A5077431017- Biochemical and Molecular Research
- Enzyme Production and Characterization
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Gene Regulatory Network Analysis
- Atrial Fibrillation Management and Outcomes
- Venous Thromboembolism Diagnosis and Management
- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Statistical Methods in Clinical Trials
- Acute Lymphoblastic Leukemia research
- Diabetes Treatment and Management
- Diabetes Management and Research
- Receptor Mechanisms and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Pancreatic function and diabetes
- Biosimilars and Bioanalytical Methods
- Cardiac Arrhythmias and Treatments
- Lymphoma Diagnosis and Treatment
- Viral Infectious Diseases and Gene Expression in Insects
- Chronic Myeloid Leukemia Treatments
- Cancer Genomics and Diagnostics
- Chronic Lymphocytic Leukemia Research
- Protein purification and stability
Daiichi Sankyo (United States)
2021-2024
Bristol-Myers Squibb (United States)
2014-2022
Bristol-Myers Squibb (Germany)
2010-2015
Pfizer (United States)
2011
National Cancer Institute
2006-2009
Center for Discovery
2009
Immunomedics (United States)
2007-2008
Mayo Clinic in Florida
2007-2008
Children's Hospital of Philadelphia
2007-2008
New York University
2007-2008
Integrins link the extracellular matrix to cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, survival. Ablation of β1 integrin all murine tissues results peri-implantation embryonic lethality. To investigate role myocardium, we used Cre-LoxP technology inactivate gene exclusively ventricular cardiac myocytes. Animals with homozygous myocyte excision were born appropriate numbers grew into adulthood. These animals had 18% control levels β1D protein...
To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone in combination with reinduction chemotherapy children relapsed acute lymphoblastic leukemia (ALL), to preliminarily assess tumor efficacy.Therapy consisted single-agent phase (epratuzumab 360 mg/m(2)/dose intravenously twice weekly x four doses), followed by doses epratuzumab standard chemotherapy. Morphologic minimal residual disease (MRD) responses were...
The trafficking of GABA A receptors is an important component the pathway that regulates plasticity inhibitory synapses. 17 kDa receptor-associated protein (GABARAP) has been implicated in because its ability to interact not only with γ2 subunit receptor but also microtubules and N -ethylmaleimide-sensitive factor (NSF). To elucidate role GABARAP receptors, we have constructed a yellow fluorescent (YFP) fusion expressed it neurons using adenovirus, so function may be examined. YFP-GABARAP...
A model-based approach was used to integrate data from a phase II study in order provide quantitative rationale for selecting the apixaban dosage regimen III trial. The exposure–response models demonstrated that an increase daily steady-state area under plasma concentration-vs.-time curve (AUCss) of 1 µg·h/ml would odds ratio major bleeding by 0.118 and decrease venous thromboembolism (VTE) 0.0499. therapeutic utility index (TUI) efficacy safety predictions quantify apixaban's...
This analysis describes the population pharmacokinetics ( PPK ) of apixaban in nonvalvular atrial fibrillation NVAF subjects, and quantifies impact intrinsic extrinsic factors on exposure. The model was developed using data from phase I–III studies. Apixaban exposure characterized by a two‐compartment with first‐order absorption elimination. Predictive covariates apparent clearance included age, sex, Asian race, renal function, concomitant strong/moderate cytochrome P450 CYP...
Abstract Quantitative systems pharmacology (QSP) places an emphasis on dynamic modeling, incorporating considerations from biology modeling and pharmacodynamics. The goal of QSP is often to quantitatively predict the effects clinical therapeutics, their combinations, doses biomarkers endpoints. In order achieve this goal, strategies for data into model calibration are critical. Virtual population (VPop) approaches facilitate while faced with challenges encountered in application, including a...
The empirical hypothesis generation and testing approach to pharmaceutical research development (R&D), biomedical has proven very effective over the last half-century; resulting in tremendous increases productivity rates of approval for new drug applications at Food Drug Administration (FDA). However, as discovery therapeutic approaches diseases with unmet medical need becomes more challenging, efficiency traditional is diminishing. Innovative are needed, such those offered by Quantitative...
Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, is a powerful tool to gain mechanistic insights into the complex dynamics of biological response drug treatment. However, even once suitable mathematical framework describe pathophysiology mechanisms interest established, final model calibration exploration variability can be challenging time consuming. QSP models are often formulated as multi-scale,...
Population pharmacokinetic (PK) and exposure–response analyses of apixaban were performed using data from phase I–III studies to predict bleeding risks for patients receiving 2.5 mg b.i.d. after total knee or hip replacement (TKR, THR) surgery ( N = 5,510). Renal function, age, gender, body weight impacted exposure. Bleeding risk increased as a function Predicted frequencies TKR THR populations at high exposure (female, age > 75 years, calculated creatinine clearance (cCrCL) < 30...
In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of majority filtered early part tubules, SGLT1 reabsorbs residual distal part. Inhibition viable mechanism removing from body improving glycemic control patients with diabetes. Despite demonstrating levels (in excess 80%) inhibition transport...
Vaccine efficacy is often assessed by levels of neutralizing antibodies, which reflect clonal diversity, amount, and affinity the antibodies induced. These properties impact vaccine efficacy, determining protection against current future strains pathogenic infectious agents like COVID-19 virus. Prior QSP models humoral immune response vaccines have used a similar generic set polyclonal antibody affinities. Our work examines: 1) how can we represent spectrum diversity IgG induced in model; 2)...
Rosuvastatin is a frequently used probe in transporter‐mediated drug‐drug interaction (DDI) studies. This report describes the development of physiologically based pharmacokinetic (PBPK) model rosuvastatin for prediction (PK) DDIs. The predicted observed single (i.v. and oral) multiple dose PK profiles, as well impact coadministration with transporter inhibitors. effects rifampin cyclosporine (6.58‐fold 5.07‐fold increase area under curve (AUC), respectively) were mediated primarily via...
GABA<sub>A</sub> receptor-associated protein (GABARAP) was isolated previously in a yeast two-hybrid screen using the intracellular loop of γ2 subunit receptor as bait. GABARAP has been shown to participate membrane-clustering and intracellular-trafficking receptors, including stimulation surface expression receptors. To assess this quantitatively, we used <i>Xenopus laevis</i> oocytes expressing α1β2γ2S-containing receptors demonstrate that coexpression increased net levels by both GABA...
We investigated the ubiquitin-like modification of GABA<sub>A</sub> receptor-associated protein (GABARAP) and its function. A fusion GABARAP with v5 in N terminus myc C was expressed rat cultured hippocampal neurons PC12 cells. Western blotting antibodies to revealed that cleaved off. Cleavage blocked by mutating C-terminal Gly116 Ala, suggesting G116 is required for processing. Unlike ubiquitin, not incorporated covalently into higher-molecular-weight complexes. Nor degraded...
A Bayesian mechanism-based pharmacokinetic/pharmacodynamic model of cytochrome P450 3A4 (CYP3A4) activity was developed based on a clinical study the effects ketoconazole and rifampin midazolam exposure plasma 4β-hydroxycholesterol (4βHC) concentrations. Simulations from demonstrated that dynamic range 4βHC as biomarker CYP3A4 induction or inhibition narrower than midazolam; an inhibitor increases area under curve by 20-fold may only result in 20% decrease after 14 days dosing. Likewise,...
Immunogenicity is a major challenge in drug development and patient care. Currently, most efforts are dedicated to the elimination of unwanted immune responses through T-cell epitope prediction protein engineering. However, because it unlikely that this approach will lead complete eradication immunogenicity, we propose quantitative systems pharmacology models should be developed predict manage immunogenicity. The potential impact such mechanistic model-based precedented by applications...
Abstract Folylpolyglutamate synthase (FPGS) catalyzes the polyglutamation of folic acid, methotrexate, and pemetrexed to produce highly active metabolites. To characterize genetic variation in FPGS gene, FPGS, have resequenced gene four different ethnic populations. Thirty-four single nucleotide polymorphisms were identified including five nonsynonymous coding that altered protein sequence: F13L V22I mitochondrial isoform R466/424C, A489/447V, S499/457F polymorphisms, which exist both...
This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 < 6 months (N = 12), 0.5 2 13), 12 15)) receiving tablet or oral suspension doses expected be equivalent 30 60 mg once daily (q.d.) adult with VTE. Sixty-six completed study. Edoxaban plasma...
Abstract The enduring changes in long‐term memory probably depend on regulation of gene expression the hippocampus. To seek genes regulated by learning, we used microarray technology to compare hippocampal mice undergoing training Morris water maze and control forced swim for same period absence a hidden platform. ANOVA was employed prioritize further study, three were confirmed real‐time PCR as being during learning. One α subunit platelet‐derived growth factor receptor (Pdgfra); another...
The genetic mechanisms underlying learning and memory remain mysterious, but many of the genes are likely to be expressed in hippocampus, a region pivotal this process. We used 9,000 gene microarray examine differences hippocampal expression between two F1 hybrid mouse strains that perform well on Morris water maze inbred poorly. This resulted identification 27 differentially genes, which could place into separate clusters based singular value decomposition. Most have unknown function, those...
Abstract Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase endometrial incidence. Here, we documented tamoxifen-induced gene expression changes cultured normal human mammary epithelial cells (strains 5, 16, 40), established from tissue taken at mammoplasty three individuals. Cells exposed to 0, 10, or 50 μmol/L for 48 hours were evaluated (E)-α-(deoxyguanosine-N2-yl)-tamoxifen (dG-N2-TAM) adduct formation using TAM-DNA (DNA modified dG-N2-TAM)...
Multiple software programs are available for designing and running large scale system-level pharmacology models used in the drug development process. Depending on problem, scientists may be forced to use several modeling tools that could increase model time, IT costs so on. Therefore it is desirable have a single platform allows setting up large-scale simulations been developed with different tools. We workflow which file compiled into self-contained executable no longer dependent was create...