29 research outputs found
TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit
Defining the Mode of Medulloblastoma Growth using the Ptch1 Heterozygous Mouse Model
Single cancers can be comprised of highly heterogeneous cell populations. In brain tumours, including the malignant pediatric brain tumour medulloblastoma, how the distinct cell types that comprise a tumour contribute to growth and relapse are unclear. Transplantation of human and mouse medulloblastomas have prospectively identified cells with the cardinal stem cell properties of self-renewal and differentiation capacity, but the identity, biology and relevance of these cells in primary tumours are unknown. Here, using Ptch1 heterozygous mice irradiated at birth, I define the cellular mechanism of mouse medulloblastoma growth. Kinetic studies using thymidine analogues showed that rare, Sox2+ cells are relatively quiescent compared to the common, proliferating progenitors expressing Doublecortin (DCX) that differentiate into post-mitotic NeuN+ cells. Transplantation and lineage tracing experiments show that Sox2+ cells act as medulloblastoma stem cells: self-renewing and differentiating to drive growth in transplants and primary tumours. Lineage tracing revealed that tumours grow as a caricature of a neurogenic system. Investigating cell-type specific drug responses revealed that Sox2+ cells are selected for by anti-mitotic and Shh pathway-targeted therapies, creating a reservoir for relapse. Accordingly, high expression of a Sox2+ cell gene signature and high frequencies of Sox2+ cells in human tumours predict poor prognosis. Sox2-expressing primary medulloblastoma cultures were screened in serum free conditions in vitro to identify compounds that inhibit Sox2+ medulloblastoma cell growth. The aureolic acid mithramycin triggered Sox2+ cell apoptosis in vitro, blocked self-renewal and extended Ptch1+/- mouse survival in vivo, and completely prevented tumour regrowth in transplantation experiments. Therefore, targeting self-renewal in medulloblastoma by disrupting the stem cell hierarchy may be of therapeutic benefit. These findings confirm the hierarchical growth paradigm described for medulloblastoma based on transplantation experiments, define the biology of tumours’ constituent cell types and identify a novel approach to prolong medulloblastoma remission by targeting self-renewing cells.Ph.D
Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function
Commonly used preparations for colonoscopy: Efficacy, tolerability and safety – A Canadian Association of Gastroenterology position paper
INTRODUCTION: The increased demand for colonoscopy, coupled with the introduction of new bowel cleansing preparations and recent caution advisories in Canada, has prompted a review of bowel preparations by the Canadian Association of Gastroenterology
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Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups
To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON).
Phase 1 clinical trial.
Setting: single institution.
Patients with G11778A LHON and chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8).
unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3.
Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes.
Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P < .001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment.
G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye
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Response to the Letter to the Editor: Reliability of Visual Field Testing in a Telehealth Setting Using a Head-Mounted Device: A Pilot Study
The effect of fetomaternal bleeding on the risk of adverse pregnancy outcome in patients with elevated second-trimester maternal serum α-fetoprotein levels
Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target
Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. SIGNIFICANCE: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition. This article is highlighted in the In This Issue feature, p.