A5063411435- Glioma Diagnosis and Treatment
- Animal testing and alternatives
- Monoclonal and Polyclonal Antibodies Research
- Zebrafish Biomedical Research Applications
- Pluripotent Stem Cells Research
- Retinopathy of Prematurity Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Chromatin Remodeling and Cancer
- Genetic factors in colorectal cancer
- Effects and risks of endocrine disrupting chemicals
- Telomeres, Telomerase, and Senescence
- Ocular Oncology and Treatments
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Fatty Acid Research and Health
- Intraocular Surgery and Lenses
- Epigenetics and DNA Methylation
- Tuberculosis Research and Epidemiology
- Ubiquitin and proteasome pathways
- Parasitic Infections and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Congenital heart defects research
- HER2/EGFR in Cancer Research
- Nutritional Studies and Diet
University of Washington
2021-2024
University of Toronto
2011-2024
Seattle University
2024
Public Health Agency of Canada
2024
Public Health Ontario
2024
Hospital for Sick Children
2011-2023
Penn State Milton S. Hershey Medical Center
2019
SickKids Foundation
2011-2018
University Health Network
2017
Toronto General Hospital
2017
To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) secondary high-grade (sHGG).We retrospectively identified patients with sHGG from a population-based cohort 886 PLGG long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed analysis entire cohort. Clinical outcome data genetically distinct subgroups obtained.sHGG was observed in 2.9% PLGGs (26 patients). Patients had high frequency nonsilent...
Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation RAS/MAPK pathway. However, clinical significance this genetic alteration is yet to be determined. We aimed test prognostic role B-K progression incompletely resected PLGA.We retrospectively identified 70 consecutive patients with "clinically relevant" PLGA. added 76 tumors diagnosed at our institution between 1985 and 2010 as...
STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance a number rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at time initial evaluation were tested factor (RF) antibodies Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin,...
Abstract BACKGROUND: Recently we reported the development and optimization of a zebrafish teratogenicity assay using dechorionated AB strain embryos, promising that was 87% concordant in correctly identifying vivo teratogens non‐teratogens from set 31 compounds (Brannen et al., 2010: Birth Defects Res 89:66–77). METHODS: This utilizes morphological score system to characterize adverse effects identify no‐observed‐adverse‐effect level (NOAEL). RESULTS: report describes detail used embryo...
A consortium of biopharmaceutical companies previously developed an optimized Zebrafish developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 6 h post fertilization and assessed for morphological integrity at days fertilization. With the original 20 compounds, this achieved overall predictive value teratogenicity 88% mammalian in vivo outcome [Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X.,...
In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for progression. Thus, activation through the interplay of mutations (TERTpMut ) epigenetic alterations in promoter may provide further insight into UBC behavior. Here, we investigated combined effect TERTpMut Hypermethylated Oncological Region (THOR) status on patient outcome a international cohort (n = 237). We...
As a part of the public health approach to child welfare, data about children placed in out-of-home care are needed assess population trends, understand drivers social and inequities, examine outcomes for families. We analyzed administrative from Canada describe care, estimate compare rates by province/territory, year, sex/gender, age group placement type.
Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by ventricle (LV) hypoplasia and abnormal LV perfusion oxygenation. We studied hypoxia-associated injury in fetal HLHS human pluripotent stem cells during differentiation to assess the effect of microenvironmental perturbations on reprogramming. myocardial samples from 32 17 structurally normal midgestation fetuses. Compared with controls, had higher nuclear expression hypoxia-inducible factor-1α but lower...
Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds clustered DNA rearrangements resulting from single dramatic event. Telomere dysfunction has been suggested play role in the initiation this phenomenon, which occurs large number tumor entities. Here, we show that telomere attrition can indeed lead catastrophic events, and patterns differ between cells analyzed before after such catastrophes. length stabilization mechanisms diverge samples...
The Dechorinated Zebrafish Embryo Developmental toxicity assay was originally developed from a training set of 31 compounds and reported to be 87% concordant with in vivo teratogenicity data (Brannen, K. C., Panzica-Kelly, J. M., Danberry, T. L., Augustine-Rauch, A. (2010). Development zebrafish embryo quantitative prediction model. Birth Defects Res. 89, 66–77.). includes scoring larva treated concentration range for malformations specific morphological structures/organ systems. model...
Abstract Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres essential for sustaining limitless replicative potential such cancers. Because telomerase thought to be active all tumor cells and normal stem cells, inhibition may nonspecific have detrimental effects on tissue maintenance development by affecting cell self-renewal. Methods: We examined activity, telomere maintenance, maturation subpopulations from freshly resected gliomas, long-term,...
Abstract Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native oxidized low-density lipoprotein (oxLDL) by macrophages (Mϕs) foam cell formation. Inflammatory processes accompany Mϕ formation in artery wall, yet relationship between lipid loading their response inflammatory stimuli remains elusive. We investigated proinflammatory gene expression thioglycollate-elicited peritoneal Mϕs, bone marrow–derived Mϕs dendritic cells, RAW264.7 cells. Loading...
Increasing need for proactive safety optimization of pharmaceutical compounds has led to generation and/or refinement in vitro developmental toxicology assays. Our laboratory developed three assays assess teratogenic liability compounds. These included a mouse molecular embryonic stem cell assay (MESCA), dechorionated zebrafish embryo culture (ZEC) assay, and streamlined rat whole (rWEC) assay. Individually, the presented good (73–82%) predictivity. However, it remains be determined whether...
vc-MMAE antibody–drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with potent anti-mitotic toxin (MMAE) through protease-labile valine-citrulline (vc) linker. The objective this study was to characterize the pharmacokinetics (PK) and explore exposure–response relationships eight ADCs, against different targets for diverse tumor indications, using data from first-in-human Phase 1 studies. PK parameters three analytes, namely antibody-conjugated MMAE (acMMAE),...
The mouse embryonic stem cell test (EST) is a 10-day screen for teratogenic potential developed to reduce animal use embryotoxicity testing of chemicals (Spielmann, 2005; Spielmann et al., 1997). In this study, we used the cytotoxicity IC(50) values and transcriptional expression changes as primary endpoints in shorter 4-day version EST, molecular assay. Mouse D3 cells were assessment (monolayers) or grown embryoid bodies low attachment plates profiling. Sixty-five compounds with known vivo...
Background and Purpose— Recent studies have suggested that autoregulation of cerebral blood flow (CBF) is impaired after traumatic ischemic brain injury. Given the levels superoxide anion (O 2 · − ) are increased in these conditions, we postulate O contributes to impairment CBF autoregulation. Methods— was monitored with laser Doppler flowmetry during increases pressure. Results— During control period, well autoregulated increase mean arterial pressure (MAP) from 98±3 140±6 mm Hg. The index...
Prediction of human pharmacokinetics (PK) based on preclinical information for antibody-drug conjugates (ADCs) provide important insight into first-in-human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method predict PK ADCs from animal data in the linear range. Different methods projecting clearance (CL) 11 exhibiting over tested dose ranges were examined: multiple species allometric (CL vs. body weight), with correction factors, rule...
Infection with Cryptosporidium spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy the populations impacted most by diarrheal disease, safe, effective treatment options are urgently needed.
Abstract Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter physiology cause diarrhea. The extent of diarrhea‐associated impact on pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used population pharmacokinetic modeling approach data collected phase IIa study matched human immunodeficiency virus (HIV)–infected adults with/without...
Abstract BACKGROUND: The rodent whole embryo culture (WEC) system is a well‐established model for characterizing developmental toxicity of test compounds and conducting mechanistic studies. Laboratories have taken various approaches in describing type severity findings organogenesis‐stage embryos, but the Brown Fabro morphological score commonly used as quantitative approach. associated criteria based upon stage growth parameters, where series embryonic structures are assessed assigned...
Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) Constitutional Repair Deficiency (CMMRD). However, the prevalence gliomas children, adolescents, and young adults (CAYA), impact germline inheritance unknown. We utilized functional genomic tools on population-based validation cohorts from 3...