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Tanaka R.,Kyoto University | Kimura S.,Saga University | Ashihara E.,Kyoto University | Ashihara E.,Kyoto Prefectural University of Medicine | And 15 more authors.
Cancer Letters | Year: 2011

ABL tyrosine kinase inhibitor (TKI), imatinib is used for BCR-ABL + leukemias. We developed an automatic method utilizing guanine-quenching probes (QP) to detect 17 kinds of mutations frequently observed in imatinib-resistance. Results were obtained from 100μL of whole blood within 90min by this method. Detected mutations were almost identical between QP method and direct sequencing. Furthermore, the mutation-biased PCR (MBP) was added to the QP method to increase sensitivity, resulting earlier detection of T315I mutation which was insensitive to any ABL TKIs. Thus, the QP and MBP-QP may become useful methods for the management of ABL TKI-treated patients. © 2011 Elsevier Ireland Ltd.

Gunn P.A.,University of Melbourne | Gliddon B.L.,University of Melbourne | Gliddon B.L.,Center for Cancer Biology Pathology | Londrigan S.L.,Walter and Eliza Hall Institute of Medical Research | And 4 more authors.
Biology of the Cell | Year: 2011

Background information. Acid-secreting gastric parietal cells are polarized epithelial cells that harbour highly abundant and specialized, H+,K+ ATPase-containing, tubulovesicular membranes in the apical cytoplasm. The Golgi apparatus has been implicated in the biogenesis of the tubulovesicular membranes; however, an unanswered question is how a typical Golgi organization could regulate normal membrane transport within the membrane-dense cytoplasm of parietal cells. Results. Here, we demonstrate that the Golgi apparatus of parietal cells is not the typical juxta-nuclear ribbon of stacks, but rather individual Golgi units are scattered throughout the cytoplasm. The Golgi membrane structures labelled with markers of both cis- and trans-Golgi membrane, indicating the presence of intact Golgi stacks. The parietal cell Golgi stacks were closely aligned with the microtubule network and were shown to participate in both anterograde and retrograde transport pathways. Dispersed Golgi stacks were also observed in parietal cells from H+,K+ ATPase-deficient mice that lack tubulovesicular membranes. Conclusions. These results indicate that the unusual organization of individual Golgi stacks dispersed throughout the cytoplasm of these terminally differentiated cells is likely to be a developmentally regulated event. © 2011 The Author(s).

Zannettino A.C.W.,Institute of Medical and Veterinary Science | Zannettino A.C.W.,Center for Cancer Biology Pathology | Zannettino A.C.W.,University of Adelaide | Paton S.,University of Adelaide | And 7 more authors.
Tissue Engineering - Part A | Year: 2010

Mesenchymal stromal/stem cells (MSC), when used in combination with biomaterial scaffolds, have been shown to contribute at varying efficiencies to bone and cartilage regeneration in preclinical large animal models and human clinical trials. In an orthopedic context, identification of the optimal scaffold, which is capable of inducing tissue regeneration, has been the subject of numerous studies. In the present study, we show that ex vivo-expanded MSC from human and ovine bone marrow display similar phenotypic properties, but exhibit differences in their ability to form bone in vivo when transplanted with different biocompatible scaffold composites. We found that the ovine MSC formed ectopic bone on all scaffolds tested with the exception of collagen-based demineralized bone matrix. In contrast, human MSC in general formed less bone and only on those biomaterials composed of ceramic particles containing at least 15% hydroxyapatite. This study demonstrates the differences in bone formation potential between human and ovine MSC in vivo based on the osteoconductive properties of different bioscaffolds currently being used for orthopedic clinical applications. © 2010 Mary Ann Liebert, Inc.

Stein A.M.,Novartis | Martinelli G.,University of Bologna | Hughes T.P.,Center for Cancer Biology Pathology | Muller M.C.,University of Mannheim | And 9 more authors.
BMC Cancer | Year: 2013

Background: We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses.Methods: Patients from the nilotinib registration trial (CAMN107A2101; registered at http://www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123).Results: More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months.Conclusions: Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS. © 2013 Stein et al.; licensee BioMed Central Ltd.

Li S.,New York Medical College | Garrett-Bakelman F.E.,New York Medical College | Akalin A.,New York Medical College | Zumbo P.,New York Medical College | And 7 more authors.
BMC Bioinformatics | Year: 2013

Background: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data.Results: Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types.Conclusions: Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at http://code.google.com/p/edmr/. © 2013 Li et al.; licensee BioMed Central Ltd.

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