Biomedical subjects

Todd G Mainprize

Publications and source records attributed to Todd G Mainprize.

8 recordsLinked to original sources

PubMed2006

Current concepts in the molecular genetics of pediatric brain tumors: implications for emerging therapies.

BACKGROUND: The revolution in molecular biology that has taken place over the past 2 decades has provided researchers with new and powerful tools for detailed study of the molecular mechanisms giving rise to the spectrum of pediatric brain tumors. Application of these tools has greatly advanced our understanding of the molecular pathogenesis of these lesions. REVIEW: After familiarizing readers with some promising new techniques in the field of oncogenomics, this review will present the current state of knowledge as it pertains to the molecular biology of pediatric brain neoplasms. Along the way, we hope to highlight specific instances where the detailed mechanistic knowledge acquired thus far may be exploited for therapeutic advantage.

Animals↗

PubMed2004

A clinicobiological model predicting survival in medulloblastoma.

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.

Adolescent↗

PubMed2004

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling.

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.

Carrier Proteins↗

PubMed2004

Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.

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.

Cell Line, Tumor↗

PubMed2003

Bioinformatics in neurosurgery.

WITH THE COMPLETION of the Human Genome Project, the amount of molecular biological sequence data available in public databases has reached staggering proportions. Data continue to accumulate at an exponential rate in the postgenomic era. Compilation, storage, searching, sharing, studying, and transmitting of all these data present formidable challenges. To keep pace with this extant database, the science of bioinformatics (sometimes called computational biology) has evolved. Bioinformatics is the combination of biology and computers and usually involves the storage or analysis of molecular biological sequence data at either the deoxyribonucleic acid, ribonucleic acid, or protein (amino acid) level. Most bioinformatics tools are freely available on the Internet for use by investigators around the globe. The collective wisdom from bioinformatics databases worldwide will continue to spawn advances in the neurological sciences for generations to come. Neurosurgeons must be aware of the power and potential applications of bioinformatics for the analysis of neurosurgical diseases.

Animals↗

PubMed2003

Advanced cancer genetics in neurosurgical research.

RAPID ADVANCES IN the technology used to study nucleic acids have revealed a great deal regarding the underlying biology of cancer. Most cancers arise as a result of chromosomal rearrangements and deoxyribonucleic acid mutations that lead to the activation of proto-oncogenes and loss of function of tumor suppressor genes. There are a number of different molecular routes that lead to these common goals, necessitating several different techniques of mutational analysis. Although many of these techniques can be difficult in practice, most are conceptually simple. We discuss several of the current techniques in cytogenetics and molecular genetics that are widely used in cancer biology laboratories. Understanding the molecular events that lead to cancer should allow the future development of targeted, nontoxic therapeutics similar to modern-day antibiotics. These technologies are being progressively applied in clinical neurosurgery, where they will be used to detect, diagnose, stratify, and treat cancers of the nervous system. High demand from an increasingly educated patient population means that neurosurgeons will need to be familiar with many of these techniques.

Cytogenetic Analysis↗

PubMed2003

Transcriptional profiling of medulloblastoma in children.

OBJECT: Although medulloblastoma is the most common malignant brain tumor found in children, little is known about its molecular pathogenesis. The authors have attempted to compare patterns of gene expression in medulloblastoma samples with those in the healthy cerebellum. METHODS: The authors used complementary (c)DNA microarray analysis to compare the expression of genes in samples of medulloblastoma and normal cerebellum. The expression levels of a subset of genes were then verified by immunohistochemical analysis. Six genes were identified that were expressed at a much higher level in at least five of six medulloblastomas: ezrin, cyclin D2, high mobility group protein 2, MAPRE1, histone deacetylase 2, and ornithine decarboxylase 1. A number of potentially important genes whose expression was much lower in medulloblastomas than in control cerebellum were also identified: tenascin R, TRK-B, FGF receptor, and death receptor 3. The expression levels of a subset of the identified genes were confirmed by immunohistochemical analysis, which was performed on fetal cerebellum and medulloblastoma samples. CONCLUSIONS: The authors demonstrate that cDNA microarray analysis is an effective method of increasing understanding of the molecular biology of medulloblastomas found in children. A comparison between gene expression patterns in medulloblastoma and those observed in healthy cerebellum may provide clues as to the origin of these tumors and may lead to the identification of new genes or pathways to be targeted for future therapies.

Brain Neoplasms↗

PubMed2002

Mutations in SUFU predispose to medulloblastoma.

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.

Base Sequence↗