5 results on '"Mainprize, Todd"'
Search Results
2. A clinicobiological model predicting survival in medulloblastoma.
- Author
-
Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S, McLaughlin J, Bouffet E, Rutka JT, and Hawkins CE
- Subjects
- Adolescent, Apoptosis, Cerebellar Neoplasms therapy, Child, Child, Preschool, Female, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Infant, Ki-67 Antigen biosynthesis, Male, Medulloblastoma therapy, Models, Biological, Multivariate Analysis, Neoplasm Metastasis, Oligonucleotide Array Sequence Analysis, Platelet-Derived Growth Factor biosynthesis, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-myc biosynthesis, Receptor, ErbB-2 biosynthesis, Receptor, trkC biosynthesis, Regression Analysis, Retrospective Studies, Time Factors, Tumor Suppressor Protein p53 biosynthesis, Tumor Suppressor Protein p53 metabolism, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms mortality, Medulloblastoma metabolism, Medulloblastoma mortality
- Abstract
Purpose: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB)., Experimental Design: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-alpha, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram., Results: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P=0.01) and p53 (HR, 2.29; P=0.02), TrkC (HR, 0.65; P=0.14), and ErbB2 (HR, 1.51; P=0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy., Conclusions: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.
- Published
- 2004
- Full Text
- View/download PDF
3. Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling.
- Author
-
Taylor MD, Zhang X, Liu L, Hui CC, Mainprize TG, Scherer SW, Wainwright B, Hogg D, and Rutka JT
- Subjects
- Carrier Proteins metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Hedgehog Proteins, Humans, Lymphoid Enhancer-Binding Factor 1, Signal Transduction, Transcription Factors genetics, Transcription Factors metabolism, Transcription, Genetic, Tumor Cells, Cultured, Wnt Proteins, beta Catenin, Carrier Proteins genetics, Cerebellar Neoplasms genetics, Cytoskeletal Proteins metabolism, Medulloblastoma genetics, Mutation, Proto-Oncogene Proteins metabolism, Repressor Proteins, Trans-Activators metabolism, Zebrafish Proteins
- Abstract
Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind beta-catenin, export it from the nucleus, and thereby repress beta-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of beta-catenin, and cannot inhibit beta-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.
- Published
- 2004
- Full Text
- View/download PDF
4. Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.
- Author
-
Yokota N, Mainprize TG, Taylor MD, Kohata T, Loreto M, Ueda S, Dura W, Grajkowska W, Kuo JS, and Rutka JT
- Subjects
- Cell Line, Tumor, Cyclin D2, Cyclins genetics, High Mobility Group Proteins genetics, Homeodomain Proteins genetics, Humans, Membrane Proteins physiology, Nerve Tissue Proteins genetics, Proto-Oncogene Proteins physiology, Receptors, Notch, Reverse Transcriptase Polymerase Chain Reaction, SOXC Transcription Factors, Trans-Activators genetics, Wnt Proteins, Cerebellar Neoplasms genetics, Gene Expression Regulation, Developmental, Medulloblastoma genetics, Nucleic Acid Hybridization
- Abstract
To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB., (Copyright 2004 Nature Publishing Group)
- Published
- 2004
- Full Text
- View/download PDF
5. Mutations in SUFU predispose to medulloblastoma.
- Author
-
Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, and Hogg D
- Subjects
- Base Sequence, Cerebellar Neoplasms pathology, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 10, Consensus Sequence, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Holoprosencephaly etiology, Humans, Loss of Heterozygosity, Male, Medulloblastoma pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Molecular Sequence Data, Mutation, Missense, Sequence Deletion, Signal Transduction genetics, Cerebellar Neoplasms genetics, Genes, Suppressor, Genetic Predisposition to Disease, Medulloblastoma genetics
- Abstract
The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.