and sex-adjusted odds ratios (ORs) for disease states; fasting circulating inflammatory markers and oxidative metabolism byproducts. Results MetS was associated with diabetes mellitus (OR = 4.1, P <.001) and bowel cancer (OR = 9.1, P =.03) but not in analyses that controlled for component conditions. Models containing component conditions had the strongest associations with heart disease. Disease associations were improved after addition of component conditions to the MetS model. The reverse did not hold: disease associations were not improved when MetS was added to the components model. Low high-density lipoprotein cholesterol (HDL-C) was independently associated with myocardial infarction (OR = 2.32) and angina pectoris (OR = 2.59) (both P <.008). Waist circumference was independently associated with cancer (OR = 1.82, P =.008). Although MetS was associated with higher C-reactive protein, vascular cell adhesion molecule, interleukin-6, amyloid A, homocysteine, and malondialdehyde, it explained less than half of the variance of models containing its components. Conclusion The observation that MetS is associated with disease states and markers of circulating inflammation in the elderly is explained mainly by abdominal obesity and low HDL-C. Longitudinal data will further clarify these cross-sectional findings that MetS appears to be less than the sum of its parts in elderly adults. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society. Source

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