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Search Results: 1 - 10 of 318251 matches for " Martin J Firth "
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Translating microarray data for diagnostic testing in childhood leukaemia
Katrin Hoffmann, Martin J Firth, Alex H Beesley, Nicholas H de Klerk, Ursula R Kees
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-229
Abstract: We examined published microarray data from 104 ALL patients specimens, that represent six different subgroups defined by cytogenetic features and immunophenotypes. Using the decision-tree based supervised learning algorithm Random Forest (RF), we determined a small set of genes for optimal subgroup distinction and subsequently validated their predictive power in an independent patient cohort.We achieved very high overall ALL subgroup prediction accuracies of about 98%, and were able to verify the robustness of these genes in an independent panel of 68 specimens obtained from a different institution and processed in a different laboratory. Our study established that the selection of discriminating genes is strongly dependent on the analysis method. This may have profound implications for clinical use, particularly when the classifier is reduced to a small set of genes. We have demonstrated that as few as 26 genes yield accurate class prediction and importantly, almost 70% of these genes have not been previously identified as essential for class distinction of the six ALL subgroups.Our finding supports the feasibility of qRT-PCR technology for standardized diagnostic testing in paediatric ALL and should, in conjunction with conventional cytogenetics lead to a more accurate classification of the disease. In addition, we have demonstrated that microarray findings from one study can be confirmed in an independent study, using an entirely independent patient cohort and with microarray experiments being performed by a different research team.Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease characterized by the presence of several subtypes that are of prognostic relevance. These subtypes can be distinguished based on immunophenotype, differentiation status, as well as chromosomal and molecular abnormalities. The identification of different ALL subtypes, the characterization of prognostic features, and the finding that ALL subtypes differ in their response to t
Gene-based outcome prediction in multiple cohorts of pediatric T-cell acute lymphoblastic leukemia: a Children's Oncology Group study
Amanda L Cleaver, Alex H Beesley, Martin J Firth, Nina C Sturges, Rebecca A O'Leary, Stephen P Hunger, David L Baker, Ursula R Kees
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-105
Abstract: Using HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (IL-7R), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low IL-7R expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-κB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort.We have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.T-cell acute lymphoblastic leukemia (T-ALL) affects approximately 15% of newly diagnosed pediatric ALL patients. Continuous complete clinical remission (CCR) in T-ALL patients is now approaching 80% due to the implementation of aggressive chemotherapy protocols [1-6]. However, patients that relapse (R) have poor prognosis and aggressive therapy can lead to long-term side effects in those that achieve CCR [7]. In the clinical setting, age and white blood cell count (WBC) at diagnosis are used to stratify B-lineage ALL patients as either standard or high risk, significantly impacting on the type and intensity of post-induction therapy used. However these NCI-defined criteria have been shown to hav
Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia
Alex H Beesley, Janelle L Rampellini, Misty-Lee Palmer, Jasmin YS Heng, Amy L Samuels, Martin J Firth, Jette Ford, Ursula R Kees
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-284
Abstract: Negative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL-rearrangements suggested that this relationship represented expression of wild-type MLL. Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis.The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.Among pediatric subtypes of acute lymphoblastic leukemia (ALL), infants and those with T-lineage ALL are particularly resistant to glucocorticoids (GCs), one of the most important classes of drug for this disease [1]. Rearrangement of the mixed lineage leukemia gene (MLL) gene affects 80% of ALL in infants and is associated with a particularly poor prognosis [2,3]. MLL is located at 11q23 and encodes a histone methyltransferase that through its regulation of HOX genes is essential for normal mammalian development and hematopoiesis [4]. A unique feature of the MLL locus is that it is subject to an extremely wide variety of rearrangements, including translocations with >50 partner genes on various chromosomes, as well as deletions, inversions, internal duplications and gene amplifications [4-6]. There are conflicting reports on the relative GC responses of patients with different MLL translocations [7,8], but those with t(4;11) translocations appear particularly resistant [3,8,9]. The biological basis for the documented GC r
Gene expression levels assessed by oligonucleotide microarray analysis and quantitative real-time RT-PCR – how well do they correlate?
Peter B Dallas, Nicholas G Gottardo, Martin J Firth, Alex H Beesley, Katrin Hoffmann, Philippa A Terry, Joseph R Freitas, Joanne M Boag, Aaron J Cummings, Ursula R Kees
BMC Genomics , 2005, DOI: 10.1186/1471-2164-6-59
Abstract: Correlations with qRT-PCR data were obtained using microarray data that were processed using robust multi-array analysis (RMA) and the MAS 5.0 algorithm. Our results indicate that when identical transcripts are targeted by the two methods, correlations between qRT-PCR and microarray data are generally strong (r = 0.89). However, we observed poor correlations between qRT-PCR and RMA or MAS 5.0 normalized microarray data for 13% or 16% of genes, respectively.These results highlight the complementarity of oligonucleotide microarray and qRT-PCR technologies for validation of gene expression measurements, while emphasizing the continuing requirement for caution in interpreting gene expression data.The use of microarray technology to assess gene expression levels is now widespread in biology and, particularly in the clinical setting, the applicability of the methodology is likely to broaden as the technology evolves, data analysis procedures improve, and costs decline [1-3]. Two distinct microarray platforms, cDNA and oligonucleotide, are currently in general use [4]. While the relative merits of the two systems continue to be discussed [5], the validation of microarray results using independent mRNA quantitation techniques, including Northern blotting, ribonuclease protection, in situ hybridization, or quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) remains a critical element of any microarray experiment [6,7]. Despite this, there have been few systematic validation studies of cDNA, or more noticeably, oligonucleotide microarray data using these independent approaches. For researchers to be confident with the interpretation of microarray results and for the establishment of consistent validation procedures in the microarray community for the purpose of data comparison, it is important that this issue be addressed.We have undertaken an extensive series of experiments examining gene expression profiles in pediatric cancer specimens and norm
Classification and Regression Tree and Spatial Analyses Reveal Geographic Heterogeneity in Genome Wide Linkage Study of Indian Visceral Leishmaniasis
Michaela Fakiola,Anshuman Mishra,Madhukar Rai,Shri Prakash Singh,Rebecca A. O'Leary,Stephen Ball,Richard W. Francis,Martin J. Firth,Ben T. Radford,E. Nancy Miller,Shyam Sundar,Jenefer M. Blackwell
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015807
Abstract: Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.
Familial Hypercholesterolaemia: The Cape Town Experience
J C Firth, A D Marais
South African Medical Journal , 2008,
Abstract: Familial hypercholesterolaemia (FH), an autosomal dominantly inherited disorder characterised by elevated plasma low-density lipoprotein (LDL) cholesterol levels, tendon xanthomata and premature ischaemic heart disease, is amenable to treatment with modern medication. The clinical and biochemical details of 1 031 patients with FH were analysed. FH is the most common monogenic disorder of lipoprotein metabolism presenting to the Lipid Clinic at Groote Schuur Hospital, accounting for about 20% of consultations. The hospital classified 55% of the FH patients as white, 43% as coloured, 1.5% as Asian and 0.5% as black. In the FH cohort (whose mean age at presentation was 44 years), 80% had tendon xanthomata, 36% had arcus cornealis, and 14% had xanthelasma. Tendon xanthomata was present in almost 90% of patients by the age of 50 years. Arcus cornealis was present in about 45% by the age of 40 years, further increasing in frequency with age. Cardiovascular complications included ischaemic heart disease (43%), stroke (1.5%), transient ischaemic attacks (1.3%), and peripheral vascular disease (3.7%). The mean age of death was 55 (±13) years; 51 (±10) years in men and 61 (±12) years in women. In 46% of the cohort, a defective gene was identified by testing for locally prevalent mutations. South African Medical Journal Vol. 98 (2) 2008: pp. 99-104
Interprofessional Relationships and Collaborative Working: Encouraging Reflective Practice
Ross, A., King, N., Firth, J
Online Journal of Issues in Nursing , 2005,
Abstract: A challenge for those involved in the education and professional development of health and social care practitioners is to find ways of encouraging and enabling them to critically reflect upon complex collaborative situations and consider how they might improve interprofessional relationships. To meet this challenge, we piloted and developed a reflective exercise derived from methods used in personal construct psychology (Hargreaves,1979; Salmon,1994), which has proved to be useful in three overlapping areas; research, professional development, and classroom teaching. To illustrate the technique, this paper presents a case study of one district nurse who used the method to help her examine complex interprofessional relationships when providing long-term community care. The reflective technique (which uses arrow-shaped cards displayed on large visual layouts) was found to provide a rich description of the individual’s relationships. By employing the visual displays the district nurse was able to explore the meanings of professional identity and roles in terms of professional relationships, and to consider her intentions and actions within a complex multidisciplinary situation.
Interaction of cavity solitons in degenerate optical parametric oscillators
Dmitry V. Skryabin,William J. Firth
Physics , 1999, DOI: 10.1364/OL.24.001056
Abstract: Numerical studies together with asymptotic and spectral analysis establish regimes where soliton pairs in degenerate optical parametric oscillators fuse, repel, or form bound states. A novel bound state stabilized by coupled internal oscillations is predicted.
Instabilities of Higher-Order Parametric Solitons. Filamentation versus Coalescence
Dmitry V. Skryabin,William J. Firth
Physics , 1999,
Abstract: We investigate stability and dynamics of higher-order solitary waves in quadratic media, which have a central peak and one or more surrounding rings. We show existence of two qualitatively different behaviours. For positive phase mismatch the rings break up into filaments which move radially to initial ring. For sufficient negative mismatches rings are found to coalesce with central peak, forming a single oscillating filament.
Modulational instability of solitary waves in non-degenerate three-wave mixing: The role of phase symmetries
Dmitry V. Skryabin,William J. Firth
Physics , 1999, DOI: 10.1103/PhysRevLett.81.3379
Abstract: We show how the analytical approach of Zakharov and Rubenchik [Sov. Phys. JETP {\bf 38}, 494 (1974)] to modulational instability (MI) of solitary waves in the nonlinear Schr\"oedinger equation (NLS) can be generalised for models with two phase symmetries. MI of three-wave parametric spatial solitons due to group velocity dispersion (GVD) is investigated as a typical example of such models. We reveal a new branch of neck instability, which dominates the usual snake type MI found for normal GVD. The resultant nonlinear evolution is thereby qualitatively different from cases with only a single phase symmetry.
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