A5030774875- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Glioma Diagnosis and Treatment
- Mitochondrial Function and Pathology
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Research and Treatments
- Protein Degradation and Inhibitors
- Research on Leishmaniasis Studies
- ATP Synthase and ATPases Research
- Medical Imaging and Pathology Studies
- Cancer-related Molecular Pathways
- Metabolism and Genetic Disorders
- Neuroblastoma Research and Treatments
- interferon and immune responses
- Microtubule and mitosis dynamics
- Redox biology and oxidative stress
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Cell Image Analysis Techniques
- Advanced Breast Cancer Therapies
- CRISPR and Genetic Engineering
- Lung Cancer Treatments and Mutations
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
Seattle University
2025
Johns Hopkins University
2013-2024
Johns Hopkins Medicine
2013-2022
Allen Institute
2022
University of Baltimore
2013-2016
Johns Hopkins Hospital
2013-2016
Heinrich Heine University Düsseldorf
2016
Düsseldorf University Hospital
2016
A subset of poor-prognosis medulloblastoma has genomic amplification MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. hypothesized that this would kill MYC-expressing medulloblastoma. treatment caused decreased growth apoptosis human cell lines. generated mouse MYC-driven model by transforming...
Abstract Purpose: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. also developed new informatics method, Disease-model Signature versus Compound-Variety Enriched Response (“DiSCoVER”), identify therapeutics that target this specific disease subtype. Experimental Design: Human neural derived from the cerebellar anlage were transduced with oncogenic elements associated aggressive An in silico analysis method for...
Abstract Background Genetic mitochondrial diseases are a major challenge in modern medicine. These impact ~ 1:4,000 individuals and there currently no effective therapies. Leigh syndrome is the most common pediatric presentation of disease. In humans, patients often treated with antioxidants, vitamins, strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been subject at least 19 clinical trials US since 2012, but effects on an...
Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infantile brain with poor survival. Recent advancements have highlighted significant molecular heterogeneity in AT/RT an subgroup featuring overexpression of the MYC proto-oncogene. We perform first comprehensive metabolic profiling patient-derived cell lines to identify therapeutic susceptibilities high MYC-expressing AT/RT.Metabolites were extracted from and separated ultra-high performance liquid chromatography mass spectrometry....
Reprograming of cellular metabolism is a hallmark cancer. Altering allows cancer cells to overcome unfavorable microenvironment conditions and proliferate invade. Medulloblastoma the most common malignant brain tumor children. Genomic amplification MYC defines subset poor-prognosis medulloblastoma. We performed comprehensive metabolic studies human MYC-amplified medulloblastoma by comparing profiles in three different conditions-in vitro, flank xenografts orthotopic cerebellum. Principal...
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied signaling promoting retinoblastoma proliferation. Moderate or strong nuclear expression Hes1 was found 10 11 human samples analyzed immunohistochemically, supporting for growth. pathway components were present WERI Rb1 Y79 lines, with Jag2 DLL4 more highly expressed than other ligands, Notch1 Notch2 abundant Notch3. The...
Abstract Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence progressive, symmetric, lesions in brainstem are defining feature disease, major cause morbidity mortality, but mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, CSF1R inhibitor,...
Abstract Background Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting infancy or early childhood. Seizures are major clinical sequelae some including Leigh syndrome, the common pediatric presentation of disease. Dietary ketosis has been used to manage seizures disease patients. Mitochondrial patients require surgical interventions, leading anesthetic exposures. Anesthetics have shown be toxic setting disease, but a ketogenic diet on toxicities this not...
<title>Abstract</title> <bold>Background</bold> Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of disease. There currently no effective clinical treatments for In humans, patients often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been subject at least 19 trials US...
Neonatal brain damage and age-related neurodegenerative disease share many common mechanisms of injury involving mitochondriopathy, oxidative stress, excitotoxicity, inflammation, neuronal cell death. We hypothesized that genes causing adult-onset neurodegeneration can influence acute outcome after CNS at immaturity on the subsequent development chronic disability early-life injury. In two different transgenic (Tg) mouse models disease, a human A53T-α-synuclein (hαSyn) model Parkinson's (PD)...
MYC amplification is common in Group 3 medulloblastoma and associated with poor survival. 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least part due high expression the H3K27 methyltransferase enhancer zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether EZH2 H3K27me3 medulloblastoma, if high-MYC particularly sensitive pharmacological blockade. Western blot analysis low (DAOY, UW228, CB...
BackgroundVolatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur rare cases, such as certain genetic disorders. Anaesthesia is well-documented a subset of mitochondrial diseases, but whether volatile toxic this setting has not been explored.MethodsWe exposed Ndufs4(−/−) mice, model Leigh syndrome, to isoflurane (0.2–0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, survival were assessed. We...
Abstract Aim Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi‐system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in brainstem are defining features disease. Patients often symptom free early life but typically develop symptoms about 2 years age. The mechanisms underlying disease onset progression LS remain obscure. Recent studies have shown that...
Abstract The MYC oncogene is associated with aggressive forms of the pediatric brain tumor medulloblastoma. promotes oncogenesis in part by altering cellular glucose and glutamine metabolism. We hypothesized that MYC-driven medulloblastoma would be sensitive to metabolic inhibitor 6-diazo-5-oxo-l-norleucine (DON). In cell lines, 10uM DON treatment increases apoptosis up 280% (p&lt;0.04) as compared vehicle control. human neural stem cells transformed MYC, but not untransformed cells,...
Abstract Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common paediatric presentation of genetic mitochondrial disease. LS a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence progressive, symmetric, lesions in brainstem are defining feature disease, major cause morbidity mortality, but mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, CSF1R inhibitor,...