A5016244575- Glioma Diagnosis and Treatment
- Virus-based gene therapy research
- Cancer Genomics and Diagnostics
- RNA Interference and Gene Delivery
- Epigenetics and DNA Methylation
- interferon and immune responses
- Cancer Research and Treatments
- Cell Adhesion Molecules Research
- Cancer Cells and Metastasis
- Nerve injury and regeneration
- Herpesvirus Infections and Treatments
- Immune cells in cancer
- Animal Virus Infections Studies
- MicroRNA in disease regulation
- CAR-T cell therapy research
- Microtubule and mitosis dynamics
- Single-cell and spatial transcriptomics
- Autophagy in Disease and Therapy
- RNA modifications and cancer
- Circular RNAs in diseases
- Viral gastroenteritis research and epidemiology
- Protein Degradation and Inhibitors
- Cellular Mechanics and Interactions
- Immunotherapy and Immune Responses
- Neurogenesis and neuroplasticity mechanisms
University of Calgary
2016-2025
McGill University
2010-2025
Jewish General Hospital
2022-2025
Alberta Children's Hospital
2018-2023
Cancer Institute (WIA)
2018-2021
Paracelsus Medizinische Privatuniversität
2017
Nuremberg Hospital
2017
Ontario Brain Institute
2015
Hospital for Sick Children
2014
Ottawa Regional Cancer Foundation
2013
Abstract Single-cell technologies have enabled the characterization of tumour microenvironment at unprecedented depth and revealed vast cellular diversity among cells their niche. Anti-tumour immunity relies on cell–cell relationships within 1,2 , yet many single-cell studies lack spatial context rely dissociated tissues 3 . Here we applied imaging mass cytometry to characterize immunological landscape 139 high-grade glioma 46 brain metastasis tumours from patients. analysis more than 1.1...
Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, presence a stem-like population cells, termed brain tumor-initiating cells (BTIC) that confer resistance conventional therapies.To develop therapeutic strategies target BTICs, we focused on repurposing approach explored already-marketed (clinically approved) drugs for...
Abstract Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that presence macrophages microglia impact tumorigenesis prevent durable response. Herein we identify dual function cytokine IL-33 as an orchestrator microenvironment contributes to tumorigenesis. We find expression in large subset glioma specimens murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In...
Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras are in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose this study was to determine the effectiveness reovirus as an experimental treatment gliomas.We investigated whether would infect and lyse human glioma cell lines vitro. We also tested effect injecting live vivo on grown subcutaneously or orthotopically (i.e.,...
Abstract Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural remain to be elucidated. We cultured isolated gliomas, using neurosphere culture understand their growth requirements. Both CD133+ CD133− adult GBM proliferated in absence exogenous mitogenic stimulation gave rise...
Abstract Myxoma virus, a poxvirus previously considered rabbit specific, can replicate productively in variety of human tumor cells culture. The purpose this study was to determine if there efficacy or toxicities oncolytic virus against experimental models malignant gliomas vitro, vivo, and ex vivo glioma specimens. In the majority cell lines tested (7 8, 87.5%) were fully permissive for myxoma replication killed by infection. intracerebral (i.c.) inoculation well tolerated produced only...
The oncolytic effects of a systemically delivered, replicating, double-deleted vaccinia virus has been previously shown for the treatment many cancers, including colon, ovarian, and others. purpose this study was to investigate potential alone or in combination with rapamycin cyclophosphamide treat malignant gliomas vitro vivo.Rat (RG2, F98, C6) human (A172, U87MG, U118) glioma cell lines were cultured treated live UV-inactivated virus. Viral gene [enhanced green fluorescent protein (EGFP)]...
The invasive nature of cancers in general, and malignant gliomas particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using novel glioma mouse model established serial vivo selection, we identified the p75 neurotrophin receptor (p75(NTR)) as critical regulator invasion. Through series functional, biochemical, studies, found that p75(NTR) dramatically enhanced migration invasion genetically distinct frequently exhibited robust expression highly...
Abstract Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that synergize with innate stimulants and checkpoint biologics produce durable cures in mouse models glioblastoma which single agent therapy is ineffective. The complementation activities between...
Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3–deficient (Nlrp3-deficient) mice displayed reduced epithelial cell and inflammation in a model of contrast-induced AKI (CI-AKI). Unexpectedly, directly induced tubular death vitro that was not dependent on Nlrp3. Rather, activated canonical Nlrp3 inflammasome macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes...
The mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of kidney. Renal ischemia reperfusion injury (IRI) induces robust monocyte causes acute (AKI). inflammation AKI phenotype were attenuated in Dpep1-/- mice or pretreated with DPEP1 antagonists, including LSALT peptide, nonenzymatic inhibitor. deficiency inhibition...
According to the current theory of retrograde signaling, NGF binds receptors on axon terminals and is internalized by receptor-mediated endocytosis. Vesicles with in their lumina, activating membranes, travel cell bodies initiate signaling cascades that reach nucleus. This predicts appearance activated molecules should coincide initiated signals. However, we observed applied locally distal axons rat sympathetic neurons compartmented cultures produced increased tyrosine phosphorylation trkA...
We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model human glioma. Here, we show that used alone or combination with rapamycin is effective and safe when experimental models medulloblastoma vitro vivo. Nine 10 cell lines tested were susceptible to lethal infection, pretreatment cells increased extent oncolysis. Intratumoral injection live compared control inactivated prolonged survival D341 Daoy orthotopic mouse [D341 median survival: 21 versus 12.5...
Abstract Oncolytic myxoma virus (MYXV) is being developed as a novel virotherapeutic against human brain cancer and has promising activity tumor models in immunocompromised hosts. Because an intact immune system could reduce its efficacy, the purpose of this study was to evaluate oncolytic potential MYXV immunocompetent racine glioma models. Here, we report that infects kills all cell lines effects are enhanced by rapamycin. Intratumoral administration with rapamycin improved viral...
Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) malignant glioma, but the mechanism of its activation unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent increases activity BTIC to promote their growth. We demonstrate proximal localization TNC and human glioblastoma specimens orthotopic murine xenografts implanted intracranially. In tissue culture, was superior amongst several proteins enhancing sphere-forming...
Abstract The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes ASPSCR1::TFE3. We demonstrate that VCP a likely...
Background: An ideal virus for the treatment of cancer should have effective delivery into multiple sites within tumor, evade immune responses, produce rapid viral replication, spread and infect tumors. Vesicular stomatitis (VSV) has been shown to be an oncolytic in a variety tumor models, mutations matrix (M) protein enhance VSV's effectiveness animal models. Methods: We evaluated susceptibility 14 glioma cell lines infection killing by mutant strain VSV ΔM51 , which contains single–amino...
The purpose of this study was to investigate the oncolytic potential recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) vitro and immunocompetent rodent models. We have found that killed all MG cell lines tested vitro. Intratumoral (i.t.) administration significantly inhibited tumor growth prolonged survival rats-bearing RG2 intracranial (i.c.) tumors mice-bearing GL261 brain tumors. Combination...
See page 1406Mammalian ortheoreoviruses are currently being investigated as novel cancer therapeutics, but the cellular mechanisms that regulate susceptibility to reovirus oncolysis remain poorly understood. In this study, we present evidence virion disassembly is a key determinant of oncolysis. To penetrate cell membranes and initiate infection, outermost capsid proteins must be proteolyzed generate disassembled particle called an infectious subviral (ISVP). fibroblasts, process mediated by...
BackgroundTenascin-C (TNC), an extracellular matrix protein overexpressed in malignant gliomas, stimulates invasion of conventional glioma cell lines (U251, U87). However, there is a dearth such information on stemlike cells. Here, we have addressed whether and how TNC may regulate the invasiveness brain tumor–initiating cells (BTICs) that give rise to progenies.
Abstract Purpose: The current standard of care for glioblastoma (GBM) involves a combination surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance is largely mediated by expression the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation MSH6 other mismatch proteins plays an important role in resistance. Here, we investigate endogenous mutations GBM, anaplastic oligodendroglial tissue,...
The invasive nature of glioblastoma renders them incurable by current therapeutic interventions. Using a novel human glioma model, we previously identified the neurotrophin receptor p75(NTR) (aka CD271) as mediator invasion. Herein, provide evidence that preventing phosphorylation on S303 pharmacological inhibition PKA, or mutational strategy (S303G), cripples p75(NTR)-mediated invasion resulting in serine within C-terminal PDZ-binding motif (SPV) p75(NTR). Consistent with this, deletion...
Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) orthotopic xenografts are widely used in investigating GBM biology new therapies for this aggressive disease. However, genomic characteristics molecular resemblance of these models to tumors remain undetermined. We massively parallel sequencing technology decode genomes transcriptomes BTICs their matched order delineate potential impacts distinct...