A5061601409- Drug-Induced Hepatotoxicity and Protection
- Multiple Myeloma Research and Treatments
- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- Drug Transport and Resistance Mechanisms
- 3D Printing in Biomedical Research
- Immune Response and Inflammation
- Monoclonal and Polyclonal Antibodies Research
- Pharmacogenetics and Drug Metabolism
- Gastrointestinal disorders and treatments
- Computational Drug Discovery Methods
- Animal testing and alternatives
- Cell death mechanisms and regulation
- Liver physiology and pathology
- Diagnosis and treatment of tuberculosis
- Hematopoietic Stem Cell Transplantation
- Cancer therapeutics and mechanisms
- Immunotoxicology and immune responses
- Pluripotent Stem Cells Research
- Liver Disease Diagnosis and Treatment
- Neutropenia and Cancer Infections
- ECG Monitoring and Analysis
- Herbal Medicine Research Studies
- Single-cell and spatial transcriptomics
IQ Samhällsbyggnad
2023
Genentech
2022
Kaiser Permanente South San Francisco Medical Center
2020
University of Colorado Denver
2014-2019
University of Colorado Anschutz Medical Campus
2017
Michigan State University
2006-2015
National Heart Lung and Blood Institute
2014-2015
National Institutes of Health
2014-2015
University of Colorado Cancer Center
2014
Alma College
2006
Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform field medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) chemical literature, enable controlled degradation specific their direction cellular proteasome. In this report, we describe second phase our research focused on exploring antibody–drug conjugates (ADCs), which...
This white paper presents principles for validating proarrhythmia risk prediction models regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate progress in development new cardiac safety paradigm, Comprehensive Vitro Proarrhythmia Assay (CiPA). opinions regarding these reflect collective views...
Complex in vitro models (CIVM) offer the potential to improve pharmaceutical clinical drug attrition due safety and/ or efficacy concerns. For this technology have an impact, establishment of robust characterization and qualification plans constructed around specific contexts use (COU) is required. This article covers output from a workshop between Food Drug Administration (FDA) Innovation Quality Microphysiological Systems (IQ MPS) Affiliate. The intent was understand how CIVM technologies...
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as polymodal sensor for exogenous and endogenous stimuli, has been implicated neuropathic pain respiratory disease. Herein, we describe optimization of potent, selective, orally bioavailable TRPA1 small molecule antagonists with strong vivo target engagement rodent models. Several lead molecules preclinical single- short-term repeat-dose toxicity...
Clinical evidence suggests that many cases of serious idiosyncratic drug‐induced liver injury are mediated by the adaptive immune system in response to hepatic drug‐protein adducts, also referred as “drug‐induced allergic hepatitis”; but detailed mechanistic proof has remained elusive due lack animal models. We have hypothesized hepatitis is rare animals it humans at least part tolerogenic nature liver. provide tolerance can be overcome a murine model halothane‐induced initiated...
Drug-induced intestinal toxicity (GIT) is a frequent dose-limiting adverse event that can impact patient compliance and treatment outcomes. In vivo, there are proliferative differentiated cell types critical to maintaining homeostasis. Traditional in vitro models using transformed lines do not capture this cellular complexity, often fail predict toxicity. Primary tissue-derived organoids, on the other hand, scalable Complex Model (CIVM) recapitulates major lineages function. Intestinal...
Severe halothane (HAL)-induced hepatotoxicity occurs in one 6000–30,000 patients by an unknown mechanism. Female sex is a risk factor humans and rodents. We tested the hypothesis that difference natural killer (NK) cell activity contributes to HAL-induced liver injury. HAL (15 mmol/kg, ip) treatment resulted severe injury 12 h female, wild-type BALB/cJ mice, magnitude of varied with stage estrous cycle. Ovariectomized (OVX) mice developed only mild Plasma interferon-gamma (IFN-γ) was...
Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem.IDILI is characterized as occurring in minority of individuals exposed drug, yet it accounts for much 17% all cases acute failure.Despite these concerns, the mechanisms underlying IDILI remain unknown.Trovafloxacin (TVX), which causes humans, also hepatocellular death vitro when combined with tumor necrosis factor-alpha (TNF) treatment.However, molecular involved this toxicity are not fully...
For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development progression of injury. Concanavalin A (Con A) administration to rodents has been used as a model immune-mediated injury resembling human hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) demonstrated alter diseases. Mice pretreated with TCDD developed exacerbated response mild dose (6mg/kg) Con A. In present study, we tested hypothesis that pretreatment exacerbates...
Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. A phase I, dose escalating study assess safety, tolerability, pharmacokinetics efficacy...
Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease remained largely unknown. In regard, it was recently shown that eosinophils played a pathogenic mouse model halothane-induced (HILI). However, the signaling events drove hepatic expression eosinophil-associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating epithelial-derived...
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The bone marrow is an important site for assessment of the hematopoietic toxicity new drug candidates. Here, we extended our previous work, where developed a computer algorithm to automatically quantitate overall cell density by analyzing digitized images standard hematoxylin and eosin (H&E) slides rat further evaluated capability quantify myeloid: erythroid + lymphoid (M:EL) ratio megakaryocyte density. We tested in study, rats were dosed with two molecules known affect composition,...
Abstract RO7297089 is a bispecific antibody (IgG-scFv) targeting Bcell maturation antigen (BCMA) and CD16a (FcγRIIIA) that being developed for the treatment of multiple myeloma (MM). BCMA exclusively expressed on plasmablasts differentiated plasma cells (PCs), overexpressed malignant PCs in MM patients. natural killer (NK) cells, monocytes, mast macrophages. Herein, we characterized mode action safety profile vitro vivo. showed potent cell killing when using BCMA+ tumor lines as target human...